Pharm Res (2016) 33:2373–2387

DOI 10.1007/s11095-016-1958-5

EXPERT REVIEW

Nanoparticle-Based Medicines: A Review of FDA-Approved

Materials and Clinical Trials to Date
Daniel Bobo 1,2,3,4 & Kye J. Robinson 4,5 & Jiaul Islam 2,4,5 & Kristofer J. Thurecht 1,2,4 &
Simon R. Corrie 1,2,4,5

Received: 19 April 2016 / Accepted: 26 May 2016 / Published online: 14 June 2016
# Springer Science+Business Media New York 2016

ABSTRACT In this review we provide an up to date snap- classify new materials and what additional testing (e.g. safety
shot of nanomedicines either currently approved by the US and toxicity) is required before products become available.
FDA, or in the FDA clinical trials process. We define
nanomedicines as therapeutic or imaging agents which com- KEY WORDS clinical trials . FDA . nanomedicine .
prise a nanoparticle in order to control the biodistribution, nanoparticles . nanopharmaceuticals . nanotherpeutics
enhance the efficacy, or otherwise reduce toxicity of a drug
or biologic. We identified 51 FDA-approved nanomedicines
that met this definition and 77 products in clinical trials, with ABBREVIATIONS
~40% of trials listed in clinicaltrials.gov started in 2014 or CHOP Chemotherapy containing cyclophosmphamide,
2015. While FDA approved materials are heavily weighted doxorubicin, vincristine, and prednisolone
to polymeric, liposomal, and nanocrystal formulations, there CKD Chronic Kidney Disease
is a trend towards the development of more complex materials CMC Critical micelle concentration
comprising micelles, protein-based NPs, and also the emer- cRGDY Cyclic arginine-glycine-aspartic acid
gence of a variety of inorganic and metallic particles in clinical EPR Enhanced permeability and retention
trials. We then provide an overview of the different material IDE Investigational device exemption
categories represented in our search, highlighting IND Investigational New Drug
nanomedicines that have either been recently approved, or MTAs Molecularly targeted agents
are already in clinical trials. We conclude with some comments NABs Albumin bound nanoparticles
on future perspectives for nanomedicines, which we expect to NCL Nanotechnology Characterization Laboratory
include more actively-targeted materials, multi-functional NDA New Drug Application
materials (Btheranostics^) and more complicated materials that NIR Near-infrared
blur the boundaries of traditional material categories. A key NP Nanoparticle
challenge for researchers, industry, and regulators is how to PEG Poly (ethylene glycol)
PLGA Polyactide-co-glycolic acid
* Simon R. Corrie
PPX Poliglumex
[email protected] PSMA Prostate-specific membrane antigen
PTCL Peripheral T-cell lymphomas
1
Centre for Advanced Imaging, University of Queensland, St
Lucia, QLD 4072, Australia
2
Australian Institute for Bioengineering and Nanotechnology, University of INTRODUCTION
Queensland, St Lucia, QLD 4072, Australia
3
School of Medicine, Faculty of Medicine and Biomedical Nanomedicine is an emerging field that combines nanotech-
Sciences, University of Queensland, St Lucia, QLD 4072, Australia nology with pharmaceutical and biomedical sciences, with the
4
ARC Centre of Excellence in Convergent Bio-Nano Science and goal of developing drugs and imaging agents with higher effi-
Technology, Queensland node, St Lucia 4072, QLD, Australia cacy and improved safety and toxicological profiles. Due to
5
Department of Chemical Engineering, Monash their sub-micrometer size and high surface area to volume
University, Clayton, VIC 3800, Australia ratio, these materials show key differences in comparison to
2374 Bobo et al.

bulk materials, including changes in biochemical, magnetic, nanomedicine behavior in vivo, it is clear that size, shape
optical, and electronic properties (1–7). Like traditional and surface chemistry can all affect the potential for
drugs, biologics and devices, pre-market authorization is accumulation and/or cell uptake in different tissues.
regulated by the FDA, and hence nanomedicines are We define nanomedicines to be drugs or biologics that
subject to the usual range of pre-clinical and clinical incorporate nanoparticles (1–100 nm) in order to achieve ei-
validation (8). This review provides a snapshot of the ther improved targeting, reduced toxicity, or otherwise en-
range of materials that have been used to develop spe- hanced efficacy of therapeutic or imaging agents in vivo.
cific FDA-approved therapeutics, along with a descrip- Typically, these are administered orally or intravenously,
tion of key materials that are emerging through the however examples of transdermal delivery also exist (e.g.
clinical trials pipeline. This is a rapidly evolving field; Estrasorb™). Most commonly, nanoparticles are conjugated
in just 3 years, the number of clinical trials involving to existing drugs in order to change the pharmacokinetic and/
nano-sized components has increased 3-fold, based on a or the pharmacodynamic properties in order to bring about
set of search criteria employed in a review published by these improvements. In the majority of cases, these
Etheridge, et al., in 2013 (9). nanoparticle/drug conjugates achieve their effects through
Interactions of nanomedicines with their biological sur- passive targeting, which relies on non-specific accumulation
roundings (at the level of molecules, cells, organs, etc.) is de- in diseased tissue (usually tumors). This approach has been
pendent on a complex interplay between the controllable used to target solid tumors, since the increased permeability
properties of the particles and the largely uncontrollable prop- of blood vessels in combination with poor lymphatic drainage
erties of the surrounding media. Particle size, shape, and sur- or transport (the so-called enhanced permeability and reten-
face chemistry are key factors that determine performance tion (EPR) effect) leads to accumulation of nanomedicines
criteria, including the degree of protein adsorption, cellular within the tumor microenvironment (16). Targeting specific
uptake, biodistribution patterns, and clearance mechanisms cells that over-express certain cell-surface receptors can also
(for a detailed review, see Nel, et al., 2009 (10)). Particle size be achieved by immobilizing ligands (e.g. proteins, antibodies,
plays a key role in clearance of these materials from the body, small molecules) to the surface of the nanoparticle, leading to
with small particles (<10 nm) being cleared via the kidneys, active targeting which results in accumulation followed by
and larger particles (>10 nm) being cleared through the liver specific uptake of the nanomedicine into the tissue of interest
and the mononuclear-phagocyte system (MPS) (11–14). The (e.g. tumors). To date only one of the active targeting
desired clearance mechanism can be a factor in the design of nanomedicines, Ontak®, has been FDA approved (the excep-
the nanomedicine; e.g. selecting small, actively targeted parti- tion being the antibody-drug conjugates, which do not contain
cles that are rapidly cleared if they are not taken up into the bespoke nanoparticles and thus are beyond the scope of this
target organ after first-pass distribution. This might be an review; for a full review see Casi & Neri, 2012 as well as
important factor when designing molecular imaging agents, Diamantis & Banerji, 2016 (17,18)).
for example, where minimal background signal is desirable. In Currently, the approval process for nanomedicines in
contrast, it is typically considered favorable for drug-delivery humans is regulated by the Food and Drug Administration
vehicles to circulate for longer times, allowing greater accu- (FDA) in the USA, and is essentially the same as that for any
mulation in the disease site. When nanoparticles are exposed other regulated drug, device or biologic (for a detailed review,
to the biological milieu, the process of non-specific protein see Eifler & Thaxton, 2011 (8)). The entire process is estimat-
adsorption results in the formation of a protein corona around ed to take ~10–15 years and approximately $1 billion per
the material. It appears practically impossible to completely new drug. Following the discovery/invention of the ma-
avoid the formation of this protein layer (15), however its terial, the pre-clinical phase of testing usually involves
composition can be altered through the addition of low- animal studies to demonstrate efficacy, safety, toxicity
fouling polymer coatings on the particle surface (e.g. polyeth- profile, and to identify appropriate dose ranges. For
ylene glycol (PEG)). Such coatings lead to the formation nanomedicines it is becoming increasingly important to
of hydration shells at the solid/liquid interface which have a comprehensive understanding of the physico-
minimizes the passage of protein molecules, leading to chemical parameters of the material, and the reproduc-
protein repulsion. The main issue associated with pro- ibility and scalability of the manufacturing process.
tein adsorption is the subsequent denaturing of the pro- Publications from the Nanotechnology Characterization
tein, leading to a signaling cascade that results in either Laboratory (NCL; established by the National Cancer
aggregation of the nanoparticles and/or phagocytosis via Institute) are available to guide this process, and researchers
activated macrophages. This in turn results in non-ideal have the option to send material for testing and validation at
biodistribution and unpredictable pharmacokinetics of the NCL according to a series of emerging protocols (19–21).
the nanomaterial. While researchers are still developing However, significant research is still required to understand
universal design criteria that lead to predictable and predict how these materials will behave in biological
Nanomedicines - Approved Products and Clinical Trials 2375

systems, including the development of new assays and readout Trends in FDA-Approved Nanomedicines and Clinical
methods that are not confounded by the presence of the nano- Trials
particle component. The issue of nanomaterial characteriza-
tion is at the heart of several guidance documents issued by the Figure 1a/b shows that an average of ~13 nanomedicines
FDA in the past several years, hence it is a particularly impor- have been approved for specific clinical indications per 5-
tant aspect of research and development. The efficacy, toxic- year period since the mid-1990s. This includes approval for
ity, and physicochemical properties can then be compiled into both novel materials (51 unique products) along with the use
an Investigational New Drug (IND) application for FDA con- of approved materials for new clinical indications (e.g.
sideration. Upon approval of the IND, human trials can be Abraxane® has been approved for several different indica-
initiated to determine the safety and efficacy of the new tions). The list is dominated by liposomal and polymeric nano-
nanomedicine. This process is broken into Phase I (dosing, particles, which accounted for the majority of nanomedicines
toxicity, excretion in healthy subjects), Phase II (safety, efficacy approved in the 1990s. Approvals appeared to peak in the
in a larger group of patients with the target illness), and Phase 2001–2005 time period, with a subsequent drop leading up
III (multi-center, randomized, placebo-controlled) trials, after to 2008, a trend that may be related to funding limitations
which a New Drug Application (NDA) can be filed with the associated with the global financial crisis of 2008 (27,28). The
FDA requesting approval for marketing purposes. Further clinical trials data in Fig. 1c/d shows some interesting trends in
Bpost-marketing^ (Phase IV) studies are also often undertaken comparison to those for FDA approvals. Firstly, the number of
at the request of the FDA, clinicians, or other groups, based on nanomedicines which have been granted IND approval to
specific questions raised during the Phase III trials. undertake clinical trials has increased steadily since ~2007.
In this review, we aim to provide a Bsnapshot^ of the 2014 and 2015 were the best years to date, suggesting that
nanomedicines that have been FDA approved, a compar- the pipeline for FDA-approved products is healthy. In terms
ison of the different materials commonly employed, and of the material categories under consideration, there are sig-
to highlight some examples of topical nanomedicines that nificantly more micellar, metallic and protein-based particles
have been granted IND approval for clinical trials. coming through the development process in comparison to
Importantly, our definition of nanomedicines excludes what has previously been approved. However, this does not
several classes of closely-related drugs and biologics, in- mean that polymeric particles and liposomes are necessarily
cluding those involved in composites for bone regenera- out of favor. Indeed, most of the micelle and liposome systems
tion or dental implants, immunotherapies, vaccines, being developed incorporate polymers as synthetic building
and adjuvants (e.g. Gardasil®, Cervarix® and MF59®), blocks (29), while the protein-based systems may also have a
antibody-drug conjugates (e.g. Kadcyla® and Adcetris®) synthetic polymer component.
and those observational trials in which endogenous par-
ticles are identified as part of a disease process (e.g. Key Examples of Nanomedicines by Material Category
NCT02549248) (22). The data we present on clinical trials
in Fig. 1 was extracted from the clinicaltrials.gov website Polymeric Nanoparticles
in February 2016 using search terms centered around
Bnano^. Compliance with US law (FDAAA 801) re- Polymeric nanoparticles are perhaps the simplest form of soft-
quires sponsors to provide entries into this database materials for nanomedicine applications owing to their facile
for any interventional trials conducted that involve synthesis and wide applicability across all aspects of the field.
FDA-regulated drugs, biologics, or devices, initiated un- Polymer utility in enhancing therapeutic and diagnostic ad-
der an IND or investigational device exemption (IDE) vantages over conventional medicines is evidenced by their
after September 27, 2007, or with a completion date prevalence in Table I, and continuing investigations in clinical
after December 26, 2007 (23). It is therefore possible trials. Indeed, two of the top 10 best-selling drugs in the US in
that trials conducted prior to 2007, or outside of the 2013 were polymeric drugs (Copaxone® and Neulasta® (30)).
US and FDA regulatory system are not included here; Polymer nanomedines usually fall into one of two categories:
however after cross-checking with the World Health (a) polymer-drug conjugates for increased drug half-life and
Organization’s International Clinical Trials Registry bioavailability, and (b) degradable polymer architectures for
Platform (ICTRP) and previous reviews in this area controlled release applications. However, it should be noted
(8,9,24–26), we confirmed that that the vast majority that aspects of polymer chemistry are emerging in nearly all of
of trials we identified were present in both resources. the categories, because many of the components required (e.g.
A comparison between those nanomedicines currently amphiphilic block copolymers) can be designed and controlled
approved and those in trials provides insights on how through organic synthesis methods. The polymers themselves
this field is changing and what products might be ex- include those that are synthetic, pseudo-synthetic or those that
pected in the near future. arise from natural sources. Their application has spanned the
2376 Bobo et al.

Fig. 1 Trends in the development

of nanomedicines. (a) FDA-
approved nanomedicines stratified
by category; (b) FDA-approved
nanomedicines stratified by
category overall; (c) clinical trials
identified in clinicaltrials.gov from
2001 to 2015 with arrow indicating
approximate start date of US law
(FDAAA 801) requiring reporting to
FDA database; (d) nanomedicines
under clinical trial investigation
stratified by category overall.

full nanomaterial size-scale, from single polymer chains up to the therapeutic protein improved biological half-life and ex-
large aggregates, depending on the required therapeutic posure in comparison to the protein alone (34). In comparison
outcome. to Copaxone® and other IFN-based MS treatments which
The most basic class of polymeric nanomedicines is utiliza- are often administered daily, PLEGRIDY® can be adminis-
tion of single polymer chains either directly as the therapeutic, tered every 2–4 weeks. In 2015, PEGylated anti-hemophilic
or as a modifying agent for a drug or diagnostic agent. As factor VIII (ADYNOVATE) was approved for treatment of
direct drugs, there are a number of examples of both FDA- hemophilia A, both in terms of preventing bleeding episodes,
approved products and those under clinical trial. The best or treating acute bleeding. Based on the increased half-life of
example is Copaxone® (glatiramer acetate), which is a ran- this drug in comparison to non-PEGylated factor VIII, there is
dom copolymer composed of L-glutamic acid, L-alanine, L- also hope that the need for less frequent administration may
lysine and L-tyrosine (31). Initially approved in 1996, reduce the incidence of anti-factor VIII antibody generation,
Copaxone® was a revolutionary treatment that acted as an which affects up to 30% of patients (for most biologics, anti-
immunomodulator in the treatment of multiple sclerosis. drug antibody generation occurs in <5% of patients) and leads
More frequently in terms of polymeric nanomedicines, drugs to reduced drug efficacy (35). There are also a large number of
are attached to a hydrophilic polymer to increase circulation polymer-immobilized nanomedicines that are under Phase II
or improve biocompatibility/solubility (32). The most well- or III investigation in clinical trials. By way of example,
established polymer is poly (ethylene glycol) (PEG). Such sys- NKTR-102 is a PEGylated etirinotecan drug, that has ex-
tems include the extremely popular and successful drug tended into Phase III clinical trials (36). The trial showed that
Neulasta® (PEGylated granulocyte colony stimulating factor), extended exposure of tumor cells to the topoisomerase-I in-
which has been FDA-approved since 2002 for chemotherapy- hibitor typically showed enhanced therapeutic response – this
induced neutropenia. In this case, PEGylation resulted in a is attributed to the longer circulation of PEGylated
significant increase in biological half-life in plasma (15–80 h nanomaterials. In addition to PEGylation, other hydrophiles
compared to only 3–4 for the basic filgrastim (33)). More re- can be utilized to increase circulation. A Polymer-drug conju-
cently, the FDA has approved 2 new PEGylated biologic gate of paclitaxel and polyglutamic acide (poliglumex (PPX))
drugs. In 2014, PEGylated interferon gamma beta-1a has entered phase III trials and is showing significantly im-
(PEGylated IFN beta-1a; PLEGRIDY®) was approved for proved standard of living for patients who undergo paclitaxel
treatment of relapsing multiple sclerosis. Addition of PEG to therapy for non-small cell lung cancer (37). This exemplifies
Nanomedicines - Approved Products and Clinical Trials 2377

Table I List of FDA-Approved Nanomedicines Stratified by Material Category

Name Material Description Nanoparticle Advantage Indication(s) Year(s)

approved

Polymer Nanoparticles – synthetic polymer particles combined with drugs or biologics

Adagen®/pegademase PEGylated adenosine Improve circulation time and Severe combined 1990
bovine (Sigma-Tau deaminase enzyme decreased immunogenicity immunodeficiency
Pharmaceuticals) disease (SCID)
Cimzia®/certolizumab pegol PEGylated antibody fragment Improved circulation time and Crohn’s disease 2008
(UCB) (Certolizumab) greater stability in vivo. Rheumatoid arthritis 2009
Psoriatic Arthritis 2013
Ankylosing Spondylitis 2013
Copaxone®/Glatopa (Teva) Random copolymer of Large amino-acid based Multiple Sclerosis (MS) 1996
L-glutamate, L-alanine, polymer with controlled
L-lysine and L-tyrosine molecular weight and
clearance characteristics
Eligard® (Tolmar) Leuprolide acetate and polymer Controlled delivery of payload Prostate Cancer 2002
(PLGH (poly (DL-Lactide-co- with longer circulation time
glycolide))
Macugen®/Pegaptanib PEGylated anti-VEGF aptamer Improved stability of aptamer as Macular degeneration, 2004
(Bausch & Lomb) (vascular endothelial growth a result of PEGylation neovacular age-related
factor) aptamer
Mircera®/Methoxy Chemically synthesized ESA Improved stability of aptamer as Anemia associated with 2007
polyethylene glycol-epoetin (erythropoiesis-stimulating a result of PEGylation chronic kidney disease
beta (Hoffman-La Roche) agent)
Neulasta®/pegfilgrastim PEGylated GCSF protein Improved stability of protein Neutropenia, 2002
(Amgen) through PEGylation Chemotherapy
induced
Pegasys® (Genentech) PEGylated IFN alpha-2a protein Improved stability of protein Hepatitis B; Hepatitis C 2002
through PEGylation
PegIntron® (Merck) PEGylated IFN alpha-2b protein Improved stability of protein Hepatitis C 2001
through PEGylation
Renagel®[sevelamer Poly(allylamine hydrochloride) Increase circulation and Chronic kidney disease 2000
hydrochloride]/ therapeutic delivery
Renagel®[sevelamer
carbonate] (Sanofi)
Somavert®/pegvisomant PEGylated HGH receptor Improved stability of protein Acromegaly 2003
(Pfizer) antagonist through PEGylation
Oncaspar®/pegaspargase Polymer-protein conjugate Improved stability of protein Acute lymphoblastic 1994
(Enzon Pharmaceuticals) (PEGylated L-asparaginase) through PEGylation leukemia
Krystexxa®/pegloticase Polymer-protein conjugate Improved stability of protein Chronic gout 2010
(Horizon) (PEGylated porcine-like uricase) through PEGylation;
introduction of unique
mammalian protein
Plegridy® (Biogen) Polymer-protein conjugate Improved stability of protein Multple Sclerosis 2014
(PEGylated IFN beta-1a) through PEGylation
ADYNOVATE (Baxalta) Polymer-protein conjugate Improved stability of protein Hemophilia 2015
(PEGylated factor VIII) through PEGylation
Liposome formulations combined with drugs or biologics
DaunoXome® (Galen) Liposomal Daunorubicin Increased delivery to tumour Karposi’s Sarcoma 1996
site; lower systemic toxicity
arising from side-effects
DepoCyt© (Sigma-Tau) Liposomal Cytarabine Increased delivery to tumour Lymphomatous 1996
site; lower systemic toxicity meningitis
arising from side-effects
Marqibo® (Onco TCS) Liposomal Vincristine Increased delivery to tumour Acute Lymphoblastic 2012
site; lower systemic toxicity Leukemia
arising from side-effects
Onivyde® (Merrimack) Liposomal Irinotecan Increased delivery to tumour Pancreatic Cancer 2015
site; lower systemic toxicity
arising from side-effects
AmBisome® (Gilead Liposomal Amphotericin B Reduced nephrotoxicity Fungal/protozoal 1997
Sciences) infections
Liposomal Morphine sulphate Extended release Analgesia (post-operative) 2004
2378 Bobo et al.

Table I (continued)

Name Material Description Nanoparticle Advantage Indication(s) Year(s)

approved

DepoDur® (Pacira
Pharmaceuticals)
Visudyne® (Bausch and Liposomal Verteporfin Increased delivery to site of Macular degeneration, 2000
Lomb) diseased vessels; wet age-related;
photosensitive release myopia; ocular
histoplasmosis
Doxil®/Caelyx™ (Janssen) Liposomal doxorubicin Improved delivery to site of Karposi’s Sarcoma; 1995
disease; decrease in systemic Ovarian cancer; 2005
toxicity of free drug. multiple myeloma 2008
Abelcet® (Sigma-tau) Liposomal Amphotericin B lipid Reduced toxicity Fungal infections 1995
complex
Curosurf®/Poractant alpha Liposome-proteins SP-B and Increased delivery for smaller pulmonary surfactant for 1999
(Chiesei farmaceutici) SP-C volume; reduced doxicity Respiratory Distress
Syndrome
Micellar nanoparticles combined with drugs or biologics
Estrasorb™ (Novavax) Micellar Estradiol Controlled delivery of Menopausal therapy 2003
therapeutic
Protein nanoparticles combined with drugs or biologics
Abraxane®/ABI-007 Albumin-bound paclitaxel Improved solubility; improved Breast cancer 2005
(Celgene) nanoparticles delivery to tumor NSCLC 2012
Pancreatic cancer 2013
Ontak® (Eisai Inc) Engineered Protein combining Targeted T-cell specificity; Cutaneous T-Cell 1999
IL-2 and diphtheria toxin lysosomal escape Lymphoma
Nanocrystals
Emend® (Merck) Aprepitant Surface area allows faster Antiemetic 2003
absorption and increases
bioavailability
Tricor® (Lupin Atlantis) Fenofibrate Increases bioavailability simplifies Hyperlipidemia 2004
administration
Rapamune® (Wyeth Sirolimus Increased bioavalibility Immunosuppresent 2000
Pharmaceuticals)
Megace ES® (Par Megestrol acetate Reduced dosing Anti-anorexic 2001
Pharmaceuticals)
Avinza® (Pfizer) Morphine sulfate Increased drug loading and Psychostimulant 2002
bioavailability; extended (2015)
release
Focalin XR® (Novartis) Dexamethyl-phenidate HCl Increased drug loading and Psychostimulant 2005
bioavailability
Ritalin LA® (Novartis) Metyhlphenidate HCl Increased drug loading and Psychostimulant 2002
bioavailability
Zanaflex® (Acorda) Tizanidine HCl Increased drug loading and Muscle relaxant 2002
bioavailability
Vitoss® (Stryker) Calcium phosphate Mimics bone structure allowing Bone substitute 2003
cell adhesion and growth
Ostim® (Heraseus Kulzer) Hydroxyapatite Mimics bone structure allowing Bone substitute 2004
cell adhesion and growth
OsSatura® (IsoTis Hydroxyapatite Mimics bone structure allowing Bone substitute 2003
Orthobiologics) cell adhesion and growth
NanOss® (Rti Surgical) Hydroxyapatite Mimics bone structure allowing Bone substitute 2005
cell adhesion and growth
EquivaBone® (Zimmer Hydroxyapatite Mimics bone structure Bone substitute 2009
Biomet)
Invega® Sustenna® Paliperidone Palmitate Allows slow release of injectable Schizophrenia 2009
(Janssen Pharms) low solubility drug Schizoaffective Disorder 2014
Ryanodex® (Eagle Dantrolene sodium Faster administration at higher Malignant hypothermia 2014
Pharmaceuticals) dses
Inorganic and metallic nanoparticles
Nanotherm® (MagForce) Iron oxide Glioblastoma 2010
Nanomedicines - Approved Products and Clinical Trials 2379

Table I (continued)

Name Material Description Nanoparticle Advantage Indication(s) Year(s)

approved

Allows cell uptake and

introduces
superparamagnetism
Feraheme™/ferumoxytol Ferumoxytol SPION with Magnetite suspension allows for Deficiency anemiairon 2009
(AMAG pharmaceuticals) polyglucose sorbitol prolonged steady release, deficiency in chronic
carboxymethylether decreasing number of doses kidney disease (CKD)
Venofer® (Luitpold Iron sucrose Allows increased dose iron deficiency in chronic 2000
Pharmaceuticals) kidney disease (CKD)
Ferrlecit® (Sanofi Avertis) Sodium ferric gluconate Allows increased dose iron deficiency in chronic 1999
kidney disease (CKD)
INFeD® (Sanofi Avertis) Iron dextran (low MW) Allows increased dose iron deficiency in chronic 1957
kidney disease (CKD)
DexIron®/Dexferrum® Iron dextran (high MW) Allows increased dose iron deficiency in chronic 1957
(Sanofi Avertis) kidney disease (CKD)
Feridex®/Endorem® SPION coated with dextran Superparamagnetic character Imaging agent 1996 (2008)
(AMAG pharmaceuticals)
GastroMARK™; umirem® SPION coated with silicone Superparamagnetic character Imaging agent 2001 (2009)
(AMAG pharmaceuticals)

the fact that while PEGylated polymers have been most ex- Polymeric Micelles
tensively utilized in nanomedicine, other examples of
hydrophiles can be equally successful in improving therapeu- Polymeric micelles consist of self-assembled polymeric amphi-
tic outcomes. philes tailored for controlled delivery of hydrophobic drugs.
Beyond just extending the circulation time of established Through careful design of the hydrophobic/hydrophilic bal-
drugs, polymeric nanoparticles can be developed based on ance in the amphiphile, the size and morphology of the as-
hydrophobic materials that facilitate controlled release of the sembled micelles can be controlled. The internal core is hy-
therapeutic. This is achieved by using slowly-degradable func- drophobic and can be used to encapsulate poorly water solu-
tionality that subsequently leads to kinetically-driven release of ble drugs, whereas the exterior surface is polar enough to
the drug. A long established polymer nanoparticle that allow dissolution in aqueous solution. The use of block copol-
has had significant success is based upon incorporation of ymers as the amphiphiles has led to lower critical micelle con-
leuprolide (a testosterone inhibiting drug) into a centration (CMC) and thus higher stability in comparison to
polylactide-co-glycolic acid (PLGA) nanoparticle. This traditional surfactant-based micelles (40). To date, a tradition-
drug is sold under the tradename Eligard® and is indi- al micellar formulation of estradiol (Estrasorb™) is the only
cated as an effective treatment for the symptoms of pros- FDA-approved micelle, indicated as a topical treatment for
tate cancer (38). PLGA is a well-established degradable moderate to severe vasomotor symptoms of menopause.
polymer that slowly decomposes into the constituent mo- Transdermal delivery avoids first pass metabolism and also
nomeric units over controlled time-courses. Another che- gastrointestinal side-effects, leading to stable serum levels for
motherapeutic, Camptothecin (a DNA topoisomerase I 8–14 days (41). Beyond this example, a number of micelle
inhibitor), has been encapsulated in cyclodextrin-PEG formulations are in late-stage clinical trials.
copolymers to form nanoparticles ~20–50 nm in diame- Intravenously-administered micellar systems are emerging
ter (39). These nanoparticles (named CRLX101 by li- with notable performances in clinical trials. The first of
censee Cerulean Pharma Inc.) are administered by intra- these that will be discussed is BIND-014 which has re-
venous injection and utilize the so-called enhanced per- ceived significant attention for its potential as a prostate can-
meability and retention effect (EPR) that relies on leaky cer therapeutic and is a commercial entity of the company,
vasculature in tumors to increase accumulation of the Bind Therapeutics. Docetaxel, an anti-mitotic chemothera-
drug molecules at the target of interest. CRLX101 has peutic agent, is incorporated into the core of core-shell poly-
achieved phase I/II trials in patients with rectal, ovarian, meric micelles which contain a degradable and hydrophobic
tubal and peritoneal cancer and is an example of classi- polymeric core and hydrophilic PEG shell. Upon assembly,
cal nanomedicine therapeutics utilizing biocompatible the hydrophobic docetaxel is incorporated into the core of the
polymeric nanoparticles. micelle. In the case of prostate cancer trials, these micelles are
2380 Bobo et al.

targeted to prostate-specific membrane antigen (PSMA) large macromolecules. Liposomes arguably are the most easily
which is a well-defined protein marker on the surface of many synthesized class of nanoparticle that can integrate established
prostate cancer cells (42). Recently, there has been a move targeting ligands into already approved liposome drug carriers
away from cytotoxic cancer drugs towards molecularly to create new potential combinations to improve therapeutic
targeted agents (MTAs) that have had little attention in the delivery. They are self-assembling and have amphipathic do-
nanomedicine field. While highly efficacious, these drugs are mains surrounding an aqueous core that chemically allows for
associated with serious toxicity profiles on their own, and the rapid integration of multiple molecules with different
therefore the combination with nanoparticles may help to physico-chemical properties. Advances have facilitated active
reduce toxicity and allow higher dosing (43). Next generation targeting by conjugating cell surface receptor ligands to the
BIND micelles that incorporate kinase inhibitors as future liposome surface. These materials are currently in various
drug therapeutics have been used to investigate efficacy phases of clinical trials (47).
against metastatic colon cancers, showing promising results Liposomes became the first nanomedicines in FDA clinical
in pre-clinical trials. In a similar strategy to that utilized by trials. Starting with approval of liposomal formulations of
the BIND system, micellar nanoparticles have also been uti- doxorubicin and Amphotericin B in mid-1990s there has
lized to deliver docetaxel to various solid tumors using been a growing number of trials and approvals using liposo-
CriPec® particles through the company, Cristal mal delivery (48). The most recently approved liposomal drug
Therapeutics (44). Here, degradable lactate-based hydropho- carrier is Onivyde® (liposomal irinotecan), a topoisomerase I
bic blocks were linked to PEG-based hydrophilic blocks and inhibitor approved as a second line treatment for metastatic
the resulting therapeutic was incorporated through a degrad- pancreatic cancer. There are still very few options for these
able linker into the hydrophobic block. The authors demon- patients and no consensus of care has been established.
strated complete remission of breast cancer tumors in rodents Patients given Onivyde® in addition to flurouracil and folinic
owing to the favorable biodistribution profile of this therapeu- acid were shown to have a 6.1 month median survival vs
tic. One final micellar complex worthy of mention is the 4.2 months with the addition of the liposomal irinotecan for-
transferrin-targeting cyclodextrin-based micellar system for mulation (49,50). Like all of the approved liposomal systems
delivering siRNA directly to tumor cells. This is an important before it, Onivyde® is based on passive targeting.
study as it clearly highlights how polymeric micelles can be In terms of intravenous delivery, classical liposomes typi-
used to deliver biologically-sensitive molecules, such as gene cally exhibite short circulating half-lives due to rapid clear-
therapeutics. CALAA-01, a PEG-stabilized micelle developed ance. In general, the lipid bilayer structure of liposomes results
by Calando Pharmaceuticals and regarded as the first targeted in recognition by the immune system and subsequent clear-
nanoparticle study in humans, entraps siRNA against the M2 ance from circulation by macrophages. Clearance has been
subunit of ribonucleotide reductase (45). The polymeric minimized by PEGylation of the liposome surface. PEGylated
micelles act not only to protect the siRNA against enzy- liposomal doxorubicin (Doxil®), the first example of a liposo-
matic degradation (by RNAses in the blood), but also mal nanoparticle drug, was proven effective in the reduction
increases accumulation and provides a cellular transport of cardiotoxic side effects of doxorubicin treatment. Doxil®
mechanism of action for the gene therapeutic. Such trials has been approved for Karposi’s sarcoma, ovarian cancer,
are expected to increase the utility of gene therapies such and multiple myeloma, as well as for metastatic breast cancer
as siRNA in future applications. Combined, these (51). In comparison to free doxorubicin (DOX), the
approaches exemplify the robust and broad applicability PEGylated liposome resulted in 4 to 16 fold enhancement of
of polymeric micelles, and new products are eagerly drug levels in malignancies (52). The PEGylated liposomal
anticipated in the near future. carrier was quickly adopted for the delivery of other drugs
such as Ambisome®, an amphotericin B to treat fungal infec-
Liposomal Nanoparticles tions, and Visudyne®, delivering verteporphin for wet macu-
lar degeneration (53,54). These and many of the other ap-
The utilization of liposomal platforms for drug delivery has proved liposomes rely strictly on passive targeting which suc-
had a significant impact on pharmacology. Approved drugs cessfully increases distribution to diseased tissue.
with high toxicity or low bioavailability benefit from the sta- More complex liposomal systems are also in the clinical
bilizing nature and improved biodistribution of liposomes in trial phase. A multifunctional particle in advanced clinical
circulation. First described in 1965, the simplest form of lipo- trials is Thermodox®. It is a liposome bound doxorubicin
some is a phospholipid bilayer surrounding an aqueous core similar to Doxil®, but is formulated with thermally sensitive
(46). lipids that degrade the bilayer when exposed to high heat. The
There have been many improvements to manufacturing coupling of this chemotherapeutic with radiofrequency ther-
and loading of these systems allowing delivery of hydrophobic mal ablation of tumor cells allows for site-specific release of the
and hydrophilic compounds ranging from small weak bases to drug (55). A dual targeting example in preclinical use is the
Nanomedicines - Approved Products and Clinical Trials 2381

combination of cyclic arginine-glycine-aspartic acid (RGD) receptor antagonist designed to direct the cytocidal action of
peptide and transferrin (TF). Cyclic RGD has been previously diphtheria toxin to cells that overexpress the IL-2 receptor on
used to increase tumor cell uptake and TF is a potential ligand T-cells. In this case diphtheria toxin may be considered the
to enable delivery across the blood–brain barrier. These have cytotoxic drug and the engineered IL-2 the delivery platform.
been added to a liposome to establish RGD/TF-LP, a IL-2R-targeted therapy appears to be an effective treatment
Bcascade^ delivery system. When combined with paclitaxel, option for PTCL patients. Combination therapy with
RGD/TF-LP forms a complex new system that may precisely Ontak® and CHOP (the traditional first-line chemotherapy
target gliomas in the brain, which is by its anatomical nature for the disease) has an overall survival rate of 63.3% as op-
difficult to access (56). Liposomal drug delivery has become a posed to 32–35% with CHOP alone (59,60). Ontak® is not
clinical staple and it is clear that with improvements in nano- myelosuppressive, nor is it associated with significant organ
technology, they will continue to evolve into next generation toxicity. Ontak® represented one of the first actively targeted
nanomedicines into the future. proteinaceous nanoparticles, but is still a singular protein sys-
tem. It could be used for a range of hematological tumors,
Protein Nanoparticles many of which overexpress IL-2R (61).
Rexin-G® is a targeted gene therapy system in phase I/II
Protein nanoparticles span a number of different trials. Its active targeting relies on a collagen-binding peptide
nanomedicine classes, from drugs conjugated to endogenous from human von Willebrand factor (vWF). This protein nor-
protein carriers to engineered proteins where the active ther- mally induces platelet aggregation in the instance of vascular
apeutic is the protein itself, and to combined complex plat- injury. In Rexin-G®, vWF serves to enhance particle deposi-
forms that rely on protein motifs for targeted therapeutic de- tion by guiding the whole particle into a tumor where exposed
livery. Early protein nanoparticles sought to use the natural collagen is often found (62). In contrast to previous protein
properties of protein circulating in serum, allowing dissolution nanoparticles, Rexin-G® is a mixed system that is based on
and transport of drug compounds in blood during circulation. the murine leukemia virus. The von Willenbrand factor de-
This approach consisted of natural protein combined with rived binding motif is expressed in the modified viral envelope
known drugs in order to reduce toxicity. Abraxane® is an for particle delivery. The proteinaceous envelop is responsible
early example of protein-drug conjugation. Approved by the for nanoparticle accumulation and ultimate transfection of a
FDA in 2005, Abraxane® is albumin-bound paclitaxel in par- cytotoxic cyclin G1 gene. This therapeutic is in phase I/II trials.
ticle form designed to eliminate the need for the toxic solvent, Leveraging the body’s platelet activation system by using von
Cremophor, normally required for paclitaxel delivery (57). Willebrand factor as a form of targeting general disease states
The 130 nm human serum albumin protein-bound paclitaxel is an interesting shift away from non-targeted protein nano-
particles improved infusion time and eliminated the need for particles and the cell-specific receptor targeting used in
co-administration of powerful antihistamines or dexametha- antibody-drug conjugates. As opposed to receptor-specific
sone in order to prevent immunoreaction to the Cremophor targeting, Rexin-G® is targeted against the general disease
solvent (polyethoxylated castor oil). Beyond the initial goal of state characteristics found in tumor environments. Avoiding
reducing toxicity, further study of Abraxane® has found im- reliance on a specific receptor may avoid the confounding
proved pharmacokinetics and enhanced tumor inhibition effects of mutation and adaptation. Rexin-G®’s proponents
when compared to the Cremophor-based therapy due to en- have stated this general targeting of invasive cancer character-
hanced endothelial binding and transcytosis of the nanoparti- istics has improved delivery of the genetic payload to where it
cle (58). Abraxane® has exemplified protein-drug nanoparti- is needed while reducing target selection of normal tissues and
cles as excellent nanomaterials for improving toxicity and pas- tumor adaptation (63).
sive delivery to a desired target. As such, several albumin
bound nanoparticles (NABs) have been entered into clinical Inorganic Nanoparticles
trials seeking to improve the therapeutic efficacy of other
drugs. Examples include NAB-docetaxel, NAB-rapamycin, Inorganic nanoparticles are a well-studied field, with a large
and NAB-heat shock protein inhibitor. Since its approval in number of inorganic platforms being investigated for thera-
2005, there has been a shift from unmodified protein to the peutic and imaging treatments. For the purposes of this re-
utilization of more highly engineered particle complexes in view, we use the term inorganic nanoparticles to cover both
order to gain active targeting functionality. metallic and metal oxide materials. Iron oxide nanoparticles
Ontak®, (Denileukin Diftitox) is an example of an ap- have undergone a number of clinical trials. Despite EU ap-
proved engineered fusion protein combining cytotoxic mole- proval of several iron oxide nanoparticles, to date only three
cules with targeting proteins. It was initially designed to treat particles have completed FDA approval (Feraheme®,
the aggressive form of non-Hodgkin’s Peripheral T-cell Feridex®, and GastroMARK™); two of which have been
Lymphomas (PTCL). Ontak®, approved in 2008, is an IL-2 later withdrawn from the market. Beyond these, there are
2382 Bobo et al.

examples of metallic particles and unique oxides coming this study, Libutti et al. found that the dose of rhTNF admin-
through the trial pipeline with applications in both therapeutic istered after immobilization to gold could be 3 times higher
and imaging applications (theranostics). than native rhTNF without causing toxic effects. The polyeth-
Iron oxide nanoparticles have an emerging research profile ylene glycol layer also decreased uptake by the MPS and aided
as contrast enhancement reagents for magnetic resonance im- in accumulation in tumor masses via the EPR effect. In anoth-
aging, however the majority of FDA-approved materials are er example a silica coating was employed as an alternative
indicated as iron replacement therapies. There are several anti-fouling approach to PEG (75). These silica-coated gold
approved compounds (Venofer®, Ferrlecit®, INFed®, particles were conjugated to iron oxide particles in order to
Dexferrum® and Feraheme®), which are employed to treat control particle biodistribution via the modulation of exterior
anemia related to chronic kidney disease (CKD). Each of these magnetic fields. This allowed the localized ablation of plaque
is composed of an iron oxide core, coated with hydrophilic in a blood vessel using only an injection and externally applied
polymers (e.g. dextran, sucrose), which provide slow dissolu- magnetic fields and light. These particles were also adminis-
tion of the iron following intravenous injection. This allows tered with protein-targeted microbubbles or stem cells to aid
rapid administration of large doses without increasing free delivery.
iron in the blood to a level which causes toxicity (64). Developed by Nanobiotix, NBTXR3 is a novel radio en-
Interestingly, ferumoxytol (Feraheme®) is also under investi- hancer utilizing a high electron density metal oxide (hafnium
gation as an imaging agent (65). Despite a number of similar oxide) nanoparticle to increase radiotherapy efficacy without
superparamagnetic iron oxide nanoparticles (SPIONs) being increasing the surrounding tissue dose (76). Incorporation of a
granted FDA approval, they have since been discontinued for high electron density material maximizes x-ray interactions
reasons that remain unclear (66). In 2010 there was EU-wide producing a larger number of excited electrons and in turn
regulatory approval for Nanotherm™, which consists of forming more reactive radical species (77). Developed for in-
aminosilane-coated SPIONs designed for tumor therapy jection into a tumor site these particles are designed to under-
(glioblastoma) using local tissue hyperthermia (67). go cell uptake. Uptake is increased by tuning the particle size
Nanotherm™ is in late stage clinical trials in the US, and and surface properties (50 nm diameter and negative zeta
FDA approval is pending. Here, the Bmagnetic fluid^ is potential), which prevents leakage to surrounding tissue while
injected directly into the tumor, and then an alternating mag- maximizing the local cellular damage when particles are
netic field applicator is used to selectively heat the particles, irradiated (76). Once again, antifouling coatings are
resulting in local heating of the tumor environment (temper- usually employed to stabilize the nanoparticles in
atures reach 40–45°C), leading to programmed and non- biological environments. Entering phase I clinical trials
programmed cell death. In a recent clinical trial, treatment in 2011 NBTXR3 has since reached phase II/III for treat-
of glioblastoma with this magnetic nanomedicine was associ- ment of soft tissue sarcoma due for completion towards the
ated with increased overall survival of up to 12 months (68). end of 2016. Phase I trials have also begun for indications
Gold has been utilized as a nanomedicine in clinical trials including head and neck cancer and have been completed
due to its unique combination of optical properties, thermal for rectal cancer in conjunction with PharmaEngine under
properties, and tunable size, shape, and surface chemistry (69). the name of PEP503.
Tuning the size of the particles on the nanoscale allows a Cornell dots (C-dots) are inorganic silica nanoparti-
plasmonic characteristic to be established and augmented cles designed for fluorescence imaging applications.
(70). Although well represented in a range of research fields, Under development by the Wiesner group at Cornell
there are few examples of gold nanoparticles being actively University these particles entered into phase I clinical
investigated in clinical trials, and there are no gold-based trials in 2014. Designed for lymph node mapping in
nanomedicines that have been approved to date by the cancer patients these particles comprise a targeting moi-
FDA. Previous uses of colloidal gold in treatment of arthritis ety, an antifouling polymer layer, and an internal silica
have been largely surpassed by more effective drugs with few- core labelled with a near-infrared (NIR) fluorescent dye.
er side effects (71). This is likely due to the influence of gold Cyclic arginine–glycine–aspartic acid peptide (cRGDY;
nanoparticles on cell function (72) owing to their affinity for targeting agent for tumor and tumor endothelial cells)
DNA. Different changes in gene expression have been shown was conjugated to the PEG-coated surface of the Cy5.5
for acute and chronic exposure to gold nanoparticles (73). labelled C-dots. The particle design leads to a nano-
Particles placed into clinical trials recently have incorporated particle that is 20–30 times brighter and more stable
a biocompatible coating. In one trial CYT-6091 (recombinant than the constituent dye in solution. A first in human
human tumor necrosis factor (rhTNF) bound to colloidal gold) trial in five patients recently indicated favorable
was studied for solid tumor treatment (Phase I) (74). Here, the PK/distribution profiles and safety as a tumor imaging
rhTNF was attached to gold nanoparticles using a PEG linker agent, paving the way for other trials in the near future
which doubled as a biocompatible antifouling layer. During (78).
Nanomedicines - Approved Products and Clinical Trials 2383

Crystalline Nanoparticles Future Perspectives

Crystalline nanomedicines are unique because the nano- The data presented in Fig. 1 on clinical trials highlights the
particles themselves are composed of 100% drug com- significant expansion in clinically-validated nanomedicine-
pound. The increased surface area for dissolution, ow- based drugs and biologics and suggests that we are likely to
ing to the nanoscale dimensions, leads to increased dis- see an increase in the number of FDA-approved therapeutic
solution velocity and also increased saturation solubility. and imaging agents over the foreseeable future. Modern ap-
This last point is particularly important – at the nano- proaches in protein engineering, as well as advances in poly-
scale, saturation solubility increases with decreasing par- mer and inorganic chemistry have resulted in an explosion of
ticle size, leading to enhanced driving forces for novel nanomaterials in the academic literature; these
diffusion-based mass transfer through biological struc- nanomaterials often contain elements of a number of different
tures (e.g. walls of the gastro-intestinal tract). The pro- materials such that the boundaries between the traditional
duction of crystalline nanoparticles has been applied to material categories is blurred. This is leading to a distinct
both organic drugs as well as inorganic materials. trend which evolves beyond the initial goal for nanomedicine
(79,80). The solubility issues related to a number of drug (i.e. longer circulation times and reduced toxicities), to com-
compounds have been Brescued^ by conversion into plex particle system designs which may allow for controlled
nanocrystals and are marketed for a range of indications. release, active targeting of disease, and diversification of drug
Inorganic crystalline nanoparticles approved by the FDA approaches beyond traditional chemotherapeutics (e.g. pacli-
are limited to hydroxyapatite and calcium phosphate for taxel). Nanoparticles were introduced to decrease some of the
use as bone graft substitutes. Synthesis methods include challenges of traditional drug delivery, but come with their
either Btop-down^ diminution approaches (including own difficulties and limitations that will continue to be an
milling and homogenization) which are often employed important area of research. In vivo bio-distribution and toxicity
for the organic compounds, and Bbottom-up^ precipita- studies currently guide particle design and clinical trial candi-
tion methods that are more commonly applied to the dates, but the real world use of nanomedicines need
inorganics. The milling approach developed by Elan Phase IV post-marketing review after clinical application
Nanosystems was employed to produce the first three to show the full benefits and limitations of these tech-
FDA-approved nanocrystals – Rapamune®, Tricor®, nologies (11,20,83–86). Several nanomedicine products
and Emend®, and is expected to be broadly applicable have undergone clinical trials only to be later with-
to a range of drugs that suffer from solubility issues, drawn due to efficacy or safety concerns e.g.
which is an estimated 70–90% of potential drug compounds Feruglose® (NC100150) and Resovist® (87,88).
(80,81). While the majority of FDA-approved nanomedicines rely
Rapamune (Wyeth Pharmaceuticals) is a milled or- on passive targeting via the EPR effect, there is a clear trend in
ganic nanocrystalline drug and was the first of its kind emerging studies towards active targeting to further increase
to be approved by the FDA in 2000. Containing the drug accumulation and ultimately efficacy at the disease site,
active component sirolimus, a bacterial derived 914 Da while reducing toxicity in other organs. While the EPR effect
macrocyclic immunosuppressant (82), Rapamune is used enables non-specific uptake of nanomedicines, there are com-
to prevent organ rejection following transplantation, peting effects that are yet to be overcome. Key problems in-
specifically for kidneys. The nanocrystalline nature of clude the hyper-permeable tumor blood vessels that cause
the formulation provides the poorly soluble drug a con- excessive fluid and drug leakage. This in turn leads to the lack
stant extended release profile well suited to ongoing of a pressure differential between the microvasculature of the
indications. The milling technology that produces these tumor and the interstitial environment, effectively limiting the
nanocrystals as well as others including Emend®, driving force for mass transfer into the tumor to diffusion
Tricor® and Megace ES® involves a pearl/ball mill alone. Given that diffusion decreases with increasing size of
able to shear particles apart during agitation. A disper- the drug or biologic, the relatively large nanoparticles may not
sion media as well as stabilizing agents are also com- reach the target tissue effectively (89). Beyond the EPR effect,
bined with the drug to facilitate milling. This technolo- many of the next generation nanomedicines in clinical trials
gy has been shown flexible in terms of administration as employ active targeting approaches wherein the nanoparticles
demonstrated by the variety of formulations including can bind to the surface of cells via affinity interactions.
oral suspension, tablet and intramuscular injection. CALAA-01 is widely regarded as the original targeted
Following the approval of Rapmune several other ap- nanomedicine under investigation, whereupon the inventors
proved nanocrystalline drug formulations have been immobilized human transferrin to the particle surface to bind
produced in this manner, the last of which was ap- transferrin receptors which are upregulated on the surface of
proved in 2009. cancer cells. Beyond this approach, others including the
2384 Bobo et al.

BIND-014 (contains specific targeting ligand for PSMA- To achieve both image enhancement as well as controllable
expressing prostate cancers) and SGT-53 (90) (contains an drug delivery, development of nanomedicines that combine
anti-transferrin antibody fragment that interacts with transfer- different traditional categories together is also apparent – e.g.
ring glycoprotein receptor over-expressed on cancer cells), the development of biocompatible polymeric agents with con-
both of which are in Phase 2 trials for solid tumor therapy. trolled release properties, combined with molecular imaging
An ongoing challenge in the development of actively-targeted contrast agents to enable visualization of the treatment process
therapies is the careful balance that needs to be struck inside (93).
the tumor between the rates of drug uptake, release, and se- While the development of exciting new nanomedicines
lective target binding, to encourage uniform distribution of continues, a significant challenge for both researchers, regula-
the drug throughout the tumor (89). tors, and industry, is the classification of these materials. We
Another clear trend is the move from relatively simple are not the first to identify that the simple act of gathering data
nanoparticles originating from the traditional material cate- on the approved and emerging nanomedicines was hampered
gories, to complex and multi-component materials that blur by a lack of clear guidelines on what constitutes a
the boundaries between organic/inorganic chemistries and nanomedicine, and how they are categorized (9). While in
molecular biology. While the number of materials categorized our study we used a number of search terms based on the
as Bpolymeric nanoparticles^ is likely to reduce based on the Bnano^ prefix (including nanomedicine, nanoparticle, nano-
clinical trial data, in reality polymer chemistry is permeating technology, etc.), it is possible that in some cases, these terms
all of the categories. Micelles and liposomes are now often are specifically avoided. Furthermore, we excluded a range of
synthesized using synthetic polymers, or at the very least they material categories which others may have included (e.g. an-
are coated with synthetic polymers to avoid protein adsorp- tibody drug conjugates, vaccines, etc.). This is a significant
tion. Similarly, with inorganic materials, surface coatings com- challenge, because as researchers are still learning about the
prised of anti-fouling polymers is nearly a universal require- Bstructure-function^ relationships of their nanomaterials in
ment. These complex multilayered particles include silica biological systems, key material characteristics are constantly
nanoparticles, metal and metal oxide nanoparticles, nano- being varied and applied in different disease contexts (e.g. size,
tubes, graphenes, dendrimers, polymers, cyclodextrins, lipids, shape, charge, composition, complex architectures), resulting
hydrogels, and semiconductor nanocrystals, which may serve in an in-exhaustive list of individual candidates. This issue also
as future vehicles for delivery of new therapeutic categories complicates genuine efforts within the research community to
such as RNA interference gene regulation mechanisms (91). A investigate the potential toxicity of nanomedicines, because
challenge here is that increased complexity may also be asso- there is a significant lack of uniformity across toxicology pro-
ciated with higher costs and difficulty for scaling the process tocols (94). With recent draft guidelines published by the FDA
for trials and beyond. However, the development of platform on the importance of nanomaterial characterization for differ-
technologies such as the BAccurin^ particles from BIND ent regulated environments, and the emergence of standard
Therapeutics is an interesting example of how this complexity approaches for material characterization (e.g. http://ncl.
can be handled. This group has effectively synthesized a cancer.gov (21)), significant effort is now being placed into
library of nanoparticles based on commonly employed developing standards for nanomaterial characterization.
building blocks, which can be screened for specific traits This is likely to lead to better information on the effects of
related to drug encapsulation, in vitro and in vivo stability, nanomaterials in terms of medical and environmental
controlled release, and targeting ability. This is an approach toxicity, etc.
that is designed to lend itself to relatively simple scale-up,
once the screening process has identified lead candidates for
specific applications. CONCLUSION
Beyond increased complexity in nanomedicine synthesis,
emerging nanomedicines are also being designed to be This up to date snapshot of nanoparticles in medicine affirms
multi-functional. The merging of therapeutic and diagnostic an increase in the number of FDA approvals and clinical trials
modalities is referred to as Btheranostics^ and there are a utilizing nanoparticles within the past 3 years. Most of the
number of exciting examples of products in pre-clinical trials, currently approved nanomedicines consist of relatively simple
but not necessarily yet in clinical trials (92). Examples of nanoparticles and build on the success of well described sys-
theranostic agent development can be seen across the spec- tems and prior approved drugs, e.g. PEGlyated liposomes.
trum of material categories highlighted previously. Imaging There has been both a broadening in particle types and an
modalities most commonly employed include MRI, optical increase in the complexity of particles within these categories
imaging (fluorescence), and ultrasound, and the therapeutic over time. It is reasonable to assume that this trend will con-
modalities usually involve photothermal therapies, or con- tinue and the number of overall approvals will increase given
trolled delivery of chemotherapeutic or thrombolytic agents. that there has been a threefold increase in the number of
Nanomedicines - Approved Products and Clinical Trials 2385

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