Clinical Cancer Investigation Journal‐ISSN: 2278‐0513

Design and use of pH-responsive polymers in drug delivery applications

Abstract Mohammadreza
Karvanpour*, Yasamin
Drug Delivery (DD) is an important matter in the pharmaceutical industry in recent decades.
Scientists have found that the effectiveness of a drug can be influenced by how the drug is delivered to
Karvanpour, Samin
the body. A Targeted Drug Delivery (TDD) system enables doctors to deliver drugs to a precise part Atabakhsh
of the body (e.g. cancerous tumor). Also, it minimizes (or even eliminates) systemic side effects or Department of Biomedical
damage to the tissues around the treatment site. The focus of the current study is on the most recent Engineering, Najaf Abad
advancements in pH-responsive Polymer-Drug conjugates (PDC), including the activation mechanism, branch, Islamic Azad
synthesis (generation), and description of particular features. Additionally, this research presents University, Esfahan, Iran
conjugate compounds with varied chemical structures and architectures as well as chosen samples from * Corresponding author:
a variety of materials (such as books and articles). The conjugates of pH-responsive polymers and Email:
drugs are given a sneak peek. The design and development of drug pH-responsive polymers is a more [email protected]
intelligent platform for TDDs, according to a literature study, because of their well-established benefits,
including controlled drug delivery (CDD), tumor-specific characteristics, intracellular drug delivery,
and superior therapeutic effectiveness. Additionally, it removes MDR resistance and lessens both the
drug's and the carrier's negative effects.

Keywords: Drug release system, pH changes responsive, polymers sensitive to pH changes,

controlled release

Introduction can be accomplished by using this modification in nanoparticle

As is well known, the capacity of polymeric nanoparticles characteristics. In this way, pH-responsive nanoparticles offer
to shield the delicate charge until it reaches the target location a strong approach for creating therapeutic delivery systems [5].
gives them the potential to enhance therapeutic delivery. The The fact that endosome/lysosome membranes can be damaged
capacity to escape the immune system, the ability to target by pH-responsive nanoparticles is crucial. This means that
certain cells and tissues, and the ability to transfer charge to distribution to the cellular regions where therapies are most
particular intracellular locations are only a few of the active (such as the cytosol) will always have the greatest
challenges to attaining successful therapeutic delivery, impact. As illustrated in Fig. 1, the three primary methods for
according to research [1]. There are currently few instances of creating pH-responsive nanoparticles (for therapeutic
polymer delivery systems being employed in the clinic, despite administration) are highlighted in the current research. These
great progress being made in overcoming these barriers. methods include (a) the use of charge-delivery polymers; (ii)
Utilizing stimulus-responsive nanoparticles is one of the key the use of acid-sensitive bonds to chelate iron; and (iii) the
methods for delivering charge to the active site. It is possible formation of cross-linked particles using acid-sensitive bonds.
to create responsive nanoparticles such that they respond to Recent examples demonstrate how each of these techniques
different biological stimuli by changing their material may be employed to create eye-catching nanoparticle delivery
characteristics [2]. The design of responsive nanoparticles has systems [6]. There is rising hope that the use of
been influenced by a wide range of stimuli, including internal nanotechnology in medicine may lead to major improvements
and external ones like pH or redox conditions, as well as in the identification and management of several illnesses. A
external ones like light and temperature. Because of the pH variety of nanotechnology-based biomedical applications have
changes that take place when nanoparticles enter a cell, pH- been created as a result. They currently serve a function that is
responsive nanoparticles are a topic of interest for researchers rapidly expanding in the detection and management of human
[3]. From 7.4 in the blood, the pH lowers to 6.5 in the early illnesses [7–8]. Polymer nanoparticles, metal nanoparticles,
endosome and less than 5 in the lysosome. Additionally, dendrimer nanoparticles, liposomes, micelles, nanocrystals,
certain extracellular areas have a pH that is lower (tumors, for nanotubes, and other nanostructures are just a few of the many
example, have a pH of 6.4-6.8 and are mildly acidic). The pH- nanoparticles (NPs) with numerous applications that have
responsive materials are appealing as well. Since a wide range recently been made possible by developments in materials
of polymer architectures may easily incorporate pH-responsive science and nanoparticle identification technology. Compared
characteristics, pH-responsive nanoparticles can be designed to using traditional medications, using nanoparticles provides
[4]. Nanoparticles can be made to change their surface a number of benefits. By enhancing the specificity of
chemistry, shape or size, separation, or release of charge in medication molecules through targeting, for instance,
response to pH. Regulation of cell uptake and charge release nanotherapeutics minimize drug doses. As a result, they
improve bioavailability and eventually aid patient
acceptability. Reduced toxicity and greater effectiveness are example of how their physical and chemical characteristics
the effects of using nanoparticles to deliver poorly soluble enable them to adapt to very tiny changes in the environment.
substances through easier administration routes. Smart Polymers (SP) are also excellent candidates for DDSs
Multimodality is a differentiating feature of nanocarriers. because of their adaptability and relative simplicity in
Several diagnostic and therapeutic compounds can be processing and formulation. To ensure targeted delivery,
delivered simultaneously as a result [8]. Due to their use as increase biocompatibility, and enable high-resolution imaging,
DDS, polymer-based nanocarriers will be the only topic of this different agents can be applied to the surface depending on the
study. DDSs with a controlled release mechanism that kind of polymer set. Additionally, a variety of bioactive
responds to stimulation have a lot of promise for use in substances (including medicines, nucleic acids, and imaging
therapeutic settings. Polymers are used for a variety of stimuli- contrast agents) can be encapsulated using the polymer
responsive systems in pharmaceuticals. With a focus on the nanocarrier. The correct scaffold must be chosen in order for
design, development, and commercialization challenges these DDS to produce the intended results. The right scaffolds are
nanomemories for drug delivery face, this research was probably going to provide therapeutic advantages (such as
conducted from a chemical and pharmacological point of view. improved penetration, favorable specificity, excellent
Here, we will highlight future problems and clinical pharmacokinetics, and hence advantageous medication
applications. Hence, the purpose is to design and use pH- effectiveness). Through pathological alterations, polymeric
responsive polymers in DDSs. nanoparticles can efficiently enter tissues and deliver
The pH-responsive polymers for drug delivery applications medications to certain target locations. Typically, these
1. DDSs nanosystems deliver the medicine by encapsulating it at the
The science of nanotechnology is regarded as a potent target, where it is released when the microenvironment's pH
tool for creating nanotherapies for different therapeutic and changes. Polymeric NP sand is mostly made by emulsification
diagnostic reasons. The medicine is given and released techniques [13] employing stabilizers such as polyvinyl
specifically and selectively with a DDS that combines targeted alcohol (PVA), in contrast to micelles and polymersomes
delivery with controlled distribution [9–10]. Therefore, (which self-assemble). Poly(Pactic-co-Glycolic) (PLG)
numerous aspects (such as the size, shape, and surface nanoparticles were created by Chen et al. PDCs are possibly
properties of nanocarriers) should be taken into account while the most popular nanostructures for the simultaneous delivery
choosing and building an appropriate DDS. In order to create of chemotherapeutic medications to breast cancer tumor cells
nanotherapeutics, which is what DDSs are ultimately aiming (with MultiDrug Resistance, MDR), in which the drug is
for, it may be necessary to select a good biocompatible material covalently attached to the polymer carrier through a
with the ideal size, shape, and surface. The absorption of biodegradable linker [14–15].
nanotherapeutics through mucosal routes, blood flow, the
bloodstream, and elimination are all significantly influenced 3. Strategy for designing DDSs based on pH-responsive
by size. Deeper tumor tissue penetration is achieved by small polymers
nanocarriers. Their formulation, however, is frequently Using the body's pH gradient and a few chosen pH-
challenging [11]. Nanotherapeutics less than 5 nm are removed responsive polymers, DDSs may be created. This section
by renal clearance, albeit they are not eliminated as quickly as discusses several methods and techniques applied in the
molecular medicines. Mononuclear phagocytic organs development of pH-responsive DDSs. The processes by which
frequently gather larger particles. Nanotherapeutic circulation pH stimuli are triggered and result in drug release are the major
and tissue penetration are similarly impacted by surface emphasis here [16–17]. The outcome of the delivery platform
charges. As an illustration, cationic polymer nanoparticles is greatly impacted by the medication pricing methodology. In
circulate in the blood for a shorter period of time than anionic general, there are two approaches to charging drugs: drug
nanoparticles. But they can pierce deeper than anionic encapsulation and drug conjugation. Each approach has pros
nanoparticles. and cons. The process for making drugs is simpler and leaves
the body with fewer unidentified metabolites. However, it has
2. Drug release scaffold based on pH-responsive polymer issues with early medication release and a lack of space for
A gradient of pH between extremely acidic pH levels and huge shipments. Contrarily, drug compounding offers a
physiological pH (=7.4) may be seen in the human body. The platform for delivery where high drug charges and controlled
physical and chemical characteristics of polymers make them drug release are guaranteed. Additionally, compared to
one of the most appealing DDSs. The capacity to attach polymer-drug conjugates, the physical and chemical
pharmaceuticals at physiological pH and release them at a characteristics of nanocarriers are more visible because of the
lower pH (lysosome pH or certain tumor settings) is only one relatively unique structure of the nanocarrier. The polymer-

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drug conjugation method has some key drawbacks, too, Since many oral medications are ineffective, intravenous
including the drug's requirement for a chemical functional administration is frequently employed and is the favored
group to assure covalency. In both situations, the medication technique in the field of polymer-drug conjugation. The
must be stored and stabilized in the designated cases until it conjugated molecules can instantly reach the circulation
reaches its intended destination (i.e., the location where it is following intravenous delivery. It is anticipated that the drug's
released in a regulated way as a result of pH stimulation). To pH-responsive linker will maintain a stable enough state. In
achieve this, many methods were investigated in order to create this way, it is ensured that the conjugates reach the diseased
the most potent pH-responsive DDS. [18]. This method has tissues (without any significant chemical changes during the
been used to develop a number of polymer-based DDSs based passing medium) (pH of bloodstream = 7.4). After entering the
on protonation-deprotonation processes. They are divided into pathological sites (e.g. interstitial tumor), macromolecular
two categories: (i) Anionic and (ii) Cationic, depending on the polymer-drug compounds quickly enter the cell by
ionizable polycarboxylic or polyamine groups. Ionizable endocytosis. Compared to unbound drug molecules that enter
groups often have an appropriate pH value that is near the the cell through the plasma membrane, this is entirely different.
intended target pH value and are weak acids or alkalines. The Phagocytosis and pinocytosis are two extremely wide subtypes
design of DDSs includes instances of pH-responsive anionic of endocytosis [23–24].
and cationic polymers [19]. One of the most commonly utilized
types of polymers that react to pH is anionic. These include 2. Synthesis and description of pH-responsive features of
citraconic anhydride, polymers with sulfonamide groups, and polymer-drug conjugates
polyacids including poly(acrylic acid), poly(methacrylic acid), To couple doxorubicin (DOX) with a carrier polymer at
poly(ethylacrylic acid), poly(glutamic acid), and first, the hydrozone bond was a component of a pH-responsive
poly(allylamine hydrochloride). [20]. These proteins become linker. Because of the reliability of the response in DDs,
ionized and hydrophilic at physiological pH, respectively. hydrozine has received the most attention among pH-
However, they become protonated and hydrophobic in acidic responsive chemical bonds. The hydrazine group is an
environments. To enhance cancer therapy, Li et al. have important component of hydrazine bonds. Hydrazine is simple
created a pH-sensitive PEG-PCL-PGA-based active targeted to integrate into polymeric materials from a chemical
delivery system. In the acidic milieu of the tumor cell, this standpoint, and the response conditions are good. In order to
polymeric nanocarrier's pH-sensitive feature causes a fast modify the carboxyl group of the polymer and create
release of the medication. The breakdown of the polymer conjugates that include hydrazones, monoprotected hydrazines
complex as a result of the change in water solubility in various are often utilized, as illustrated in Figure 3. Chloroformate is a
pH settings (particularly neutral PGA carboxylate groups) was desirable reagent in cases where the polymer carrier has a
a key component of the drug release mechanism. [21]. The hydroxyl group because it can operate as an active site for
benefit of pH-sensitive cationic polymers is that they increase subsequent reactions and is sensitive to hydrazine hydrate.
cellular absorption because of their positive charge surface. Drug compounds may occasionally include hydrazines. In
They are therefore promising DDSs, particularly in the order to create effective hydrazone conjugates, they are
treatment of cancer. The polyamines in these polymers are therefore linked to the -thiol group in different carriers of the
ionizable. At acidic pH levels, the pH value is protonated. polymer [25]. Other chemical linkages can also produce pH-
Typically, the charge shift is what weakens the nanostructure responsive polymer-drug conjugates, even though the majority
and results in drug release. Another cationic polymer that has of research is concentrated on hydrazones. In contrast to the
found widespread usage in drug delivery applications is many different ways that hydrazones may be made, research
poly(L-histidine) [22]. on additional pH-responsive chemical linkages is still in its
early stages, and only a small number of synthetic methods
The pH-sensitive polymers in drug compounds: Design and have been created. Two single-bonded oxygen atoms are
Development joined to a central carbon in the commonly used group known
1. Practical mechanism of pH-responsive polymer-drug as acetal. Vinyl ether, a functional polymer with a hydroxyl
conjugates group, and a medication can be combined to create this
Based on the practical mechanism, pH-responsive molecule by acid catalysis. In vitro drug release utilizing the
polymer-drug conjugates should be rationally designed. The dialysis technique is commonly used to measure the degree of
linker of the conjugates created by the designer is often pH responsiveness in polymer-drug conjugates. In this
responsive to pH level fluctuations in the environment. It can experiment, solutions grown with various pH values—such as
undergo hydrolytic degradation, and the rate of this hydrolysis phosphate-buffered saline (PBS) with a pH of 7.4
has an inverse relationship with the pH of the environment. (corresponding to the pH of blood) and a pH of 5.0

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(corresponding to the pH of endosomes)—are used to measure resistance (MDR). As one of the causes of MDR, extensive
the interior environment of the human body. Polymer-drug studies have been conducted on the increase of P-gp pump in
conjugates often release free medicines significantly more the cell membrane. From the study point of view, nanoparticles
quickly in acidic settings than in neutral situations, depending (such as micelles) can pass through the P-gp pump system,
on the pH. When drug molecules are covalently bound to increase the accumulation of the drug inside the incoming cell,
polymer carriers by various linkers, diverse behaviors are and promote the chemical drug inside the cell. Free drugs
shown in vitro and in vivo. For the comparative analysis of pH- actively cross the plasma membrane and reach the perinuclear
responsive polymer-drug conjugates, several molecules with region. Polymer-conjugated medications, however, penetrate
various acid-dependent chemical linkages were created and the surrounding cytoplasm before leaving it after being
manufactured. While both bonds are pH-responsive, the drug liberated from conjugates in the lysosomal compartment. The
release rates for hydrazone and cis-ecotonal bonds differ distribution of drugs into cancer cells is totally altered by this
substantially. A hydrazone bond or a cis-acotynyl bond was procedure [26–27]. In order to create pH-responsive conjugate
effectively used by Park et al. to conjugate DOX to Poly(L- systems, several linear polymers besides the traditional linear
Lactic Acid)-block-Poly(Ethylene Glycol) (PLLA-b-PEG) polymers HPMA and PEG were utilized. Polylactide that had
copolymers. It was discovered that hydrazone-based linkers been functionalized with acetylene was changed into
are a preferable alternative to the cis-acotinyl bond for pH- polylactide-linked aldehyde by Cheng et al. Then, using an
responsive drug delivery by comparing the drug release acid-sensitive Schiff base bond, it was conjugated with DOX.
characteristics of these two pH-responsive bonds. Under The conjugate-based nanoparticles displayed acid-sensitive
slightly acidic circumstances, the entire intact structure of release behavior and up to 32% DOX charge following
DOX may be produced from conjugates containing hydrazone. nanoencapsulation with a PEGylated surfactant. In the area of
Conversely, the natural DOX was only partially released by DOX-based conjugates, the Emrick group created a brand-new
conjugates bearing the cis-ecotinyl bond. carrier known as Poly(Methacryloyl Oxide
Phosphorylcholine) (PMPC). Using a pH-sensitive hydrazone
3. Linear polymer-drug compounds link to create PMPC-DOX conjugates has benefits including
PHPMA and PEG are the most often employed carriers for (i) a prolonged plasma circulation half-life of DOX (from 15
the creation of pH-responsive polymer-drug conjugates out of min to 2 h), (ii) drug accumulation at the tumor site, (iii)
all the linear polymers studied and used at the bedside. Due to effective tumor growth suppression, and (iv) the absence of an
their innate inability to degrade, the MW of these two polymers inherent immune response. A P-gp inhibitor and an apoptotic
must be kept below 40,000 g/mol in order to be eliminated product called disulfiram were recently physically
from the body through the kidney. High MW in polymers, encapsulated by Duan et al. after being connected to a
however, causes a lengthy duration in the blood, as evidenced Poly(Styrene-co-Maleic Anhydride) (PSMA) carrier. The pH-
by a wealth of research. Using the amine group of the polymer sensitive drug release performance was great, and the system's
to connect the C13 carbonyl group of doxorubicin by a cis- synergistic impacts on tumor development were also evident.
aconityl bond, Kopecek initially reported pH-responsive As was already indicated, both in vitro and in vivo, pH-
PHPMA-drug conjugates. After that, other pH-responsive sensitive polymer-drug conjugates are excellent choices for
DDSs were created. The most prevalent type of pH-responsive DDSs.
polymer-drug conjugation among them is the hydrazone-based
PHPMA-DOX combination. Most hydrazone-based PHPMA- 4. Dendritic polymer-drug compounds
DOX conjugates with significantly pH-dependent DOX Dendritic polymer-drug compounds are highly branched
release characteristics, in general, have quick and high release and globular molecules named called dendritic. They are used
rates in buffers with a pH value of 5 and relatively low release as carriers of drugs and medical materials. These compounds
rates at physiological pH. Studies conducted in vitro have have (i) A low-density distribution index, (ii) Uniform
shown that the toxicity of these PHPMA-drug conjugates is molecular weight, (iii) Controllable size, and (iv) Specific
often on par with that of the free drug and, in some cases, even chemical composition. Because dendritic cells have many
higher. The PEG copolymer (as a possible polymer carrier) is adaptable end groups for drug attachment, they are desirable
typically reformed with other polymers to create block or graft for pH-responsive drug delivery. Acid-sensitive drug release
copolymers in pH-responsive DDSs. In an aqueous solution, depends on the linker between the medication and the dendritic
these PEG-based copolymers are anticipated to change into a carrier. The application of many dendritic-drug compounds in
self-assembled micelle structure since they typically have biological systems has been constrained by their intrinsic
highly amphiphilic properties. Almost all DDSs in cancer toxicity (such as cytotoxicity, immunogenicity, and
treatment are complicated by the establishment of multi-drug hematotoxicity), despite the fact that many of these compounds

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have been found to be appealing pH-responsive DDSs. and magnetic field-assisted radionuclide treatment are just a
Compounds with core-shell structures can be created as a few of the in vivo biomedical uses of body-compatible
solution to this issue. A pH-responsive linker connects the Superparamagnetic Iron Oxide Nanoparticles (SPIONs) (such
medication to the dendritic core, which is active. Hydrophilic as Fe3O4) [30]. Gold nanomaterials (nanorods or
and safe polymers, mostly PEG, make up the shell. Highly nanoparticles) have significant near-infrared absorption and
branching molecules are peptide dendrites, which are can be used for a variety of purposes, including optical imaging
composed of many little amino acid monomers. Their dendritic and photothermal treatment. In order to create pH-responsive
architecture resembles proteins and is susceptible to inorganic polymer conjugates, both of these nanomaterials
degradation by biological processes. Peptide dendritics persist have recently been joined to DOX using hydrazone bonds.
in the circulation significantly longer than linear polymers due These nanocomposite conjugates can enable targeted cancer
to their distinctive dendritic structure and high degradability. treatment and PET imaging employing cRGD and NOTA, in
Its safety index is high [28]. addition to their capacity to transport and release medicines
(particularly in acidic cancer tissues and cells). Mesoporous
5. The crosslinking polymers-drug silica polymers offer rich locations for transporting many
In cancer treatment, crosslinking amphiphilic polymers molecules with high density due to their enormous internal
based on amphiphilic copolymers (which may form self- surface area and pore capacity. It enhances the absorption of
assembled micelles) have received a lot of attention because of hydrophobic medicines into the circulation and slows down the
their ideal size for active cancer targeting and intracellular quick departure of charged molecules to the environment
delivery. But, the sudden release of drugs in the systemic outside. After forming a pH-responsive hydrazone bond with
circulation causes a serious limitation in their delivery to the DOX to form mesoporous silica nanoparticles (MSNs), these
patient's bedside. Recent attempts have concentrated on using MSNs demonstrated an impressive pH-sensitive drug release
cross-linking to make such cross-linked micelles more stable mechanism. The passage of MDR through the P-gp enhancer
in order to solve this issue. Strong interactions between pump was also successfully blocked. These MSNs may be
intraparticles can be produced through covalent crosslinking. made more integrable for fluorescence and MRI (using pH-
To put it another way, the crosslinked micelles will have great sensitive drug release) by adding tiny fluorescent dye
colloidal stability following crosslinking. They'll be immune molecules and SPIONs. This opens up new possibilities for
to both controlled medication release kinetics and destabilizing cancer detection and therapy.
agents as a result. Additionally, the crosslinking technique can
greatly enhance the performance of crosslinked micelles in Conclusions
vivo [29]. There are currently three widely used techniques for Due to their potential to present a number of treatment
creating crosslinked micelles: (i) radical polymerization; (ii) a difficulties (such as a poor therapeutic response and severe side
twinning agent as a crosslinker (typically cisplatin); and (iii) effects for clinical trials), DDS targeting tumors has drawn
disulfide bridging. more and more interest over the past 10 years in terms of
research and development. Generally speaking, a targeted drug
6. Inorganic polymer-drug conjugates consists of two parts: (i) delivering the chosen drug to the target
Inorganic polymers (IP) have received a lot of interest areas; and (ii) releasing a particular medication at the target
lately for use in medicine. The majority of nanomaterials are site. The use of stimuli-responsive drug delivery systems based
made of inorganic polymers, which have several benefits, on various bodily settings might enable CDD in addition to
including (i) high body compatibility, (ii) high stability under cell-targeted biomolecules for a particular delivery. Targeted
physiological settings, (iii) simple manufacture, and (iv) therapy research has recently been conducted in this area. A
simple controllability of size, shape, and surface features. stimulus-stimulation state is a response state, and drug systems
More than other qualities, inorganic nanostructures' innate that are stimuli-responsive can produce particular responses in
optical, electrical, and magnetic capabilities serve many response to minute external changes in the physiological
purposes. For instance, Single-Walled Carbon Nanotubes environment. These adjustments are triggered by both internal
(SWCNTs) have a very high potential to infiltrate cellular and external stimuli, including pH, redox potential (a chemical
tissues and give significantly more options for drug reaction in which the oxidation state of a layer changes), ionic
conjugation because of their one-dimensional (1-D) structure strength, and lysosome enzymes. For instance, some
and large surface area. The cytotoxicity and intracellular intracellular compartments exhibit a lower pH value when
accumulation of DOX were boosted by connecting it to compared to the matrix (intracellular substance) and typical
SWCNTs via pH-sensitive hydrazone bonding. Site-specific ExtraCellular Fluid (ECF), both of which have a pH of 7.4
medication release, hyperthermia, MRI contrast enhancement, (such as endosomes and lysosomes with a pH of 4.5–6.5). The

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