NIH Public Access

Author Manuscript
Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
Published in final edited form as:
NIH-PA Author Manuscript

Annu Rev Chem Biomol Eng. 2010 ; 1: 149–173. doi:10.1146/annurev-chembioeng-073009-100847.

Polymers for Drug Delivery Systems

William B. Liechty1, David R. Kryscio1, Brandon V. Slaughter2, and Nicholas A. Peppas1,2,3
1Department of Chemical Engineering, University of Texas, Austin, Texas 78712-1062

2Department of Biomedical Engineering, University of Texas, Austin, Texas 78712-1062

3College of Pharmacy, University of Texas, Austin, Texas 78712-1062; [email protected]

Abstract
Polymers have played an integral role in the advancement of drug delivery technology by
providing controlled release of therapeutic agents in constant doses over long periods, cyclic
dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings
using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations
NIH-PA Author Manuscript

of chemical engineers. Modern advances in drug delivery are now predicated upon the rational
design of polymers tailored for specific cargo and engineered to exert distinct biological functions.
In this review, we highlight the fundamental drug delivery systems and their mathematical
foundations and discuss the physiological barriers to drug delivery. We review the origins and
applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-
protein and polymer-drug conjugates. The latest developments in polymers capable of molecular
recognition or directing intracellular delivery are surveyed to illustrate areas of research advancing
the frontiers of drug delivery.

Keywords
controlled release; stimuli-responsive; responsive polymers; recognitive polymers; polymer
therapeutics; intracellular delivery

INTRODUCTION
Hierarchical progress in modern drug delivery begins with the use of polymer carriers to
NIH-PA Author Manuscript

elicit spatiotemporal release of therapeutics in both pulsatile dose delivery products and
implanted reservoir systems. Although conventional drug delivery formulations have
contributed greatly to the treatment of disease, the emergence of potent and specific
biological therapeutics has escalated the impetus for intelligent delivery systems. Heller (1)
and Langer & Peppas (2) pointed out the importance of chemical engineering innovation in
the development of new drug delivery systems and suggested that feedback control should
be a standard component of such systems. These systems must overcome many hurdles
before clinical implementation is realized; a truly intelligent delivery system must address
the need for specific targeting, intracellular transport, and biocompatibility while integrating
elements of responsive behavior to physiological environments and recognitive feedback
control.

Copyright © 2010 by Annual Reviews. All rights reserved

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
 Liechty et al. Page 2

Tremendous progress has been made as a result of the exploration of diffusion-controlled

and solvent-activated formulations in drug delivery. Hydrogels and other polymer-based
carriers have been developed to provide safe passage for pharmaceuticals through
NIH-PA Author Manuscript

inhospitable physiological regions. Polymers of controlled molecular architecture can be

engineered to give a well-defined response to external conditions as a result of a solid
understanding of the underlying mechanisms and the nature of behavioral transitions.
Polymers incorporated with therapeutics can be bioactive to provide their own therapeutic
benefit or can be biodegradable to improve release kinetics and prevent carrier
accumulation. Pharmaceutical agents have been conjugated to polymers to modify transport
or circulation half-life characteristics as well as to allow for passive and active targeting.
And finally, the latest drug delivery research using polymeric materials has produced
recognitive systems and polymer carriers that facilitate cytoplasmic delivery of novel
therapeutics.

This review aims to provide a unique coverage of the field of polymers in drug delivery,
addressing the foundations of drug delivery in a conceptual and mathematical context and
critically reviewing the recent developments in responsive polymers, polymer therapeutics,
and advanced systems designed for molecular recognition or engineered for intracellular
delivery of novel therapeutics.

CONVENTIONAL APPLICATIONS OF POLYMERS IN DRUG DELIVERY

NIH-PA Author Manuscript

For more than 50 years, techniques such as compression, spray and dip coating, and
encapsulation have been used in the pharmaceutical industry to incorporate bioactive agents
with polymers. Such polymers have largely included cellulose derivatives, poly(ethylene
glycol) PEG, and poly(N-vinyl pyrrolidone) (3). From a drug delivery perspective, polymer
devices can be categorized as diffusion-controlled (monolithic devices), solvent-activated
(swelling- or osmotically-controlled devices (5)), chemically controlled (biodegradable), or
externally-triggered systems (e.g., pH, temperature) (4).

Diffusion-Controlled Systems
Most diffusion-controlled carriers are simple and monolithic in nature. In these systems, a
drug is dissolved (or dispersed if the concentration exceeds the polymer's solubility limit) in
a nonswellable or fully swollen matrix that does not degrade during its therapeutic life. In
dissolved systems (C0 < CS), C0 is the initial loading concentration and CS is the saturation
concentration. Fick's second law, for slab geometry,

(1)
NIH-PA Author Manuscript

can be solved under the appropriate boundary conditions to obtain an expression for
concentration Ci(x,t). Di is the diffusivity of the solute in the polymer matrix, and Ci is the
concentration of species i. Equations for calculating Di for porous, microporous, and
nonporous hydrogels have been tabulated (6). Differentiating Ci(x,t) with respect to x allows
for substitution of this result into Fick's first law:

(2)

This expression can then be integrated under the appropriate boundary conditions at the
interface, x, to develop an equation for Mt, where Mt is the cumulative mass or moles
released from the system (7):

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 3

(3)
NIH-PA Author Manuscript

With dispersed systems (C0 > CS), the situation is more complex as the precipitated regions
are considered nondiffusing and disappear as a function of drug release to create a moving
boundary problem. The well-known Higuchi equation (for planar geometry),

(4)

provides a simple model for release by treating the problem as a pseudosteady state (8). In
this expression, S represents the surface area available for drug release. Expansions to this
model have produced expressions for spherical geometries (9) and to account for drug
concentrations near the solubility limit for the polymer (10).

Solvent-Activated Systems
In traditional swellable systems, drugs are loaded into dehydrated hydrophilic polymers or
hydrogels by simply packing the two substances together. In the absence of a plasticizing
aqueous solvent, these systems are usually well below their glass transition temperature, Tg,
and have very low diffusivities. Once exposed to an aqueous environment, the hydrogels
imbibe water and swell. If the polymer is not chemically crosslinked (or crystalline), then
NIH-PA Author Manuscript

dissolution creates an erosion front. Drug delivery devices that operate as swelling-
controlled systems undergo a transition from the glassy to rubbery state during solvent
swelling, which relaxes polymer chains and dissolves dispersed drug deposits. This process
creates two simultaneously moving fronts, diffusion and swelling, in addition to the erosion
front, if present. This has been shown dramatically using cylindrical hydroxypropyl
methylcellulose (HPMC) sections loaded with buflomedil pyridoxal phosphate (11). The
diffusion front is created at the dissolved-dispersed drug boundary where the localized
solvent volume fraction is higher than at the core of the polymer matrix. The swelling front
is created as water is imbibed into the matrix, thus increasing chain motility. Starting in the
center of a polymer matrix, a negative gradient in polymer volume fraction and
entanglement exists relative to the outside surfaces. The dispersion-dissolution and erosion
boundaries are continuously moving relative to each other, and the associated diffusion
lengths are constantly changing. A popular empirical model that can be used to describe
transport for swellable systems is based on the power-law expression (12):

(5)
NIH-PA Author Manuscript

In this equation, M∞ is the total mass loaded into the polymer, and k and n are the constants
of the power-law expression.

This expression provides the fractional mass released from a polymer matrix as a function of
time. The value for n is dependent on the type of transport, geometry, and polydispersity.
Case I or Fickian diffusion describes the condition in which diffusion is slow compared with
the rate of chain relaxation. This condition is correlated to n = 0.50 for thin film geometries.
For cylindrical and spherical geometries, the characteristic n values are 0.45 and 0.43,
respectively (13, 14). For Case II diffusion, the system is relaxation controlled because the
chain relaxation rate is the kinetically-limiting component, thus n = 1. Systems with values
of n (0.43 < n < 1) experience anomalous transport and indicate that diffusion and relaxation
mechanisms are similar in rate. This model has been expanded to account for lag times in
release (15) and burst effect (16) as well as for separating diffusion and Case II contributions

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 4

into separate terms (17). For more in-depth reviews of several mathematical models of
polymer drug release, the reader is referred to Arifin et al. (18) and Masaro & Zhu (19).
NIH-PA Author Manuscript

Biodegradable Systems
Biodegradable and bioerodible polymers represent an important class of materials for drug
delivery. Although often used interchangeably, degradation and erosion differ in that
covalent bond cleavage by chemical reactions occurs in degradation. Erosion occurs by the
dissolution of chain fragments in noncrosslinked systems without chemical alterations to the
molecular structure. For dissolution to occur, the polymer must absorb the surrounding
aqueous solvent and must interact with water via charge interactions (such as with polyacids
and polybases) or hydrogen bonding mechanisms.

Both degradation and erosion can occur as surface or bulk processes. In surface degradation,
the polymer matrix is progressively removed from the surface, but the polymer volume
fraction remains fairly unchanged. Conversely, in bulk degradation, no significant change
occurs in the physical size of the polymer carrier until it is almost fully degraded or eroded,
but the fraction of polymer remaining in the carrier decreases over time. The dominant
process is determined by the relative rates of solvent penetration into the polymer, diffusion
of the degradation product, and degradation or dissolution of the macromolecular structure
(20). These rate considerations are especially important in designing biodegradable
hydrogels because they are often polymerized in the presence of an aqueous solvent.
NIH-PA Author Manuscript

To be chemically degradable, polymers require hydrolytically or proteolytically labile bonds

in their backbone or crosslinker. The majority of biodegradable synthetic polymers rely on
hydrolytic cleavage of ester bonds or ester derivatives such as poly(lactic/glycolic acid) and
poly(ε-caprolactone). In addition to ester derivatives, hydrolysis also acts on
poly(anhydrides), poly(orthoesters), poly(phosphoesters), poly(phosphazenes), and
poly(cyanoacrylate) derivatives (21, 22). Degradation and dissolution processes can auto-
accelerate because degradation mechanisms may release an acid product that catalyzes
further degradation or ionizes an initially hydrophobic structure that encourages the matrix
to further imbibe water, for example by hydrolyzing pendant anhydrides on poly(methyl
acrylate).

A well-known issue with biodegradable polymers is uncertainty with regard to the safety of
degradation products. Because degradation often results in a distribution of fragment sizes,
toxicity is challenging to determine experimentally. Ideally, parenterally-administered
polymers would degrade into small, metabolic compounds that are known to be nontoxic
and are small enough for natural clearance mechanisms.
NIH-PA Author Manuscript

Pharmacological Considerations in Drug Delivery

The central objective of a delivery system is to release therapeutics at the desired anatomical
site and to maintain the drug concentration within a therapeutic band for a desired duration
(Figure 1).

Whether a drug is absorbed orally, parenterally, or by other means, such as inhalation or

transdermal patches, bioavailability in the bloodstream allows for distribution to virtually all
bodily tissues. Once in blood, drugs disseminate to all or most tissues by crossing
endothelial barriers or by draining though endothelial gaps in tissues with “leaky”
vasculature. Additionally, active targeting mechanisms may be employed by the polymer
carrier, a polymer-drug conjugate, or the drug itself to disproportionally partition itself into
the tissue of interest.

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 5

Physiology of oral delivery—Oral formulations represent the most common platform

for drug delivery. In conventional pharmaceutical formulations, such as those employing
tablets and capsules, delivery of relatively small organic molecules via the gastrointestinal
NIH-PA Author Manuscript

(GI) tract occurs by means of passive absorption down a concentration gradient on the
intestinal surfaces as determined by three primary factors: extent of ionization, molecular
weight (MW), and oil/water partition coefficient of the drug (23). Just as in the absorption of
nutrients and ions, drugs generally pass through several physical barriers during
transcytosis before entering intestinal capillaries or central lacteals, as shown in Figure 2
(see color insert). The boundaries, beginning with the lumen of the intestine, are the mucous
layer, brush border (microvilli), epithelial apical membrane, cytoplasm, basal membrane,
and basement membrane, before entering the lamina propria, where substances can either
enter capillaries by diffusing through endothelial cells or pass into the central lacteal for
passage into the lymphatic system, thereby avoiding first-pass metabolism. Except for
extremely large molecules or molecules that partition heavily into chylomicrons, the vast
majority of absorbed substances take the capillary exit from the intestine owing to the
substantial perfusion of blood vessels.

It is important to emphasize that effective release of a therapeutic agent in the vicinity of the
mucous layer does not imply sufficient bioavailability. Significant fractions of a drug that
diffuses into the mucous membranes may be effluxed back into the intestinal lumen,
metabolized in the intestinal mucosa, or removed by the hepatic portal system during first-
NIH-PA Author Manuscript

pass metabolism.

Physiology of parenteral delivery—Many therapeutic agents, such as proteins, lack the

stability or absorption characteristics necessary for absorption in the GI tract. These and
agents with very narrow therapeutic windows must be administered parenterally. Parenteral
delivery bypasses the GI tract by direct injection, usually intravenously or interstitially, and
is far more predictable and generally more rapid than oral delivery. Intravenous injection
results in immediate drug availability, which is advantageous in many cases, but it also
generally results in shorter drug circulation owing to rapid access to excretory mechanisms,
and it can make overdoses nearly impossible to counteract. Drugs and polymer carriers for
intravenous delivery must generally be soluble in aqueous environments. With subcutaneous
and intramuscular routes, a drug bolus is temporarily implanted by injection into an
interstitial environment and subsequently cleared from the site by absorption into the
vasculature or drainage into the lymphatic system. This mechanism allows for slower
absorption of the drug and may be used for oily substances. MW determines whether an
injection site will be cleared by the tissue capillaries or lymphatics. As in the central lacteals
of the intestine, substances with higher MWs (or greater hydrodynamic diameters) enter
lymphatic capillaries and subsequently systemic circulation by drainage at the thoracic duct.
NIH-PA Author Manuscript

Because tissue perfusion is substantial, absorption vastly dominates lymphatic draining with
molecules of less than 5 kDa (25).

RESPONSIVE POLYMERS FOR DRUG DELIVERY

Environmentally-responsive polymers, or smart polymers, are a class of materials comprised
of a large variety of linear and branched (co)polymers or crosslinked polymer networks. A
hallmark of responsive polymers is their ability to undergo a dramatic physical or chemical
change in response to an external stimulus. Temperature and pH changes are commonly
used to trigger behavioral changes, but other stimuli, such as ultrasound, ionic strength,
redox potential, electromagnetic radiation, and chemical or biochemical agents, can be used.
These stimuli can be subsumed into discrete classifications of physical or chemical nature
(26). Physical stimuli (i.e., temperature, ultrasound, light, and magnetic and electrical fields)
directly modulate the energy level of the polymer/solvent system and induce a polymer

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 6

response at some critical energy level. Chemical stimuli (i.e., pH, redox potential, ionic
strength, and chemical agents) induce a response by altering molecular interactions between
polymer and solvent (adjusting hydrophobic/hydrophilic balance) or between polymer
NIH-PA Author Manuscript

chains (influencing crosslink or backbone integrity, proclivity for hydrophobic association,

or electrostatic repulsion) (26). Types of behavioral change can include transitions in
solubility, hydrophilic-hydrophobic balance, and conformation (27). These changes are
manifested in many ways, such as the coil-globule transition of polymer chains (28),
swelling/deswelling of covalently crosslinked hydrogels (29), sol-gel transition of physically
crosslinked hydrogels (30), and self-assembly of amphiphilic polymers (31) (Figure 3, see
color insert). The aim of this section is to review recent developments in temperature and
pH-responsive polymers and highlight the emerging area of redox-responsive polymers for
drug delivery systems. Additionally, a brief introduction to magnetically-triggered polymer
nanocomposites is given below. Several excellent reviews that provide a comprehensive
treatment of these topics are available (26, 27, 32–37).

Applications and Examples

The majority of responsive polymers for drug delivery can be broadly categorized as
hydrogels, micelles, polyplexes, or polymer-drug conjugates, which are covered in more
detail below. Hydrogels are hydrophilic (co)polymeric networks capable of imbibing large
amounts of water or biological fluids (38). Physical or covalent crosslinks render hydrogels
insoluble in water. Hydrogels can be engineered to respond to various stimuli (32) and have
NIH-PA Author Manuscript

demonstrated significant utility in the medical and pharmaceutical arenas. Peppas and
coworkers have pioneered the use of pH-responsive complexation hydrogels of
poly(methacrylic acid) grafted with PEG, referred to as P(MAA-g-EG), for oral protein
delivery. Through interpolymer complexation in acidic conditions, this system has been
shown to successfully entrap, protect, and mediate delivery of insulin (39), calcitonin (40),
and interferon β (41). Micelle-forming polymers, such as block copolymers of poly(ethylene
oxide) and poly(propylene oxide), or Pluronics®, have been thoroughly studied in drug
delivery (33). These polymers exhibit temperature-responsive micellization (42), as do block
copolymers of poly(N-isopropylacrylamide) (PNIPAAm) coupled with hydrophilic PEG
(31). Polyplexes formed by cooperative electrostatic interactions between polyethyleneimine
(PEI) and DNA are widely studied for gene delivery. Since the seminal paper by Boussif et
al. (43), several facets of PEI-mediated gene delivery have been investigated, including the
influence of crosslinking, MW, branching, and biodegradability (44--46).

Responsive Systems Based on Temperature

Temperature has been widely investigated as a stimulant for responsive polymer systems
owing to its ease of modulation and applicability in drug delivery applications (26). Tanaka
NIH-PA Author Manuscript

observed temperature-dependent swelling of polymer gels (47) following its theoretical

prediction more than 40 years ago (48). One thermo-responsive polymer, PNIPAAm, has
been thoroughly investigated for its ability to undergo a reversible, inverse (or negative)
temperature-dependent phase transition (32). Below its lower critical solution temperature
(LCST) near 32°C, PNIPAAm exists as a hydrophilic coil, whereas above the LCST,
PNIPAAm chains collapse sharply into a hydrophobic globule (49). The nature of this
volume phase transition stems from the hydrophilic/hydrophobic balance of polymer chains
(50), which is modulated by continual establishment and disruption of intra- and
intermolecular electrostatic and hydrophobic interactions. Below the LCST, water molecules
exist in an ordered state in the local environment of polymer chains (51). As temperature
rises above the LCST, polymer-polymer hydrophobic interactions dominate (49).
Consequently, polymer chains collapse and water molecules are released to the bulk,
resulting in a net entropic gain for the polymer/solvent system (52).

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 7

For drug delivery applications, it may be desirable to shift the critical temperature for
volume phase transition to a specific temperature range. This can be accomplished through
the inclusion of hydrophobic or hydrophilic moieties in the polymer chain. Polymers with a
NIH-PA Author Manuscript

larger hydrophobic hydration area possess stronger hydrophobic interactive forces and
undergo collapse at a lower temperature (28, 53). Conversely, increasing the hydrophilic
content of the polymer chain will increase the LCST. Polymers that exhibit positive
temperature-dependent swelling behavior, i.e., a globule-to-coil transition with increasing
temperature, possess an upper critical solution temperature (UCST). These materials, such
as poly(acrylic acid) and poly(acrylamide) interpenetrating networks (IPNs), are discussed
in more detail elsewhere (54).

Physically crosslinked gels, such as methoxy-substituted cellulose derivatives, PNIPAAm

copolymers, and various Pluronics can undergo a sol-gel phase transition near their LCST
(33). These materials are attractive candidates for in situ implants in which thermoreversible
gelation is exploited for the facile implantation of solid drug-depot preparations (55). In
these systems, a liquid drug/polymer solution is injected into a target site at ambient
temperature. As the solution temperature warms to body temperature, the polymer gels,
which entraps the drug in the physically crosslinked matrix. Diffusion of the drug from the
solid gel allows for sustained-release formulations. This approach was used in a study
describing the release of model protein bovine serum albumin (BSA) from temperature-
responsive chitosan grafted with PEG (PEG-g-chitosan) (56). PEG-g-chitosan containing 45
NIH-PA Author Manuscript

and 55 wt% grafted PEG were loaded with BSA and incubated at 37°C to evaluate release
kinetics. Both gels demonstrated initial burst release of BSA during the first 5 hours
followed by sustained, diffusion-driven release until approximately 70 hours. Crosslinking
the gels with genipin resulted in prolonged release of BSA for up to 40 days.

Novel polymerization techniques, such as controlled radical polymerizations and click

chemistry reactions, offer superior control over molecular architecture and present the
opportunity to create novel materials highly tailored for specific responsive behavior. This
approach was employed by Sumerlin and colleagues to produce folate-conjugated
temperature-responsive block copolymers of N,N-dimethylacrylamide (DMAAm) and
PNIPAAm with reversible addition fragmentation chain transfer RAFT polymerization (57).
Above the LCST (34°C) of this polymer system, PNIPAAm blocks collapsed into
hydrophobic globules whereas DMAAm blocks remained hydrophilic. Ensuing aggregation
resulted in particles of approximately 46 nm postulated to be micelles with PNIPAAm cores
and DMAAm shells. Surface decoration of the polymer chains with folate enables the
system to be actively targeted to certain tissues via receptor-mediated endocytosis. Folate
ligands are particularly applicable in cancer therapy and are discussed more thoroughly in
the section on Other Areas of Polymer Therapeutics. Self assembled folate-conjugated
NIH-PA Author Manuscript

polymers provided controlled release of a model hydrophobic drug, dipyridamole, over the
course of 12 days.

Responsive Systems Based on pH

Physiological pH varies systematically in the body, particularly along the GI tract, where
harsh pH and enzymatic conditions in the stomach (pH ~ 2) degrade macromolecules. The
small intestine is substantially more alkaline, with pH ~ 6.2--7.5. Physiological pH profiles
will also change among cellular compartments. For example, endosomes typically exhibit
pH values of 5.0--6.8 and lysosomes 4.5--5.5 (58, 59). Also, it is well known that diseased
or inflamed tissues and exhibit different pH profiles than normal tissue (35). Tumors have
been widely reported to produce acidic conditions (pH ~ 6.5) in the extracellular milieu (60).
Thus, it is no surprise that scientists and engineers have devoted considerable effort toward
the rational design of polymers capable of exploiting these pH variations to selectively

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 8

deliver valuable therapeutics to specific intracellular or extracellular sites of action. By

judicious materials selection and careful engineering of molecular architecture, pH-
responsive polymer delivery systems can be developed to give well-controlled pH response
NIH-PA Author Manuscript

and drug release.

Recently we synthesized polycationic nanomatrices capable of well-defined hydrophilic-

hydrophobic transitions near physiological pH (61, 62). Relatively uniform particles of
poly[2-(diethylamino)ethyl methacrylate-co-t-butyl methacrylate-g-PEG] (PDBP)
measuring 51 nm were synthesized using a novel photoemulsion polymerization technique
(61). Relevant properties of the system, such as swelling ratio, critical swelling pH, surface
charge, and biocompatibility, were tailored by tuning polymer composition, crosslinking
density, and the incorporation of hydrophobic moieties into the hydrogel core. Ongoing
work aims to optimize these systems for intracellular small interfering RNA (siRNA)
delivery.

Promising work by Hu et al. (63) describes the development of pH-responsive core-shell

hydrogels for intracellular delivery of ovalbumin to dendritic cells, a class of cells intimately
involved with adaptive immunity. Emulsion polymerization was used to create crosslinked
poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) core--poly(2-aminoethyl
methacrylate) (PAEMA) shell nanoparticles measuring 205 nm in diameter. The authors
hypothesized that PDEAEMA would exhibit pH-responsive behavior whereas PAEMA
NIH-PA Author Manuscript

would remain constitutively ionized throughout the physiological pH range. Interestingly,

the authors used the cationic PAEMA shell to adsorb and protect a model ovalbumin protein
rather than the archetypal practice of loading therapeutics into the hydrogel core. Subsequent
studies demonstrated the versatility of this approach through intracellular delivery of siRNA
and influenza A particles (64). This strategy of using a charged, pH-insensitive shell distinct
from the pH-responsive domain represents an intriguing departure from the current
paradigm of using a neutral, hydrophilic shell, such as PEG, to shield surface charges.
However, several drawbacks may limit the feasibility of this design in vivo. First, charged
particles have a much higher opsonization rate than neutral particles (65), and the cationic
PAEMA shell may attract opsonin proteins or promote adsorption of anionic serum proteins,
resulting in rapid clearance by the reticuloendothelial system. Secondly, the slow
dissociation of electrostatically bound cargo from a polymer shell may provide a kinetic
barrier to therapeutic efficacy.

Bae and colleagues (66--68) have recently reported polymer micelles possessing dynamic,
multifunctional behavior for drug delivery. Self-assembling amphoteric polyamine-based
block copolymers were functionalized with folate (66), biotin (68), and HIV peptide trans-
activating transcriptional activator (TAT) ligands (67), thus demonstrating robust
NIH-PA Author Manuscript

applicability in targeted delivery. Folate or biotin ligands enhance cellular uptake via
receptor-mediated endocytosis (69), and TAT is a well-known peptide transduction domain
(70). By conjugating the cell-penetrating peptide TAT, particles of up to 200 nm gain direct
access to the cell (71), effectively circumventing the intracellular trafficking pathway. The
polymer system, a mixture of two block copolymers, poly(L-histidine)-b-PEG (polyHis-b-
PEG) and poly(L-lactic acid)-b-PEG-b-polyHis-ligand (pLLA-b-PEG-b-polyHisligand), self-
assembled into mixed micelles capable of ligand exposure, micelle destabilization, and
endosomal disruption in response to pH (67, 68). A short polyHis block preceding the ligand
serves to anchor the ligand at the core-shell interface, which effectively shields its
presentation on the micelle surface at neutral pH. Upon exposure to a slightly acidic (6.5 <
pH < 7.0) environment, the short polyHis anchor ionizes and PEG-b-polyHis arm unfurls,
exposing the ligand on the micellar surface. This response is expected to confer tumor
specificity to the micelle carrier, as the ligand will be unavailable to promote receptor-
mediated endocytosis or cellular transduction in normal (pH 7.4) tissue. Further acidification

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 9

(pH < 6.5) induced micelle dissociation by ionization of the His residues in the micelle core.
Breast adenocarcinoma cells exposed to doxorubicin (Dox)-loaded mixed micelles displayed
prominent intracellular distribution and nuclear localization of Dox after 30 minutes and
NIH-PA Author Manuscript

experienced ~60% reduction in cell viability after 48 hours.

Responsive Systems Based on Redox Potential

Polymers containing labile linkages present an attractive opportunity to develop
biodegradable or bioerodible delivery devices. Much of the early work in this field focused
on acid labile linkages of polyanhydrides (72, 73), poly(lactic/glycolic acid) (74), and more
recently poly(β-amino esters) (75, 76). However, intracellular cues are now being
investigated as a means to trigger cytoplasmic degradation of polymer carriers incorporating
advanced therapeutics such as siRNA and anticancer drugs. Disulfide linkages are well
known to be unstable in a reductive environment as the disulfide bond is readily cleaved in
favor of corresponding thiol groups. Polymers with disulfide cross-links have been
synthesized as polymersomes (77), nanogels (78), and core-cross-linked polyplexes (79) and
degrade when exposed to cysteine or glutathione, reductive amino-acid based molecules
present at intracellular concentrations 50–1000 fold greater than those of the extracellular
milieu (79).

The Hubbell group (77) has used amphiphilic copolymers of PEG and poly(propylene
sulfide) (PPS) to form vesicular compartments. Rather than relying on hydrolytic linkages,
NIH-PA Author Manuscript

which may respond too slowly to avoid nonproductive lysosomal accumulation of the
polymer carrier, they have incorporated a disulfide linkage between the hydrophilic PEG
and hydrophobic PPS portions of the polymer, which imparts a high degree of reductive
sensitivity to the polymersomes.

In another study, glutathione-degradable nanogels were prepared by inverse emulsion atom

transfer radical polymerization (ATRP) (78). Upon exposure to 10 wt% glutathione, half of
the polymer degraded in nearly 6 hours. Exposing polymers to 20 wt% glutathione resulted
in 85% degradation within 1 hour. Dox was efficiently incorporated into the polymer matrix
at 16 wt% of the polymer with more than 50% loading efficiency, and the authors
demonstrated in vitro release of fluorescent dye Rhodamine G6 and Dox. Dox-loaded
nanogels displayed negligible toxicity toward HeLa cells in the absence of glutathione while
causing approximately 40% reduction in cell viability following introduction of exogenous
glutathione to the cellular media. It remains to be determined if this polymer system is
capable of degrading and releasing drug upon exposure to intracellular glutathione
concentrations or if the timescale for degradation in the presence of endogenous glutathione
will allow efficient cytoplasmic delivery of incorporated therapeutics.
NIH-PA Author Manuscript

In a more recent investigation, Kataoka and colleagues (79) synthesized and thoroughly
characterized a core-cross-linked polyplex composed of iminothiolane-modified PEG-block-
poly(L-lysine), or [PEG-b-(PLL-IM)], for intracellular siRNA delivery. The use of a block
copolymer affords modular functionality; the polycationic poly(L-lysine) segment serves to
bind siRNA and provide endosomal buffering capacity (80) whereas the hydrophilic PEG
segment prolongs circulation time, prevents aggregation, and reduces opsonization (65).
Lysine groups of the PEG-b-PLL copolymer were reacted with 2-iminothiolane and
subsequently oxidized to form disulfide cross-links. Introducing crosslinks to the micelle
core confers stability to the system, as crosslinked polymers maintained micellar structure in
physiological salt conditions whereas their noncrosslinked counterparts could not. The
resulting polyion complex micelles were approximately 60 nm in diameter, a particle size
well within the accepted limits (20–100 nm) for avoiding uptake by the RES and renal
exclusion (81). Not surprisingly, micellar stability strongly influenced the ultimate siRNA
transfection efficiency. The authors observed a narrowly defined N/P ratio at which stable

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 10

micellization occurred. Interestingly, this optimum N/P ratio shifted to higher values with
increased crosslinking. Highly efficient (more than 80%) knockdown of a reporter gene was
detected at the optimum N/P ratio; however, a considerable decrease in transfection
NIH-PA Author Manuscript

efficiency was observed upon slight departure from this critical value.

POLYMER THERAPEUTICS FOR DRUG DELIVERY

Polymer therapeutics is a term used to describe an increasingly important area of
biopaharmaceutics in which a linear or branched polymer chain behaves either as the
bioactive (a polymeric drug) or, more commonly, as the inert carrier to which a therapeutic
is covalently linked, as in the case of polymer-drug conjugates, polymer-protein conjugates,
polymeric micelles, and multicomponent polyplexes (82). Conjugation of the therapeutic to
the polymer improves the pharmacokinetic and pharmacodynamic properties of
biopharmaceuticals through a variety of measures, including increased plasma half-life
(which improves patient compliance because less frequent doses are required), protection of
the therapeutic from proteolytic enzymes, reduction in immmunogenicity, enhanced stability
of proteins, enhanced solubility of low MW drugs, and the potential for targeted delivery
(82–84).

The majority of polymer conjugates are designed as anticancer therapeutics, although other
diseases have also been targeted, including rheumatoid arthritis, diabetes, hepatitis B and C,
NIH-PA Author Manuscript

and ischemia (85). The popularity of conjugates for anticancer agents is a result of a passive
tumor targeting phenomenon first coined by Matsumura & Maeda (86) as the enhanced
permeation and retention (EPR) effect. It has been shown that the tumor concentration of
anticancer therapeutics can increase up to 70-fold as a part of circulating macromolecular
systems such as polymer conjugates (82). However, recent studies have shown that tumor
targeting may not be able to be achieved exclusively by the EPR effect owing to difficulties
in reaching cancer cells deep inside malignant tissues (87), which underscores the need for
synergistic passive and active targeting strategies. Since the advent of controlled release
polymer drug delivery systems (DDS), the polymer therapeutics field has exploded as the
focus has shifted toward strategies that facilitate targeted release, especially for anticancer
drugs, which often have severe negative side effects. For a polymer-drug conjugate to be
both practical and effective, several features are desired: (a) nontoxic and nonimmunogenic
polymer carrier, (b) MW high enough to ensure long circulation times, but <40 kDa for
nonbiodegradable polymers to ensure renal elimination following drug release [N-(2-
hydroxypropyl)methacrylamide (HPMA) has an optimal MW of ~30 kDa (82)], (c) adequate
loading/carrying capacity in relation to the potency of the drug [PEG is not an ideal carrier
as it has only two reactive groups, which leads to a low drug payload (82, 88)], (d) linker
must be stable during transport but easily cleaved for optimum delivery upon arrival at
NIH-PA Author Manuscript

target (frequently achieved using a Glycine-Phenylalinine-Leucine-Glycine, or GFLG,

peptide linkage), and (e) the ability to target desired tissue by active and/or passive means
(83).

The traditional approach to synthesizing polymer-protein conjugates involves the

postpolymerization modification of the polymeric carrier, usually PEG, with protein-
reactive end groups that facilitate binding between its own pendant groups and those of the
amino acids in the protein. There are three general requirements for an effective polymer-
protein conjugate system: a polymer with a single reactive group at only one terminal end
(to prevent protein crosslinking), a nontoxic/immunogenic linker (including intermediate
byproducts), and a method that will yield site-specific conjugation (82). The two main types
of polymers are amine- and thiol-reactive polymers that target lysine and cysteine side
chains, respectively. Thiol-reactive polymers have been used more recently in an effort to
create site-specific conjugates because cysteines are not as common as lysine.

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 11

Postpolymerization techniques typically employed to add thiol-reactive end groups include

the use of vinyl sulfone, maleimide, iodoacetamide, and activated disulfide end groups (84,
89). In addition, several new approaches have been investigated to circumvent
NIH-PA Author Manuscript

postpolymerization modifications and protein-polymer coupling reactions. There has been a

strong impetus recently for these techniques, which enable the synthesis of the polymer
directly from protein-reactive initiators, owing to the advent of living/controlled
polymerization methodologies, such as RAFT and ATRP, as they are straightforward, less
time intensive, and almost guarantee that each polymer chain contains only one reactive
end-group (89–91).

Applications and Examples

The most common carriers for polymer therapeutics are HPMA (polymer-drug) and PEG
(polymer-protein), but other systems studied include poly(glutamic acid), PEI, dextran,
dextrin, chitosans, poly(L-lysine), and poly(aspartamides) as polymeric carriers (92).
Polymer-drug and polymer-protein conjugates typically studied have a tripartite structure:
polymer, linker, and therapeutic agent. However, more complex systems now exist that
incorporate additional features for targeted delivery or combination therapies.

The large number of polymer conjugates either approved for clinical use or currently in
clinical trials is a reflection of the fact that polymer therapeutics is no longer just an
academic curiosity. The first-to-market products, with their brand name and year of approval
NIH-PA Author Manuscript

in parentheses, include PEG-L-asparaginase (Oncaspar, 1994) for leukemia, styrene maleic

anhydride-neocarzinostatin (Zinostatin Stimalmer, 1993) for hepatocellular carcinoma,
PEG-granulocyte colony-stimulating factor (Neulasta, 2002) for neutropenia prevention
associated with chemotherapy, PEG-interferon-α (PEGasys, 2002) for hepatitis C, and PEG-
adenosine deaminase (Adagen, 1990) for severe combined immunodeficiency disease (83,
88, 93). Several excellent reviews have been published over the past several years that
provide a more expansive overview of the field and conjugates currently in clinical testing
(82, 83, 85, 93).

Polymer-Drug Conjugates
One of the most commonly studied areas of polymer therapeutics is polymer-drug
conjugates in which the low MW therapeutic and polymeric carrier are most often an
anticancer agent and HPMA copolymer, respectively. This area was born from a landmark
study by Ringsdorf in 1975 (94) and then further pioneered in the 1980s by Duncan &
Kopecek, who designed the first targeted synthetic polymer-anticancer conjugates to
progress to clinical trials (95, 96). This work was comprehensively reviewed recently (97,
98). In contrast to free drugs, which usually distribute randomly throughout the body and
NIH-PA Author Manuscript

thus exert deleterious side effects, attachment of the therapeutic to polymer carriers limits
cellular uptake to endocytosis, extends circulation times to several hours, and facilitates
passive targeting of tumors via the EPR effect (83).

Angiogenesis inhibitors, such as TNP-470 [O-(chloracetyl-carbomoyl) fumagillol] are

currently receiving increased interest as anticancer drugs. In a landmark paper describing the
first polymer-antiangiogenic conjugate, Satchi-Fainaro et al. (99) synthesized a conjugate of
HPMA and TNP-470 that was covalently linked with GFLG via an enzymatically
degradable bond, ethylenediamine. The tetrapeptide linker was designed to allow
intralysosomal release of the therapeutic by cleaving the bond when in the presence of
lysosomal cysteine proteases such as cathepsin B, levels of which are elevated in many
tumor endothelial cells. In vivo studies not only demonstrated that the conjugate selectively
accumulated in tumor vessels via the EPR effect, but also enhanced and prolonged the
activity of TNP-470 without the neurotoxicity previously seen in animal studies conducted

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 12

using only the antiangiogenic drug, likely because the size of the conjugate prevented it
from crossing the blood-brain barrier. This HPMA copolymer-TNP-470 conjugate is
currently in preclinical development under the name caplostatin by SynDevRx and has since
NIH-PA Author Manuscript

been the focus of additional studies (100, 101).

Novel polymeric architectures, such as dendrimer, branched, grafted, and star polymers, are
now being explored as conjugate carriers of the future owing to advances in polymer
chemistry. In an elegant report, paclitaxil, a common chemotherapeutic with low solubility,
was covalently conjugated with linear bis(PEG) and dendritic polyamidoamine (PAMAM)
G4 to determine the influence of the architecture of the polymeric carrier on the efficacy of
the anticancer DDS (102). Both PAMAM and PEG increased the solubility of paclitaxil in
relation to the free drug (0.3 mg ml−1); however, solubility was improved further with the
dendrimer (3.2 versus 2.5 mg ml−1). Confocal microscopy analysis of FITC (fluorescein
isothiocyanate) labeled samples showed that both conjugates distributed in a more
homogeneous and uniform manner than the free drug. In vitro cytotoxicity studies of A2780
human ovarian cancer cells demonstrated that although the PEG-based conjugate reduced
the activity of the drug by 25-fold, the PAMAM-G4 dendrimer conjugate increased the
efficacy of paclitaxil by more than 10 times compared with its free state. This study suggests
that dendrimers are promising vehicles for intracellular delivery of poorly soluble drugs.

Polymer-Protein Conjugates
NIH-PA Author Manuscript

Pioneering studies published by Davis and colleagues in the late 1970s (103, 104) laid the
foundation for the area now known as PEGylation in which peptides and proteins are
covalently conjugated to PEG. This technique has become the method of choice over the
past 20 years to improve the pharmacokinetic and pharmacodynamic properties of protein
therapeutics (82, 83). PEG is commonly used as the preferred carrier in this application
because of a lack of immunogenicity, antigenicity, and toxicity (PEG is approved by the
FDA for injectable, topical, rectal, and nasal pharmaceutical formulations). Furthermore, it
is extremely hydrophilic, which helps to protect the protein from an immune response, and it
can be synthesized to facilitate specific conjugation without crosslinking the protein, which
allows the therapeutic to be released (93). And although PEGylation can lead to a decrease
in protein activity, the increased circulation time can compensate for this to still provide
drug concentrations at relevant levels. The impact of PEGylation on pharmaceuticals has
been extensively reviewed elsewhere (84, 93, 105).

Despite the successes and future promise of PEGylation in polymer-protein conjugates, PEG
is limited due to a lack of biodegradability, and conjugation can reduce or alter protein
activity. Duncan et al. (106) report a novel approach for polymer-protein conjugation called
polymer-masking-unmasking protein therapy (PUMPT) in which a model enzyme, trypsin,
NIH-PA Author Manuscript

was conjugated to dextrin, a natural polysaccharide that is biodegradable and has been
clinically approved for a variety of uses. The researchers hypothesized that a conjugation of
this nature would protect and mask the activity of the protein in transit while restoring the
activity at the desired target site by triggered degradation of the polymer. Dextrin was
functionalized via succinoylation as the resultant chemistry not only yields reactive groups
necessary for covalent modification but also a nontoxic intermediate before the complete
degradation to maltose and isomaltose occurs in the presence of α-amylase. Dextrin
conjugation reduced the activity of the trypsin by 34–69% depending on the MW and level
of succinoylation; subsequent incubation with α-amylase resulted in a return of activity to
92–115% of the original amount as analyzed using N-benzoyl-L-arginine-p-nitroanilide (L-
BAPNA). PUMPT offers a novel strategy with great potential to improve the delivery of
proteins that are toxic or typically inactivated in transit, and/or to allow targeted release of
the protein. However, additional studies are required to optimize the conjugation chemistry

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 13

on a system-by-system basis as well as to fully characterize the intermediate and final

degradation products to ensure safe elimination.
NIH-PA Author Manuscript

Other Areas of Polymer Therapeutics

Polymeric micelles are a promising area of polymer therapeutics as a result of several
advantages. These include easy conjugation for active targeting, high drug loading capacity
in the hydrophobic core (especially for hydrophobic anticancer drugs), and rapid cellular
uptake facilitated by their nanosize characteristics (107, 108). Cancerous tissues have been
shown to exhibit a local pH decrease (pH 5–6) and local hyperthermia (T ~ 42°C) relative to
surrounding normal tissues, and several studies have been conducted to exploit these
characteristics (109––113). One particular type of micellar system combines pH-induced
anticancer therapeutic release with a conjugated ligand to facilitate active tumor targeting
(114, 115).

In a recent study, Bae et al. (115) functionalized PEG- poly(β-benzyl-L-aspartate) (PBLA)

block copolymer micelles with adriamycin (an anticancer drug) via a pH-cleavable
hydrazone bond at the hydrophobic core forming poly(aspartic acid) block and with various
amounts of folate conjugated to the hydrophilic shell forming PEG block. Hydrazone is a
popular acid-labile linker because this bond is stable at pH 7.4 but hydrolyzes under mild
acidic conditions (pH 5–6) (108). Folate is commonly employed as a tumor targeting ligand
because cancer cells have been shown to overexpress folate-binding proteins (FBP) (116).
NIH-PA Author Manuscript

Previous studies from the same group showed intracellular pH-triggered release capability
with the same micellar system synthesized without folate: no appreciable drug was released
at physiological pH whereas release was observed once the pH decreased below pH= 6
(110). Surface plasmon resonance (SPR) analyses demonstrated that folate-conjugated
micelles bound rapidly and strongly to FBP whereas the micelles prepared without folate
functionalization did not show any interaction. Folate conjugation had a minimal effect on
the pharmacokinetic profile compared to those systems without the targeting ligand and
showed a fivefold increase in the safe dosage range compared with free adriamycin. More
importantly, in vivo studies clearly showed that the folate-conjugated micelles had a higher
antitumor activity (lower effective dose) than either the nonfolate-conjugated micelles or the
free drug (7.5 mg kg−1 for the folate-conjugated micelles versus 20 mg kg−1 and 10 mg
kg−1, respectively).

Due to the molecular complexity and variable nature of disease, especially cancer,
researchers are starting to investigate combination therapies as these have the potential to
improve long-term therapeutic prognosis. Over the past few years, interest has shifted
toward using FDA-approved combinations of multiple drugs conjugated to the same
polymer in an attempt to exploit potential synergy for a more robust therapeutic effect.
NIH-PA Author Manuscript

However, careful consideration must be taken as molecules of different drugs can interact
with each other to induce unfavorable side effects. Several studies have been conducted
recently to further investigate these combination therapies (117–119). In the most recent
report, Lammers et al. (119) synthesized a system of gemcitabine (Gem) and Dox
conjugated to HPMA via the same tetrapeptide, GFLG, that is commonly used in polymer
therapeutics. The circulatory, angiogenic, apoptotic, and tumor growth inhibition
characteristics of a variety of doses of the novel conjugate, termed P-Gem-Dox, were
compared with those of regimens consisting solely of HPMA, free Gem and free Dox, P-
Gem, and P-Dox control samples. The in vivo analyses showed that P-Gem-Dox circulated
for prolonged periods of time (21% and 9% of the injected dose was detected at 4 and 24
hours post IV injection, respectively) and selectively localized to the tumor, as higher levels
of conjugate were present in the tumor than in 7 of 9 other healthy tissues. P-Gem-Dox
significantly improved tumor growth inhibition (50–60% inhibition) compared with the free

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 14

drugs (~30%) and P-Gem and P-Dox conjugates (~40%). In vivo studies also showed that P-
Gem-Dox enhanced antiangiogenic and apoptotic induction relative to the free drugs without
increased toxicity, although not compared with the individual conjugate regimen. Despite
NIH-PA Author Manuscript

the promise of combination conjugates, further in vivo investigations are needed to confirm
that such systems are a significant improvement over the well-established singular
conjugates given individually or in parallel.

CURRENT THRUSTS IN DRUG DELIVERY

Molecularly Imprinted Polymers
Molecular imprinting is a promising field in which polymer networks are formed with
specific recognition for a desired template molecule. Briefly, functional monomers are
chosen that exhibit chemical structures designed to interact with the desired template
molecule via covalent or noncovalent chemistry. The monomers are then polymerized in the
presence of the desired template, the template is subsequently removed, and the product is a
molecularly imprinted polymer (MIP) with binding sites specific to the template molecule.
This technique was originally developed for separation applications; however, MIPs have
recently been studied for biomedical applications, including drug delivery (120, 121).

MIPs demonstrate great potential as advanced drug delivery systems owing to the affinity
between the drug template and polymer pendant groups. This can yield zero order release of
NIH-PA Author Manuscript

the drug over longer periods of time, a distinct advantage over conventional drug delivery.
The ideal MIP DDS will maintain a drug concentration in its therapeutic range, which
eliminates the need for frequent high concentration doses. Additionally, a closed loop
process is also possible in which the MIP can detect a biological event, such as elevated
levels of an undesired biomolecule, and release the corresponding therapeutic while
continuously monitoring the environment. When this biomarker is no longer prevalent, the
MIP responds by terminating the drug release. Several excellent review papers provide a
more detailed analysis of MIPs, especially for drug delivery applications s (120–122).

Drug delivery via the ocular route is a target application of MIPs owing to the drawbacks of
conventional systems, including low bioavailability (~5%), frequent high concentration
doses, and short term discomfort and blurred vision (123). MIPs can address some of these
issues by providing enhanced bioavailability, extended retention time, and concentrations
within the therapeutic range by exploiting the increased affinity between the drug template
and polymer pendant groups to slow the rate of release. Several papers have investigated this
application over the past few years (123–129).

In a recent study, Ali & Byrne (123) investigated the release of high MW hyaluronic acid
NIH-PA Author Manuscript

(HA) from rationally designed imprinted soft contact lenses. Acrylamide (Aam), N-vinyl
pyrrolidone (NVP), and DEAEMA were selected as monomers for this MIP system because
of their respective structural similarity to Asn, Tyr, and Arg/Lys, amino acid residues
important in the binding of HA to the CD44 receptor. Commercially available nelfilcon A
was combined with the MW ~1.2 million HA and functional monomers and subsequently
UV polymerized to prepare the imprinted hydrogels. The total amount of functional
monomer was varied between 0.05 and 5%. Release studies in artificial lachrymal solution
at 35°C showed that an increase in the amount of functional monomers decreased the rate
and total amount of HA released over a 24 hour period and uncovered that increasing the
diversity of monomers lowers the diffusion coefficient (up to 1.6 times lower than the
nelfilcon A control polymer). The imprinted polymers were easily tailored to release HA at
the therapeutic level of 6 μg hr−1 for 24 hours, which is superior to the control polymer
profile. Structural studies confirmed that the addition of monomers did not result in a change
in the mesh size, thus causing the decrease in diffusion in the MIPs.

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 15

In another study by the same group, Venkatesh et al. (130) performed structural and
transport analyses for ketotifen fumarate imprinted hydrogels with multiple functional
monomers. The formulation with the best results consisted of a total of 3 mol% of acrylic
NIH-PA Author Manuscript

acid (AA), Aam, and NVP as the functional monomers, 32 mol% 2-

hydroxyethylmethacrylate (HEMA) as the backbone monomer, and 5 mol%
PEG(200)dimethacrylate as the cross-linker. This system displayed an affinity of ~4.5
(recognition over control) and a 2.5–9 times increase in capacity in comparison with the
systems that contained one or two functional monomers. Additionally, the template diffusion
coefficients were lower for all MIPs compared with their corresponding controls, the biggest
decrease being ~18.8 times for the same system, despite comparable mesh sizes. These
studies were conducted under conditions far from physiological, namely at room
temperature (25°C) and in deionized water. However, this study was an extension of work
published previously in which the MIP released therapeutically relevant concentrations of
the antihistamine over five days under physiological conditions (129). The results of these
three studies are extremely promising for providing ocular therapeutic delivery at a constant
rate for an extended period of time.

Although MIPs have enormous potential to be used in feedback-controlled and targeted

delivery devices, much of the literature to date has focused solely on extended release via
interactions between the pendant groups along the polymer backbone and the drug template.
Even though the practical applications of such systems is a long way off, these feedback-
NIH-PA Author Manuscript

controlled systems will be able to provide personalized therapeutic properties because they
have the ability to resolve any problems before undesirable symptoms appear.

Endosomolytic Polymers
The emergence of highly specific biological pharmaceutical agents, including proteins
(monoclonal antibodies, hormones, enzymes) and nucleic acids (plasmid DNA, antisense
oligonucleotides, siRNA) has highlighted the need for carrier systems to direct these fragile
molecules to their specific site of action. Although these biopharmaceuticals hold immense
promise in the treatment of disease, their clinical implementation is hampered by the lack of
safe, effective delivery vectors (131, 132). Extracellular and intracellular trafficking barriers
represent a significant limitation in the delivery of fragile therapeutics and must be
overcome with innovative solutions (35, 131, 132). To this end, development of biomimetic
polymers has gained traction with the aim of producing synthetic polymer systems capable
of emulating the membrane-lytic abilities of toxins and viruses bearing fusogenic peptides.
Increased understanding of disease pathology and interfacial phenomena between polymers
and cell membranes as well as refined methodology for tailoring the responsive behavior of
materials has furthered the development of polymer carriers with advanced functionality.
NIH-PA Author Manuscript

Recent systematic studies have shed light on the factors influencing membrane interaction;
polymer characteristics such as composition, hydrophobic/hydrophilic balance, surface
charge, and distribution of functional groups (80, 133) have significant impact on cell
membrane interactions and ultimate endosomolytic ability.

Polymers bearing weakly ionizable groups are attractive candidates for intracellular delivery
because of their ability to undergo a pH-responsive conformational transition and destabilize
endosomal membranes. The mechanism of endosomal disruption depends on the chemical
nature of the ionizable group. Anionic polymers, such as those bearing carboxyl groups,
undergo a conformational change from charged open chains to compact, hydrophobically-
stabilized structures capable of disrupting endosomal membranes through pore formation
and disruption of membrane integrity. The mechanism of membrane destabilization by
anionic polymers is thought to be related to their pH-dependent conformational transition

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 16

(134), and the extent of polymer association with the lipid bilayer and cellular uptake can be
enhanced by increased polymer hydrophobicity (135).
NIH-PA Author Manuscript

Cationic polymers, such as those bearing amine groups, are thought to promote endosomal
rupture through the “proton sponge” mechanism. These polymers absorb incoming protons
during endosomal acidification. This action causes an accumulation of protons and
counterions, such as Cl−, within the endosome. The high osmotic strength within the
endosomal compartment subsequently leads to osmotic swelling and endosomal rupture
(131).

Most biotherapeutics must localize in a particular subcellular site of action (e.g., nucleus,
cytosol, mitochondria) to exert a therapeutic effect. Since the pioneering work of Hoffman
and Stayton (136–138), much effort has been directed toward developing polymer carriers
that can efficiently direct these molecules to their intended target site. Frequently, this
involves escape from the endosomal trafficking pathway and translocation to the cytosol.
Recently, hydrogel nanoparticles demonstrating pulsatile intracellular delivery of Dox have
been described (139). These nanogels consist of a hydrophobic poly(His-co-phenylalanine)
core surrounded by a telechelic PEG shell. An outer protein shell is formed by attaching
BSA to the opposite end of the PEG chain, imitating the capsid of many viruses. BSA was
further conjugated with folate moieties, creating a multilayer hydrogel particle. Although the
hydrophobic core was not covalently crosslinked, the nanogels maintained structural
NIH-PA Author Manuscript

integrity and demonstrated reversible swelling behavior in response to pH. Buffering

capacity provided by His residues and considerable volumetric swelling (particle diameter
increased from 55 nm at pH 7.4 to 355 nm at pH 6.4) contribute to destabilization of the
endosomal membrane. Dox loaded into the initially hydrophobic core is released during
endosomal trafficking as progressively protonated polyHis drives gel swelling and Dox
efflux. Impressively, this polymer carrier has shown propensity for multiple “infection”
cycles. After the loss of cell membrane integrity from Dox-induced apoptosis, the polymer
carrier was able to diffuse from dead cells to previously untreated populations and mediate
additional rounds of Dox delivery.

Convertine et al. (140) recently reported intracellular delivery of siRNA using ampholytic
pH-responsive block copolymers. One block, composed of DMAEMA, provides
cooperative electrostatic complexation with siRNA whereas the second block, a terpolymer
of DMAEMA, t-butyl methacrylate, and propylacrylic acid, mediates endosomal disruption.
The copolymer undergoes a transition from hydrophilic ampholyte to polycationic
hydrophobe near endosomal pH. This transition can be tuned to specific values by adjusting
the hydrophobic content of the polymer, a parameter that also modulates endosomolytic
ability. Optimizing the N/P ratio, a critical design consideration for nucleic acid delivery
NIH-PA Author Manuscript

(80), was imperative in achieving particle self-assembly. Polymers containing variable

terpolymer block compositions were screened for hemolytic ability, cell internalization,
cytotoxicity, and siRNA silencing efficiency. In general, polymers with increasing
hydrophobic content possessed more desirable properties: higher hemolytic efficiency at
endosomal pH, increased cellular uptake, and more efficient gene knockdown. Although
increasing the hydrophobic content leads to greater carrier efficacy, this comes at the cost of
solubility in aqueous media (140). These factors must therefore be carefully balanced when
optimizing molecular architecture for drug delivery applications.

Recently, Chen et al. (141–144) have published a series of compelling studies describing the
synthesis and in vitro characterization of a pH-responsive amphiphilic pseudopetide, poly(L-
lysine iso-phthalamide). At low concentrations (≤0.1 mg ml−1), the polymer undergoes a
pH-dependent conformational transition from an extended hydrophilic chain to a condensed
hydrophobic globule with progressive protonation of its pendant carboxyl groups. These

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 17

moieties provide an opportunity for functionalization with PEG (143, 144) or hydrophobic
amino acids such as L-valine, L-leucine, and L-phenylalanine (141, 142). The pH-responsive
conformational transition was examined as a function of pH, time, concentration, and degree
NIH-PA Author Manuscript

of grafting. Polymers grafted with hydrophilic PEG side chains displayed modest hemolytic
activity (~50%) in the endosomal pH range (144) whereas polymers grafted with
hydrophobic L-phenylalanine exhibited near-complete erythrocyte membrane disruption
(142). As expected, hemolytic efficiency increased with relative hydrophobicity of the
amino acid graft, with L-valine being the least effective and L-phenylalanine being the most
effective. The phenylalanine-grafted polymer, termed PP-75, displayed maximum hemolytic
efficiency from pH 6.0–7.0 and was essentially nonhemolytic at pH 7.4. On this basis, PP-75
was selected as a promising candidate for drug delivery. After demonstrating endosomal
release of the model drug calcein (142), Liechty et al. used PP-75 to successfully direct
intracellular delivery of the novel anticancer protein apoptin (145).

CONCLUSIONS
Research in polymer therapeutics has enjoyed success over the past few decades in
mediating safe and effective delivery of bioactive agents to treat an enormous variety of
medical conditions. The research initiatives highlighted in this review show great promise in
enhancing drug delivery so that drugs will be distributed only to locations where needed in
therapeutically relevant quantities and will rely less on the dosing efforts of the patient.
NIH-PA Author Manuscript

Looking ahead, research efforts should progress toward understanding more about how
polymers and polymer products interface with biological systems. Many studies in recent
years have reported on novel chemical roots for advanced drug delivery systems, but too
often biocompatibility studies are overlooked until late in development. The result is that
many new devices fail at a later stage of their development. Judicious cellular and animal
studies early in device development will help to ensure that polymer-related breakthroughs
and in vitro successes result in effective and safe drug delivery platforms.

FUTURE ISSUES
1. Endosomal and intracellular delivery: Advanced treatment of diseases will require
vehicles that can deliver their payload in a highly regulated and site-specific
manner to achieve therapeutically relevant concentrations in subcellular organelles.
2. Responding to highly specific biochemical cues: Future therapeutic systems will
have the ability to recognize key bioanalytes responsible for or indicative of a
particular disease. Through a unique triggering mechanism either physical or
chemical in nature, this recognition process will lead to delivery of a therapeutic
agent. Classical chemical engineering principles of control theory will undoubtedly
NIH-PA Author Manuscript

have a major impact on the optimization of these systems.

3. Crossing the blood-brain barrier: The blood-brain barrier, a formation of tightly
sealed endothelial cells, remains a major obstacle for effective delivery of many
therapeutics used to treat neurological and psychiatric disorders. PEG-grafted
polymer nanoparticles have shown promise as a means to facilitate transport into
deep areas of the brain without damage to the blood-brain barrier or any other brain
structures.
4. Tumor targeting: This is a major area for targeted therapeutic delivery of high
potency drugs at relatively high payloads to specific sites. Advanced delivery
systems will utilize a combination of chemical and biological means to achieve
localization and therapy at specific sites

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 18

Nanocomposites for External In Situ Triggering

The emerging area of polymer-nanoparticle composites incorporates an inorganic
nanoparticle responsive to externally-applied electromagnetic radiation. Two main strategies
NIH-PA Author Manuscript

are employed in these composites. One technique is based on dielectric-core, metal shell
nanoparticles that become excited by plasmon resonance heating in response to induced
light. This characteristic allows them to be tuned for deep-penetrating, near-infrared light,
which is useful when these nanoparticles are several centimeters below the skin. This
strategy can be used to induce a positive (146) or negative (147) sigmoidal swelling
response in hydrogels, both of which have potential utility in drug delivery applications. The
alternative strategy relies on using magnetically responsive nanoparticles surrounded by a
responsive polymer layer. This strategy develops heat by magnetic hysteresis in an
electromagnetic field. Thermal energy can be used forcibly to swell or collapse a
temperature-responsive hydrogel as with the core-shell metal nanoparticles (148), or it can
be used to trigger degradation of a polymer shell, as demonstrated by
poly(alkylcyanoacrylates) for delivery of 5-fluorouracil (149). Furthermore, drug carriers
that incorporate inorganic cores may also serve as contrast agents for several imaging
modalities such as magnetic resonance imaging (MRI) (150). This would potentially allow
for image-guided triggering of drug release coupled to information regarding the anatomical
location of the carrier system.
NIH-PA Author Manuscript

Acknowledgments
A portion of this work was supported by NIH grant EB000426. W.B.L., D.R.K., and B.V.S. acknowledge the
National Science Foundation for NSF Graduate Research Fellowships.

TERMS AND DEFINITIONS

Transcytosis the process of macromolecules traversing cells by entering and

exiting their membranes and passing through cellular constituents
N/P ratio nitrogen equivalents of cationic polymer relative to phosphate
equivalents of nucleic acid
Micelles supramolecular assemblies formed by self-assembly of amphiphilic
block copolymers into spherical particles with a hydrophilic corona
and hydrophobic core
Endocytosis the process by which cells internalize macromolecules Predominant
mechanisms include passive (pinocytosis) or receptor-mediated
internalization
NIH-PA Author Manuscript

Hemolytic ability ability of polymers to rupture red blood cell membranes; frequently
correlated with their ability to disrupt endosomal membranes in
vitro
Small interfering 21–23 nucleotide sequence of single stranded RNA capable of
RNA (siRNA) potent and specific gene silencing
Enhanced phenomenon in which macromolecules accumulate passively in
permeation and tumors owing to hyperpermeability into the leaky vasculature
retention (EPR) combined with insufficient lymphatic drainage.
Angiogenesis proliferation of new blood vessels from pre-existing vasculature,
which provides nutrients and facilitates waste removal in normal
and diseased tissues
PDEAEMA poly(2-(diethylamino)ethyl methacrylate)

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 19

DMAEMA 2-(dimethylamino)ethyl methacrylate)

NIH-PA Author Manuscript

PEG poly(ethylene glycol)

PAEMA poly(2-aminoethyl methacrylate)
RAFT reversible addition-fragmentation chain transfer
ATRP atom transfer radical polymerization
HPMA N-(2-hydroxypropyl)methacrylamide
PBLA poly(β-benzyl-L-aspartate)
DDS drug delivery systems
PNIPAAm poly(N-isopropylacrylamide)

LITERATURE CITED
1. Heller A. Integrated medical feedback systems for drug delivery. AIChE J. 2005; 51(4):1054–66.
2. Langer R, Peppas NA. Advances in biomaterials, drug delivery, and bionanotechnology. AIChE J.
2003; 49(12):2990–3006.
3. Rowe, RC.; Sheskey, PJ.; Owen, SC. Handbook of Pharmaceutical Excipients. 5th ed.
NIH-PA Author Manuscript

Pharmaceutical Press; American Pharmacists Association; Grayslake, IL: Washington, D.C.: 2005.
p. 850
4. Langer RS, Peppas NA. Present and future applications of biomaterials in controlled drug delivery
systems. Biomaterials. 1981; 2(4):201–14. [PubMed: 7034798]
5. Verma RK, Mishra B, Garg S. Osmotically controlled oral drug delivery. Drug Dev. Ind. Pharm.
2000; 26(7):695–708. [PubMed: 10872087]
6. Peppas, NA. Drug delivery using smart polymers: recent advances. In: Galaev, IM.; Mattiasson, B.,
editors. Smart Polymers: Applications in Biotechnology and Biomedicine. 2nd ed. CRC Press; Boca
Raton, FL: 2008.
7. Crank, J. The Mathematics of Diffusion. 2nd ed. Oxford Univ. Press; New York: 1975. p. 414
8. Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of
solid drugs dispersed in solid matrices. J. Pharm. Sci. 1963; 52(12):114–49.Pioneering paper in
pharmaceutical delivery that established design conditions for new pharmaceutical formulations
9. Koizumi T, Panomsuk SP. Release of medicaments from spherical matrices containing drug in
suspension: theoretical aspects. Int. J. Pharm. 1995; 116(1):45–49.
10. Cohen DS, Erneux T. Controlled drug release asymptotics. Siam J. Appl. Math. 1998; 58(4):1193–
204.
11. Colombo P, Bettini R, Santi P, Peppas NA. Swellable matrices for controlled drug delivery: gel-
NIH-PA Author Manuscript

layer behaviour, mechanisms and optimal performance. Pharm. Sci. Technol. Today. 2000; 3(6):
198–204. [PubMed: 10840390]
12. Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA. Mechanisms of solute release from
porous hydrophilic polymers. Int. J. Pharm. 1983; 15(1):25–35.
13. Ritger PL, Peppas NA. A simple equation for description of solute release. I. Fickian and non-
fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J.
Control. Release. 1987; 5(1):23–36.
14. Ritger PL, Peppas NA. A simple equation for description of solute release. II. Fickian and
anomalous release from swellable devices. J. Control. Release. 1987; 5(1):37–42.
15. Kim H, Fassihi R. Application of binary polymer system in drug release rate modulation. 2.
Influence of formulation variables and hydrodynamic conditions on release kinetics. J. Pharm. Sci.
1997; 86(3):323–28. [PubMed: 9050800]
16. Lindner WD, Lippold BC. Drug-release from hydrocolloid embeddings with high or low
susceptibility to hydrodynamic stress. Pharm. Res. 1995; 12(11):1781–85. [PubMed: 8592686]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 20

17. Peppas NA, Sahlin JJ. A simple equation for the description of solute release. III. Coupling of
diffusion and relaxation. Int. J. Pharm. 1989; 57(2):169–72.
18. Arifin DY, Lee LY, Wang CH. Mathematical modeling and simulation of drug release from
NIH-PA Author Manuscript

microspheres: implications to drug delivery systems. Adv. Drug Deliv. Rev. 2006; 58(12--13):
1274–325. [PubMed: 17097189]
19. Masaro L, Zhu XX. Physical models of diffusion for polymer solutions, gels and solids. Prog.
Polym. Sci. 1999; 24(5):731–75.
20. Tamada JA, Langer R. Erosion kinetics of hydrolytically degradable polymers. Proc. Natl. Acad.
Sci. USA. 1993; 90(2):552–56. [PubMed: 8421690]
21. Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 2007; 32(8--9):
762–98.
22. Park, K.; Shalaby, W.; Paark, H. Biodegradable Hydrogels for Drug Delivery. Technomic;
Lancaster, PA: 1993.
23. Mayersohn, M. Principles of drug absorption. In: Florence, AT.; Siepmann, J., editors. Modern
Pharmaceutics. 5th ed. Informa Healthcare; New York: 2009. p. 23-80.
24. — (Citation removed, new figure produced by authors)
25. Takakura, Y.; Hashida, M.; Sezaki, H. Lymphatic transport after paraentersal drug administration.
In: Charman, W.; Stella, V., editors. Lymphatic Transport of Drugs. CRC Press; Boca Raton, FL:
1992. p. 255-77.
26. Gil ES, Hudson SA. Stimuli-reponsive polymers and their bioconjugates. Prog. Polym. Sci. 2004;
29(12):1173–222.
NIH-PA Author Manuscript

27. Schmaljohann D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev.
2006; 58(15):1655–70. [PubMed: 17125884]
28. Schild HG. Poly (N-isopropylacrylamide): experiment, theory and application. Prog. Polym. Sci.
1992; 17(2):163–249.
29. Khare AR, Peppas NA. Swelling/deswelling of anionic copolymer gels. Biomaterials. 1995; 16(7):
559–67. [PubMed: 7492721]
30. Malmsten M, Lindman B. Self-assembly in aqueous block copolymer solutions. Macromolecules.
1992; 25(20):5440–45.
31. Topp MDC, Jijkstra PJ, Talsma H, Feijen J. Thermosensitive micelle-forming block copolymers of
poly(ethylene glycol) and poly(N-isopropylacrylamide). Macromolecules. 1997; 30(26):8518–20.
32. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev. 2001;
53(3):321–39. [PubMed: 11744175]
33. Ruel-Gariépy E, Leroux J-C. In situ-forming hydrogels---review of temperature-sensitive systems.
Eur. J. Pharm. Biopharm. 2004; 58(2):409–26. [PubMed: 15296964]
34. Alarcon CDH, Pennadam S, Alexander C. Stimuli responsive polymers for biomedical
applications. Chem. Soc. Rev. 2005; 34(3):276–85. [PubMed: 15726163]
35. Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for
drug and gene delivery. J. Control. Release. 2008; 126(3):187–204. [PubMed: 18261822]
NIH-PA Author Manuscript

36. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;
49(8):1993–2007.
37. Kost J, Langer R. Responsive polymeric delivery systems. Adv. Drug Deliv. Rev. 2001; 46(1--3):
125–48. [PubMed: 11259837] One of the earliest and most cited contributions on drug delivery
systems that respond to environmental conditions
38. Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur.
J. Pharm. Biopharm. 2000; 50(1):27–46. [PubMed: 10840191] An important review on the use of
hydrogels in pharmaceutical applications
39. Lowman AM, Morishita M, Kajita M, Nagai T, Peppas NA. Oral delivery of insulin using pH-
responsive complexation gels. J. Pharm. Sci. 1999; 88(9):933–37. [PubMed: 10479357]
40. Torres-Lugo M, Peppas NA. Molecular design and in vitro studies of novel pH-sensitive hydrogels
for the oral delivery of calcitonin. Macromolecules. 1999; 32(20):6646–51.

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 21

41. Kamei N, Morishita M, Chiba H, Kavimandan NJ, Peppas NA, Takayama K. Complexation
hydrogels for intestinal delivery of interferon β and calcitonin. J. Control. Release. 2009; 134(2):
98–102. [PubMed: 19095021]
NIH-PA Author Manuscript

42. Alexandridis P, Holzwarth JF, Hatton TA. Micellization of poly(ethylene oxide)-poly(propylene

oxide)-poly(ethylene oxide) triblock copolymers in aqueous solutions: thermodynamics of
copolymer association. Macromolecules. 1994; 27(9):2414–25.
43. Boussif O, Lezoualc'h F, Zanta MA, Hergny MD, Scherman D, et al. A versatile vector for gene
and oligonucleotide transfer into cells in culture and in-vivo--polyethyleneimine. Proc. Natl. Acad.
Sci. USA. 1995; 92(16):7297–301. [PubMed: 7638184]
44. Mok H, Park TG. Functional polymers for targeted delivery of nucleic acid drugs. Macromol.
Biosci. 2009; 9(8):731–43. [PubMed: 19655399]
45. Gosselin MA, Guo WJ, Lee RJ. Efficient gene transfer using reversibly cross-linked low molecular
weight polyethylenimine. Bioconjug. Chem. 2001; 12(6):989–94. [PubMed: 11716690]
46. Godbey WT, Wu KK, Mikos AG. Size matters: molecular weight affects the efficiency of
poly(ethylenimine) as a gene delivery vehicle. J. Biomed. Mater. Res. 1999; 45(3):268–75.
[PubMed: 10397985]
47. Tanaka T. Collapse of gels and critical endpoint. Phys. Rev. Lett. 1978; 40(12):820–23.Important
work on swelling and syneresis in gels; it laid the foundation for the development of novel
temperature-sensitive drug delivery systems
48. Duscaronek K, Patterson D. Transition in swollen polymer networks induced by intramolecular
condensation. J. Polym. Sci. Part A. 1968; 6(7):1209–16.
NIH-PA Author Manuscript

49. Heskins M, Guillet JE. Solution properties of poly(N-isopropylacrylamide). J. Macromol. Sci. Pure
Appl. Chem. 1968; 2(8):1441–55.
50. Bae YH, Okano T, Kim SW. Temperature-dependence of swelling of cross-linked poly(N,N'-alkyl
substituted acrylamides) in water. J. Polym. Sci. Part B. 1990; 28(6):923–36.
51. Shibayama M, Tanaka T. Volume phase-transition and related phenomena of polymer gels. Adv.
Polym. Sci. 1993; 109:1–62.
52. Kopecek J. Smart and genetically engineered biomaterials and drug delivery systems. Eur. J.
Pharm. Sci. 2003; 20(1):1–16. [PubMed: 13678788]
53. Inomata H, Goto S, Saito S. Phase-transition of N-substituted acrylamide gels. Macromolecules.
1990; 23(22):4887–88.
54. Katono H, Maruyama A, Sanui K, Ogata N, Okano T, Sakurai Y. Thermoresponsive swelling and
drug release switching of interpenetrating polymer networks composed pf poly(acrylamide-co-
butyl methacrylate) and poly(acrylic-acid). J. Control. Release. 1991; 16(1--2):215–27.
55. Klouda L, Mikos AG. Thermoresponsive hydrogels in biomedical applications. Eur. J. Pharm.
Biopharm. 2008; 68(1):34–45. [PubMed: 17881200]
56. Bhattarai N, Ramay HR, Gunn J, Matsen FA, Zhang M. PEG-grafted chitosan as an injectable
thermosensitive hydrogel for sustained protein release. J. Control. Release. 2005; 103(3):609–24.
[PubMed: 15820408]
NIH-PA Author Manuscript

57. De P, Gondi SR, Sumerlin BS. Folate-conjugated thermoresponsive block copolymers: highly
efficient conjugation and solution self-assembly. Biomacromolecules. 2008; 9(3):1064–70.
[PubMed: 18288803]
58. Mukherjee S, Ghosh RN, Maxfield FR. Endocytosis. Physiol. Rev. 1997; 77(3):759–803.
[PubMed: 9234965]
59. Mellman I. Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 1996; 12:575–625.
[PubMed: 8970738]
60. Vaupel P, Kallinowski F, Okunieff P. Blood-flow, oxygen and nutrient supply, and metabolic
microenvironment of human-tumors: a review. Cancer Res. 1989; 49(23):6449–65. [PubMed:
2684393]
61. Fisher OZ, Peppas NA. Polybasic nanomatrices prepared by UV-initiated photopolymerization.
Macromolecules. 2009; 42(9):3391–98. [PubMed: 20526378]
62. Fisher O, Kim T, Dietz SR, Peppas NA. Enhanced core hydrophobicity, functionalization and cell
penetration of polybasic nanomatrices. Pharm. Res. 2009; 26(1):51–60. [PubMed: 18751960]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 22

63. Hu Y, Litwin T, Nagaraja AR, Kwong B, Katz J, et al. Cytosolic delivery of membrane-
impermeable molecules in dendritic cells using pH-responsive core-shell nanoparticles. Nano Lett.
2007; 7(10):3056–64. [PubMed: 17887715]
NIH-PA Author Manuscript

64. Hu Y, Atukorale PU, Lu JJ, Moon JJ, Um SH, et al. Cytosolic delivery mediated via electrostatic
surface binding of protein, virus, or siRNA cargos to pH-responsive core-shell gel particles.
Biomacromolecules. 2009; 10(4):756–65. [PubMed: 19239276]
65. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric
nanoparticles. Int. J. Pharm. 2006; 307(1):93–102. [PubMed: 16303268] Excellent review
highlighting the opsonization and biodistribution of polymeric nanoparticles
66. Lee ES, Na K, Bae YH. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of
resistant MCF-7 tumor. J. Control. Release. 2005; 103(2):405–18. [PubMed: 15763623]
67. Lee ES, Gao Z, Kim D, Park K, Kwan IC, Bae YH. Super pH-sensitive multifunctional polymeric
micelle for tumor pHe specific TAT exposure and multidrug resistance. J. Control. Release. 2008;
129(3):228–36. [PubMed: 18539355]
68. Lee ES, Na K, Bae YH. Super pH-sensitive multifunctional polymeric micelle. Nano Lett. 2005;
5(2):325–29. [PubMed: 15794620]
69. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in
cancer therapeutics. Adv. Drug Deliv. Rev. 2008; 60(15):1615–26. [PubMed: 18840489]
70. Guelen L, Paterson H, Gäken J, Meyers M, Farzaneh F, Tavassoli M. TAT-apoptin is efficiently
delivered and induces apoptosis in cancer cells. Oncogene. 2003; 23(5):1153–65. [PubMed:
14691460]
NIH-PA Author Manuscript

71. Sethuraman VA, Bae YH. TAT peptide-based micelle system for potential active targeting of anti-
cancer agents to acidic solid tumors. J. Control. Release. 2007; 118(2):216–24. [PubMed:
17239466]
72. Mathiowitz E, Jacob JS, Jong YS, Carino GP, Chickering DE, et al. Biologically erodable
microspheres as potential oral drug delivery systems. Nature. 1997; 386(6623):410–14. [PubMed:
9121559] This contribution was the first serious effort to use biodegrable microparticles for oral
delivery of proteins and DNA
73. Leong KW, Brott BC, Langer R. Bioerodible polyanhydrides as drug-carrier matrices. I:
Characterization, degradation, and release characteristics. J. Biomed. Mater. Res. 1985; 19(8):
941–55. [PubMed: 3880353]
74. Cohen S, Yoshioka T, Lucarelli M, Hwang LH, Langer R. Controlled delivery systems for proteins
based on poly(lactic/glycolic acid) microspheres. Pharm. Res. 1991; 8(6):713–20. [PubMed:
2062800]
75. Shenoy D, Little S, Langer R, Amiji M. Poly(ethylene oxide)-modified poly(β-amino ester)
nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In
vitro evaluations. Mol. Pharm. 2005; 2(5):357–66. [PubMed: 16196488]
76. Shenoy D, Little S, Langer R, Amiji M. Poly(ethylene oxide)-modified poly(β-amino ester)
nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: Part 2. In
vivo distribution and tumor localization studies. Pharm. Res. 2005; 22(12):2107–14. [PubMed:
NIH-PA Author Manuscript

16254763]
77. Cerritelli S, Velluto D, Hubbell JA. PEG-SS-PPS: reduction-sensitive disulfide block copolymer
vesicles for intracellular drug delivery. Biomacromolecules. 2007; 8(6):1966–72. [PubMed:
17497921]
78. Oh JK, Siegart DJ, Lee H, Sherwood G, Peteanu L, et al. Biodegradable nanogels prepared by
atom transfer radical polymerization as potential drug delivery carriers: synthesis, biodegradation,
in vitro release, and bioconjugation. J. Am. Chem. Soc. 2007; 129(18):5939–45. [PubMed:
17439215]
79. Matsumoto S, Christie RJ, Nishiyama N, Miyata K, Ishii A, et al. Environment-responsive block
copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery.
Biomacromolecules. 2009; 10(1):119–27. [PubMed: 19061333]
80. Dufresne MH, Elsabahy M, Leroux JC. Characterization of polyion complex micelles designed to
address the challenges of oligonucleotide delivery. Pharm. Res. 2008; 25(9):2083–93. [PubMed:
18452054]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 23

81. Davis ME, Chen Z, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for
cancer. Nat. Rev. Drug Discov. 2008; 7(9):771–82. [PubMed: 18758474]
82. Duncan R. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2003; 2(5):347–60.
NIH-PA Author Manuscript

[PubMed: 12750738] An elegant and extensive overview of the area of polymer therapeutics
83. Duncan R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer. 2006; 6(9):688–
701. [PubMed: 16900224]
84. Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv. Drug
Deliv. Rev. 2002; 54(4):459–76. [PubMed: 12052709]
85. Vicent MJ, Dieudonné L, Carbajo RJ, Pineda-Lucena A. Polymer conjugates as therapeutics:
future trends, challenges and opportunities. Expert Opin. Drug Deliv. 2008; 5(5):593–614.
[PubMed: 18491984]
86. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy:
mechanism of tumortropic accumulation of proteins and the antitumor agent Smancs. Cancer Res.
1986; 46(12):6387–92. [PubMed: 2946403] Landmark study reporting for the first time the
significance of passive tumor targeting via the EPR effect by macromolecules
87. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat. Rev. Cancer. 2006; 6(8):583–
92. [PubMed: 16862189]
88. Pasut G, Veronese FM. Polymer-drug conjugation, recent achievements and general strategies.
Prog. Polym. Sci. 2007; 32:933–61.
89. Heredia KL, Maynard HD. Synthesis of protein-polymer conjugates. Org. Biomol. Chem. 2007;
5(1):45–53. [PubMed: 17164904]
NIH-PA Author Manuscript

90. Bontempo D, Maynard HD. Streptavidin as a macroinitiator for polymerization: in situ protein-
polymer conjugate formation. J. Am. Chem. Soc. 2005; 127(18):6508–509. [PubMed: 15869252]
91. Boyer C, Bulmus V, Liu J, Davis TP, Stenzel MH, Barner-Kowollik C. Well-defined protein-
polymer conjugates via in situ RAFT polymerization. J. Am. Chem. Soc. 2007; 129(22):7145–54.
[PubMed: 17500523]
92. Brocchini, S.; Duncan, R. Pendant drugs, release from polymers. In: Mathiowitz, E., editor.
Encyclopedia of Controlled Drug Delivery. Wiley; New York: 1999. p. 786-816.
93. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2003; 2(3):
214–21. [PubMed: 12612647]
94. Ringsdorf H. Structure and properties of pharmacologically active polymers. J. Polymer Sci. Part
C. 1975; 51(1):135–53.A milestone paper that inspired the field of polymer-anticancer conjugates
95. Duncan R, Kopecek J. Soluble synthetic-polymers as potential drug carriers. Adv. Polym. Sci.
1984; 57:51–101.
96. Duncan R, Lloyd JB, Kopecek J. Degradation of side-chains of N-(2-hydroxypropyl)
methacrylamide copolymers by lysosomal enzymes. Biochem. Biophys. Res. Commun. 1980;
94(1):284–90. [PubMed: 7387696]
97. Khandare J, Minko T. Polymer-drug conjugates: progress in polymeric prodrugs. Prog. Polym. Sci.
2006; 31(4):359–97.
NIH-PA Author Manuscript

98. Kopeček J, Kopečková P, Minko T, Lu Z-R. HPMA copolymer-anticancer drug conjugates:

design, activity, and mechanism of action. Eur. J. Pharm. Biopharm. 2000; 50(1):61–81. [PubMed:
10840193]
99. Satchi-Fainaro R, Puder M, Davies JW, Tran HT, Sampson DA, et al. Targeting angiogenesis with
a conjugate of HPMA copolymer and TNP-470. Nat. Med. 2004; 10(3):255–61. [PubMed:
14981512]
100. Chesler L, Goldenberg DD, Seales IT, Satchi-Fainaro RS, Grimmer M, et al. Malignant
progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma.
Cancer Res. 2007; 67:9435–42. [PubMed: 17909053]
101. Satchi-Fainaro R, Mamluk R, Wang L, Short SM, Nagy JA, et al. Inhibition of vessel
permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell. 2005; 7(3):251–
61. [PubMed: 15766663]
102. Khandare JJ, Jayant S, Singh A, Chandna P, Wang Y, et al. Dendrimer versus linear conjugate:
influence of polymeric architecture on the delivery and anticancer effect of paclitaxel. Bioconjug.
Chem. 2006; 17(6):1464–72. [PubMed: 17105225]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 24

103. Abuchowski A, McCoy JR, Palczuk NC, van Es T, Davis FF. Effect of covalent attachment of
polyethyleneglycol on immunogenicity and circulating life of bovine liver catalase. J. Biol.
Chem. 1977; 252(11):3582–86. [PubMed: 16907]
NIH-PA Author Manuscript

104. Abuchowski A, van Es T, Palczuk NC, Davis FF. Alteration of immunological properties of
bovine serum albumin by covalent attachment of polyethylene glycol. J. Biol. Chem. 1977;
252(11):3578–81. [PubMed: 405385]
105. Veronese FM, Mero A. The impact of PEGylation on biological therapies. Biodrugs. 2008; 22(5):
315–29. [PubMed: 18778113]
106. Duncan R, Gilbert HRP, Carbajo RJ, Vicent MJ. Polymer masked-unmasked protein therapy. 1.
Bioresponsive dextrin-trypsin and -melanocyte stimulating hormone conjugates designed for α-
amylase activation. Biomacromolecules. 9(4):1146–54. [PubMed: 18348531]
107. Nishiyama N, Kataoka K. Current state, achievements, and future prospects of polymeric micelles
as nanocarriers for drug and gene delivery. Pharmacol. Ther. 2006; 112(3):630–48. [PubMed:
16815554]
108. Wiradharma N, Zhang Y, Venkataraman S, Hedrick JL, Yang YY. Self-assembled polymer
nanostructures for delivery of anticancer therapeutics. Nano Today. 2009; 4(4):302–17.
109. Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramolecular
assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular
pH change. Angew. Chem. Int. Ed. 2003; 42(38):4640–43.
110. Bae Y, Nishiyama N, Fukushima S, Koyama H, Yasuhiro M, Kataoka K. Preparation and
biological characterization of polymeric micelle drug carriers with intracellular pH-triggered
NIH-PA Author Manuscript

drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced
in vivo antitumor efficacy. Bioconjug. Chem. 2005; 16(1):122–30. [PubMed: 15656583]
111. Han M, Bae Y, Nishiyama N, Miyata K, Oba M, Kataoka K. Transfection study using
multicellular tumor spheroids for screening non-viral polymeric gene vectors with low
cytotoxicity and high transfection efficiencies. J. Control. Release. 2007; 121(1--2):38–48.
[PubMed: 17582637]
112. Kang SI, Na K, Bae YH. Physicochemical characteristics and doxorubicin-release behaviors of
pH/temperature-sensitive polymeric nanoparticles. Colloids Surf. A. 2003; 231(1--3):103–12.
113. Soppimath KS, Liu L-H, Seow WY, Liu S-Q, Powell R, et al. Multifunctional core/shell
nanoparticles self-assembled from pH-induced thermosensitive polymers for targeted
intracellular anticancer drug delivery. Adv. Funct. Mater. 2007; 17(3):355–62.
114. Bae Y, Jang W-D, Nishiyama N, Fukushima S, Kataoka K. Multifunctional polymeric micelles
with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active
intracellular drug delivery. Mol. Biosyst. 2005; 1(3):242–50. [PubMed: 16880988]
115. Bae Y, Nishiyama N, Kataoka K. In vivo antitumor activity of the folate-conjugated pH-sensitive
polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments.
Bioconjug. Chem. 2007; 18(4):1131–39. [PubMed: 17488066]
116. Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, et al. Distribution of the folate receptor
GP38 in normal and malignant-cell lines and tissues. Cancer Res. 1992; 52(12):3396–401.
NIH-PA Author Manuscript

[PubMed: 1596899]
117. Greco F, Vicent MJ, Gee S, Jones AT, Gee J, et al. Investigating the mechanism of enhanced
cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells. J. Control. Release. 2007;
117(1):28–39. [PubMed: 17129632]
118. Greco F, Vicent MJ, Penning NA, Nicholson RI, Duncan R. HPMA copolymer-
aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines. J. Drug Target. 2005;
13(8--9):459–70. [PubMed: 16332571]
119. Lammers T, Subr V, Ulbrich K, Peschke P, Huber PE, et al. Simultaneous delivery of
doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers.
Biomaterials. 2009; 30(20):3466–75. [PubMed: 19304320]
120. Hilt JZ, Byrne ME. Configurational biomimesis in drug delivery: molecular imprinting of
biologically significant molecules. Adv. Drug Deliv. Rev. 2004; 56(11):1599–620. [PubMed:
15350291]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 25

121. Kryscio DR, Peppas NA. Mimicking biological delivery through feedback-controlled drug release
systems based on molecular imprinting. AIChE J. 2009; 55(6):1311–24.Excellent review of
recent advances of feedback controlled release systems
NIH-PA Author Manuscript

122. Alvarez-Lorenzo C, Concheiro A. Molecularly imprinted polymers for drug delivery. J.

Chromatogr. B. 2004; 804(1):231–45.
123. Ali M, Byrne ME. Controlled release of high molecular weight hyaluronic acid from molecularly
imprinted hydrogel contact lenses. Pharm. Res. 2009; 26(3):714–26. [PubMed: 19156504]
124. Ali M, Horikawa S, Venkatesh S, Saha J, Hong JW, Byrne ME. Zero-order therapeutic release
from imprinted hydrogel contact lenses within in vitro physiological ocular tear flow. J. Control.
Release. 2007; 124(3):154–62. [PubMed: 17964678]
125. Alvarez-Lorenzo C, Hiratani H, Gómez-Amoza JL, Martínez-Pacheco R, Souto C, Conchiero A.
Soft contact lenses capable of sustained delivery of timolol. J. Pharm. Sci. 2002; 91(10):2182–92.
[PubMed: 12226845]
126. Hiratani H, Alvarez-Lorenzo C. Timolol uptake and release by imprinted soft contact lenses made
of N,N-diethylacrylamide and methacrylic acid. J. Control. Release. 2002; 83(2):223–30.
[PubMed: 12363448]
127. Hiratani H, Alvarez-Lorenzo C. The nature of backbone monomers determines the performance
of imprinted soft contact lenses as timolol drug delivery systems. Biomaterials. 2004; 25(6):
1105–13. [PubMed: 14615176]
128. Hiratani H, Fujiwara A, Tamiya Y, Mizutani Y, Alvarez-Lorenzo C. Ocular release of timolol
from molecularly imprinted soft contact lenses. Biomaterials. 2005; 26(11):1293–98. [PubMed:
NIH-PA Author Manuscript

15475059]
129. Venkatesh S, Sizemore SP, Byrne ME. Biomimetic hydrogels for enhanced loading and extended
release of ocular therapeutics. Biomaterials. 2007; 28(4):717–24. [PubMed: 17007923]
130. Venkatesh S, Saha J, Pass S, Byrne ME. Transport and structural analysis of molecular imprinted
hydrogels for controlled drug delivery. Eur. J. Pharm. Biopharm. 2008; 69(3):852–60. [PubMed:
18502630]
131. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene
delivery. Nat. Rev. Drug Discov. 2005; 4(7):581–93. [PubMed: 16052241]
132. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery.
Nat. Rev. Drug Discov. 2009; 8(2):129–38. [PubMed: 19180106]
133. Verma A, Uzun O, Hu Y, Hu Y, Han H-S, et al. Surface-structure-regulated cell-membrane
penetration by monolayer-protected nanoparticles. Nat. Mater. 2008; 7(7):588–95. [PubMed:
18500347]
134. Yessine M-A, Leroux J-C. Membrane-destabilizing polyanions: interaction with lipid bilayers and
endosomal escape of biomacromolecules. Adv. Drug Deliv. Rev. 2004; 56:999–1021. [PubMed:
15066757]
135. Kurisawa M, Yokoyama M, Okano T. Transfection efficiency increases by incorporating
hydrophobic monomer units into polymeric gene carriers. J. Control. Release. 2000; 68(1):1–8.
[PubMed: 10884574]
NIH-PA Author Manuscript

136. Lackey CA, Press OW, Hoffman AS, Stayton PS. A biomimetic pH-responsive polymer directs
endosomal release and intracellular delivery of an endocytosed antibody complex. Bioconjug.
Chem. 2002; 13(5):996–1001. [PubMed: 12236781]
137. Murthy N, Robichaud JR, Tirrell DA, Stayton PS, Hoffman AS. The design and synthesis of
polymers for eukaryotic membrane disruption. J. Control. Release. 1999; 61(1--2):137–43.
[PubMed: 10469910]
138. Murthy N, Chang I, Stayton P, Hoffman A. pH-sensitive hemolysis by random copolymers of
alkyl acrylates and acrylic acid. Macromol. Symp. 2001; 172:49–55.
139. Lee ES, Kim D, Youn YS, Oh KT, Bae YH. A virus-mimetic nanogel vehicle. Angew. Chem. Int.
Ed. 2008; 47(13):2418–21.
140. Convertine AJ, Benoit DSW, Duvall CL, Hoffman AS, Stayton PS. Development of a novel
endosomolytic diblock copolymer for siRNA delivery. J. Control. Release. 2009; 133(3):221–29.
[PubMed: 18973780]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 26

141. Chen RJ, Khormaee S, Eccleston ME, Slater NKH. Effect of l-leucine graft content on aqueous
solution behavior and membrane-lytic activity of a pH-responsive pseudopeptide.
Biomacromolecules. 2009; 10(9):2601–608. [PubMed: 19642668]
NIH-PA Author Manuscript

142. Chen R, Khormaee S, Eccleston ME, Slater NKH. The role of hydrophobic amino acid grafts in
the enhancement of membrane-disruptive activity of pH-responsive pseudo-peptides.
Biomaterials. 2009; 30(10):1954–61. [PubMed: 19138797]
143. Chen RJ, Yue Z, Eccleston ME, Slater NKH. Aqueous solution behaviour and membrane
disruptive activity of pH-responsive PEGylated pseudo-peptides and their intracellular
distribution. Biomaterials. 2008; 29(32):4333–40. [PubMed: 18708250]
144. Chen RJ, Yue Z, Eccleston ME, Williams S, Slater NKH. Modulation of cell membrane
disruption by pH-responsive pseudo-peptides through grafting with hydrophilic side chains. J.
Control. Release. 2005; 108(1):63–72. [PubMed: 16139914]
145. Liechty WB, Chen R, Farzaneh F, Tavassoli M, Slater NKH. Synthetic pH-responsive polymers
for protein transduction. Adv. Mater. 2009; 21(38--39):3910–14. [PubMed: 22427722]
146. Owens DE, Eby JK, Jian Y, Peppas NA. Temperature-responsive polymer-gold nanocomposites
as intelligent therapeutic systems. J. Biomed. Mater. Res. Part A. 2007; 83A(3):692–95.
147. Sershen SR, Westcott SL, West JL, Halas NJ. An opto-mechanical nanoshell-polymer composite.
Appl. Phys. B. 2001; 73(4):379–81.
148. Satarkar NS, Hilt JZ. Magnetic hydrogel nanocomposites for remote controlled pulsatile drug
release. J. Control. Release. 2008; 130(3):246–51. [PubMed: 18606201]
149. Arias JL, Gallardo V, Ruiz MA, Delgado AV. Magnetite/poly(alkylcyanoacrylate) (core/shell)
NIH-PA Author Manuscript

nanoparticles as 5-fluorouracil delivery systems for active targeting. Eur. J. Pharm. Biopharm.
2008; 69(1):54–63. [PubMed: 18164927]
150. Mornet S, Vasseur S, Grasset F, Duguet E. Magnetic nanoparticle design for medical diagnosis
and therapy. J. Mater. Chem. 2004; 14(14):2161–75.

RELATED RESOURCES
Mikos, AG.; Murphy, R.; Bernstein, H.; Peppas, NA., editors. Biomaterials for Drug and Cell
Delivery. Mater. Res. Soc.; Pittsburgh, PA: 1994. p. 290
Peppas, NA. Hydrogels in Medicine and Pharmacy, Vol. 3: Properties and Applications. CRC Press;
Boca Raton, FL: 1987. p. 196
Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: from
fundamentals to bionanotechnology. Adv. Mater. 2006; 18:1345–60.
Peppas, NA.; Hoffman, AS.; Kanamori, T.; Tojo, K., editors. Advances in Medical Engineering, Drug
Delivery Systems and Therapeutic Systems. AIChE; New York: 2006. p. 342
Peppas NA, Huang Y, Torres-Lugo M, Ward JH, Zhang J. Physicochemical foundations and structural
design of hydrogels in medicine and biology. Annu. Rev. Biomed. Eng. 2000; 2:9–29. [PubMed:
11701505]
NIH-PA Author Manuscript

Slaughter B, Khurshid S, Fisher OZ, Khademhosseini A, Peppas NA. Hydrogels in regenerative

medicine. Adv. Mater. 2009; 21:3307–29. [PubMed: 20882499]

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 27
NIH-PA Author Manuscript

Figure 1.
Therapeutic band with showing impact of burst release, pulsatile release, and controlled
release relative to effective concentration and toxic concentration.
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 28
NIH-PA Author Manuscript

Figure 2.
Schematic representation of the diffusional boundaries on a microvillus to draining capillary
networks and lacteals
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.
 Liechty et al. Page 29
NIH-PA Author Manuscript
NIH-PA Author Manuscript

Figure 3.
Illustrative examples of responsive behavior. (a) Coil-to-globule transition of linear polymer
chain in solution (b) Responive swelling/deswelling of surface-grafted crosslinked hydrogel
particle (c) Stimuli-responsive micellization of amphiphilic block copolymers
NIH-PA Author Manuscript

Annu Rev Chem Biomol Eng. Author manuscript; available in PMC 2012 September 11.