INTRODUCTION:

Different novel drug delivery systems or specially designed formulations are gaining interest in terms of better drug absorption, targeted delivery or better stability. The list of such system or formulation includes but not limited to nano-based formulations^1,2, polymeric nanoparticle³, lipid based formulation⁴, self-emulsifying drug delivery system⁵, solid dispersion⁶, gastro retentive drug delivery⁷ and mucoadhesive formulation.⁸ Polymers are one the most critical element of many novel delivery systems or formulations such as nano-particles, in-situ gellying system, solid dispersion, controlled released oral formulation etc. Stimuli-responsive polymers, ‘smart polymers’ or intelligent polymers are being used interchangeably to define the polymers which have the properties of changing the physical characteristics in response to external stimuli such as light, pH, temperature, electric field and even ultrasound.⁹ They have been called ‘intelligent’ because their physical properties can be altered using small external stimuli and after the stimuli or inducers have been pulled off, their physical properties will return to the normal state.^10–12

The applications have been vastly used in many fields including agriculture, nanotechnology, sensing, and medical-related such as biomedical applications, drug delivery and hydrogels.¹³ For instance, generating chromatographic technique using these polymers also possible and may carve a path towards environmental friendly method.¹¹

For drug delivery, stimuli-responsive polymers, often called as bio-responsive polymers have a major advantage which is the stimuli that requires to convert the physical state of the polymer is present naturally in normal human biological system. Drug delivery system containing such bio-responsive polymers is also called ‘in-situ’ system, most commonly ‘in situ gellying’ system. There are many important criteria in selecting the most suitable polymers including the toxicity, response time, drug-polymer or polymer-polymer interactions and site of action. Each of the considerations must be wisely made before choosing the best. As an example, acrylamide polymers are common as thermosensitive polymers, but to date, it has been categorized as carcinogenic materials and also can cause neurological damage.^14–16 Readers can delve into different reviews on in situ gellying polymers for different routes of drug delivery such as intra nasal or ophthalmic.¹⁷,¹⁸ Aim of this short review is to highlight important features of stimuli-responsive polymers for drug delivery.

Special emphasis in this article has given on pH responsive polymers because they are the most studied stimuli sensitive polymer after thermo-responsive.¹⁹ Synthesis and application of pH-sensitive polymers have discussed detail in recent past too.²⁰ In our physiological system different body parts or organs have different pH. Not only normal body systems or tissues, abnormal cells like tumors and cancer tissues have different pH (Table 1).¹⁹ Therefore a pH responsive polymer based drug delivery system can be customized to deliver the drug at the intended site of action. But selection of suitable polymer based on the intended site is the most important step to extract the advantage. Therefore the objective of this article is to highlight basic features of stimuli-responsive polymers emphasizing on pH-responsive polymers for drug delivery system.

Table 1: pH in different systems, organs or tissues in human body

Organ/system/tissue	pH
Blood	7.35–7.45
Stomach	1.0–3.0
Small intestine	4.8-6.7
Colon	7.2
Tumour, extracellular	7.2–6.5
Early endosome	6.0–6.5
Lysosome	4.5–5.0

2. Different stimuli

As mentioned before, stimuli-responsive polymers currently comprise of 5 environmental stimuli which are temperature, pH, electric field, light and ultrasound.⁹ Some of the physical properties of the polymers can be altered by two stimuli, but commonly only one stimulus can cause the physical alteration towards the particular polymer.²¹ Temperature sensitive smart polymer or thermosensitive polymer is the common studied polymer among stimuli-responsive polymers.^10,22–25 Basically, it comprises two different types, the one which has lower critical solution temperature (LCST) and another has upper critical solution temperature (UCST). Below LCST, the polymer acquired the hydrogen bonding with the aqueous solution (enthalpy dominated), but above LCST, the polymer become hydrophobic and precipitation of polymer occurs (entropy dominated).²⁶ The concept of UCST is vice versa. In drug delivery applications, LCST polymers are regularly used compared to UCST polymers as the heat-labile drugs prone to degradation at high temperature. The most common temperature sensitive polymer used for drug delivery is poloxamer 407 or poloxamer 188 (in situ gel Parkinson).²⁷

Figure 1: Polymeric phase transition by temperature stimuli (A) lower critical solution temperature (LCST) behavior, (B) upper critical solution temperature (UCST) behavior T: Temperature, Φ: Polymer volume fraction

The polymers of which the phase transition can be stimulated by light, usually UV and visible light, are known as light-responsive polymers. Common polymers under this category are azobenzene, stilbene and triphenylmethane.²⁶ In general, they possess chromophore group in their chemical structure which can absorb light energy to be distributed locally as heat energy. This phenomenon causes increase in the local temperature which then affects the swelling behavior of the hydrogel.²⁸ Visible light got more favors than UV light because it is inexpensive, safe, readily available and easily manipulated.²⁹

Another type is electro-sensitive polymer, as it name depicts, it undergo gel-sol changes when stimulated by electric current. It converts electrical energy to the mechanical energy by disrupting of the hydrogen bonds between the polymers which cause the degradation of the insoluble polymer. This group contains a huge amount of ionizable group in the chemical structure and mostly also exhibit pH-responsive properties.⁹ Hence, among the application of this particular type of polymer is to develop dosage form for drug release in pulsated manner which can be acquired by controlling the intensity of the electric current.³⁰

Ultrasound smart polymer, also called Ultrasound Responsive Drug Delivery System (URDDS) which practically revolves around microbubbles, nanobubbles, nanodroplets, micelles, liposomes and emulsions.³¹ For instance, ultrasound itself had been proven to enhance permeability of the cell membrane. On top of that, microbubbles are able to potentiate the permeation effect by becoming the cavitation nuclei filled with gas inside.³² This helps to increase the accuracy of targeted delivery systems. Some of the research manipulated the ultrasound responsivity to increase the temperature at the surrounding of the carriers which can be useful in chemotherapy based targeted drug delivery system.³³ These examples show that the stimuli-responsive polymers can be manipulated and modified according to the purposes to synthesize the new beneficial products in the future.

3. pH responsive polymer

pH responsive polymers are prone to change their structural nature and physical properties such as surface activity, chain configuration, solubility etc. in response to the change in pH of the solution. Therefore different type of phenomena such as shrinkage, swelling, gellying or coating occur when a pH-responsive polymeric system comes in contact of a stimulating systemic pH.²⁰ Such unique nature of pH-responsive polymers have made them suitable for application in drug delivery especially for targeted and controlled delivery.

3.1 General characteristics

pH-responsive polymers can have linear, branched or network like structure. The most responsible element in the structure of such polymer to pH response is an ionizable group that is attached with hydrophobic backbone of the polymeric chain. pH-responsive polymers, in general, can be defined as a class of polyelectrolytes with ionic functional groups, which could be weak acidic (eg. Carboxylic, sulfonic etc.) or weak basic (imidazole, pyridine etc.).³⁴ This ionizable group can either accept H⁺ (protonation) or donate H⁺ (de-protonation). Based on the protonation or deprotonation net electrostatic charge on the polymeric chain changes that lead to alteration of conformational structure and hydrodynamic volume.³⁵ This alteration, in turn, causes the physical changes in the polymer based system.

An increase in electrostatic charge may cause electrostatic impulsion between polymer chains that may cause extension or opening of polymer chains from collapsed condition. When electrostatic charge decreases vice-versa effect takes place. Increasing electrostatic charge is also responsible for increase in hydrophilicity, which may increase polymer aqueous solubility. Alteration of electrostatic charge may also cause self-assembly such as formation of micelles, unimers, gels, vesicles and swelling, de-swelling etc.²⁰ (Figure 2). The pH at which such conformational or structural change takes place is termed as transition pH. The transition pH value is related with the pKa value of the polymer. Usually ionizable polymers that have pKa value within 3 to 10 act as pH responsive system.¹⁹

Figure 2: Different types of assembly of pH sensitive polymers

A: Micelle, B: Swelling, C:Gellying

3.2 Types of pH-responsive polymers

Numerous number of polymers have been synthesized to achieve pH mediated response. As mentioned in the earlier discussion that ionizable moiety in the polymer is the key responsible factor for pH mediated response, the polymers could be categorized based on the type of acidic or basic ionizable moiety. The polymers are classified here in three groups as i) poly acids or poly anions ii) poly bases or poly cations iii) naturally occurring. The detail classification of pH-responsive polymers is presented by table 2.³⁴

i) Poly acids or poly anions

This group includes acidic ionizable moiety which can donate proton at high pH value. The most common family under this group is carboxylic acid (-COOH) group. At basic pH it releases proton to form anionic charged molecule and at basic pH it receives proton and turns into uncharged macromolecule. Poly acrylic acid (PAA) or poly methcrylic acid (PMA) are popular candidates of this group.³⁴ Other acidic group in this class are sulfonic acid and phosphoric acid group. Both of these groups attached polymers are used to synthesize hydrogel due to their swelling nature at basic pH.³⁶

ii) Poly bases or poly cations

Weak polybases undergoing inonization-deionization transition pH ranging 7- 11 are categorized under this class. Usually these polymers contain –NH2 (amine) group at side chain.²⁰ Unlike polyanions, these groups accept proton at low pH and form polyelectrolyte and donates proton at basic pH. Table 2 describes the member of this class of polymers.

iii) Natural polymers

Apart from synthetically obtained polymers there are few natural polymers also that act as pH-responsive system. These polymers are of great interest now due to their biocompatibility. Easy chemical modification can be done on natural polymers to improve its effect. That type of substituted or grafted pH-responsive polymers are also gaining major interest of the researchers.³⁷ Major players of this group are mentioned in the table 2.

Table 2: Classification of pH responsive polymers

Type	Ionizable Group	Major member
Polyacids/poly anions	Carboxylic acid (-COOH) group	poly(methacrylic acid) Poly(acrylic acid) Acrylic acid Methacrylic acid
	Sulfonic acid (-SO3H) group	poly(2-acrylamido-2-methylpropane sulfonic acid) poly(4-styrenesulfonic acid)
	Phosphonic acid group	Phosphorus-containing (meth)acrylate
Polybases/poly cations	Primary, secondary or tertiary amine	Poly (N, N’-dimethyl aminoethyl methacrylate), Poly (2-aminoethyl methacrylate), Poly (ethylene imine)
	Nitrogen-containing aromatic groups,pyridine	poly (2-vinyl pyridine), poly (4-vinyl pyridine)
	Nitrogen-containing aromatic group, imidazole,	poly (N vinyl imidazole), poly (4-vinyl imidazole)
Natural	Anionic polysaccharide	Alginate, carboxymethyl cellulose, pectin, hyaluronic acid, agar, carrageenan
	Cationic polysaccharide	Chitosan

3.3 Application in drug delivery

pH responsive or pH sensitive polymers used in drug delivery for different purposes and by different routes. Commonly studied delivery system containing pH responsive polymers are discussed below with few instances of recent relevant researches.

3.3.1 In situ gellying (intra nasal and ophthalmic)

In situ gellying system is defined as a delivery system which remains a liquid in external environment but converted to gel when administered into body system. Not only pH sensitive, in situ gel is also prepared with thermo-sensitive polymer.³⁸ However the present discussion is focused on pH responsive in situ gellying system. Compared to normal solution or gel, in situ gel is advantageous in terms of higher retention on applied mucosa, higher rate of penetration, measurement of accurate dosing etc.³⁹

At present an alternate route of drug delivery to brain is popular to the researchers, which is intra nasal delivery.⁴⁰ The main advantage is to bypass blood brain barrier for drugs targeted for brain. Recently an anti-schizophrenic drug, palperidone has been developed as an intranasal pH sensitive in situ gellying delivery system.⁴¹ An optimized ratio of carbopol 934 (0.2%) and hydroxypropyl methyl cellulose K4M (0.4% w/v) was used as polymers. Carbopol 934 has pH responsive gellying nature. Above a certain concentration and respective pH carbopol solution turns to gel. For instance, we have observed that 0.3 % w/w carbopol 940 P solution turned into gel at pH above 6.8.⁴² Palperidone intra-nasal formulation has showed better retention on skin due to mucoadhesion nature and better permeation too.

In another research ciprofloxacin ophthalmic drop has been formulated as in situ ophthalmic gel using sodium alginate and HPMC as carriers.⁴³ Sodium alginate, an ophthalmic gel forming mucoadhesive polymer was chosen as polymer. It can undergo instantaneous gel formation due to formation of calcium alginate by reacting with divalent cation (Ca²⁺) present in ophthalmic fluid. Hydroxy Propyl Methyl Cellulose was further incorporated as a viscosity enhancer. The formulation resulted in sustained release drug property.

3.3.2 Tumor targeted delivery

For cancer therapy, pH-responsive polymers are used to control the drug release and for better penetration into tumor cells. In a recent research, bleomycin was formulated as a liposomal delivery system indicated for cancer chemotherapy.⁴⁴ The pH-responsive effect was imparted to the long circulating liposome by incorporating 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidy lethanolamine (CHexPG-PE). The result showed that PEG-PE/CHexPG-PE-introduced liposomes resulted in pH-mediated release of drug and 25 times higher uptake by tumor cells than that of liposome without CHexPG-PE. The authors assumed that the higher cellular association could be attributed to hydrophobic interaction derived from bulky cyclohexyl units of CHexPG-PE.

In another research cellular uptake of curcumin (Cur) by tumour cells was increased when it was formulated as a novel flexible acid-responsive micelle by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers.⁴⁵ The curcumin conjugate synthesized with pluronic F68-cis aconite can spontaneously precipitate to form homogenous micelles of about 100 nm in aqueous solution. In acidic pH, cic-aconite pH sensitive linkage breaks and cur release occurs subsequently.

Another tumor-related pH responsive application is tumor specific targeting based on its surface marker. In a study, hyaluronic acid was introduced with dicarboxylic anhydrides which are 3-methyl glutarylated (MGlu) units or 2 carboxycyclohexane-1-carboxylated (CHex) units to compare the sensitivity of the pH for each combination. Here hyaluronic acid having two roles which are pH responsive polymer and specific targeting towards cancer cells surface marker, CD44. The study proved that at neutral pH the polymer-modified liposome is stable but not in weakly acidic condition resulting the liposome to release its content at CD44 environmental pH.⁴⁶

3.3.3 Intestinal targeted delivery

Some diseases occur in the gastro intestinal tract (GIT), particularly in intestinal part. For example, inflammatory bowel disease which normally occurs in colon requires local compared to systemic drug delivery because more specific delivery can reduce systemic side effect and also reduce the dose of the drug used.⁴⁷ One of the methods to achieve the intestinal targeted delivery is by utilizing pH-sensitive polymer as a component of site-specific delivery of the drugs.

In a recent research alginate was modified with sodium acrylate and N-vinylpyrrolidone to become pH sensitive polymer to carry the drug to the small intestine via hydrogel. It used bovine serum albumin as the protein drug to investigate the swelling profile of the hydrogel in pH 7.4 (environmental pH of small intestine) which directly related to drug release behavior.⁴⁸ The optimized ratio of modified alginate, sodium acrylate and N-vinylpyrrolidone has been selected for release mechanism, Fickian diffusion and pseudo-Fickian diffusion.

In another research pH sensitive microparticles were used to deliver the drug at the small intestine. The polymer responsible as pH sensitive action is poly (methacrylic acid-co-ethyl acrylate) in 1:1 ratio. The model drug used for the study is pravastatin.⁴⁹ The incorporation of pH sensitive polymer enhances the ability of the drugs to stay in the harsh acidic condition.

pH sensitive nature of some polymer was also used to develop pH sensitive lignin-based micelles complex. The drug used is ibuprofen and the target site of action is small intestine. The result shows that more than 75% ibuprofen can be preserved in simulated gastric fluid (pH 1.2) and more than 90% ibuprofen can be released in simulated intestinal fluid (pH 7.4).⁵⁰ Besides, the same drug also has been utilized in another research but using different polymers for micelles and pH sensitive carboxylic groups are attached to the micelles. This study shows that less than 10% of the drug loss in simulated gastric fluid over 2 hours, whereas almost immediate drug release takes place in simulated intestinal fluid.⁵¹

3.4 Application in imaging

In biomedical application, particularly in tumor medical treatment, several researches have been made to exploit the differences in environmental pH inside and outside the solid tumor as proven that extracellular tumor is more acidic than the intracellular (pH 7.0-7.2).^52,53 Instead of tumor pH, it is also been utilized to detect intracellular pH value by using the ratiometric fluorescent nanogel which is able to sense pH in the range of 6.0 to 8.0 using polyurethane polymer after consolidating with the pH indicator bromothymol blue (BTB). In short, two standard fluorophores (coumarin 6 and Nile Red) that exhibit efficient fluorescence resonance energy transfer (FRET) were chosen which are capable to give dual read and green ratio of fluorescence. The ratio is obtained from Nile Red (NR) that forms red colour at pH 6.0 and coumarin 6 (C6) that appears as green at pH 8.0.⁵⁴

Furthermore, dopamine-modified polyfluorene derivative (PFPDA) also can be used as pH responsive polymer by covalently attached dopamine to the polyfluorene derivative. The mechanism is related to the property of dopamine, at high pH, it will form quinone (oxidized dopamine) which suppress the ability to fluoresce, whereas at low pH, it forms hydroquinone (reduced state) which allow the fluorescence due to the absence of electron transfer from the polymer backbone to the hydroquinone.⁵⁵ By applying PFPDA, the pH value of autophagy reaction of the cells can be detected. Few more notable applications of pH-responsive polymeric drug delivery system published in last 2-3 yrs. have been compiled by table 3.

Table 3: Recent studies on pH-responsive drug delivery system

Name of the drug	Type of delivery system	pH responsive polymer	Objective	Reference
Doxorubicin	Nanoparticle	Chitosan	To deliver drug targeted to cancer cells by chitosan coated magnetic nanoparticle	⁵⁶
Afatinib	Liposome	Cholesteryl hemisuccinate	To deliver the drug to cancer cells by pH-sensitive liposome.	⁵⁷
Erlotinib	Nanoparticle	Poly ethylene imine	For controlled release of the drug at targeted cancer cells	⁵⁸
Desipramine	Nanoparticle	Polydopamine (PDA)	For controlled release and cancer therapy	⁵⁹
Ibuprofen	Hydrogel	Alginate-Brushite (Alg-Bru)	To investigate the controlled-release of the drug from the hydrogel	⁶⁰
Salicylic acid	Hydrogel	Acrylic acid, Polyethylene glycol (PEG) diacrylate	To obtain sustained-release of the drug at the intended site of action	⁶¹
Concanavalin A	Liposome	Glucosylated ampiphile (GA)	To achieve drug with controlled-release at low pH associated with pathological tissues.	⁶²
Atenolol	Nanohybrid	Sodium carboxymethylcellulose (SCM)	To investigate drug release profile.	⁶³
Curcumin	Micelles	Konjac glucomannan (KGM)	To deliver drug at the intended site of cancer cells.	⁶⁴
Doxorubicin	Nanoparticle	Chitosan, Methacrylic acid	To carry and release the drug towards the cancer cells.	⁶⁵
Doxorubicin	Nanoparticle	Carboxymethylcellulose (CMC)	To investigate drug release profile at the cancer cells.	⁶⁶
Doxorubicin	Micelles	Methyl poly (ethylene glycol) ether-b-poly (β-amino esters)-b-poly lactic acid	To enhance drug release rate in well-controlled behavior to deliver the drug to the cancer cells	⁶⁷
Paclitaxel	Nanoparticle	Modified glycol chitosan	To deliver the drug at the breast cancer	⁶⁸
Silibinin	Nanoemulsifying	Oleic acid, Glycerol monocaprylate	To protect the drug from acidic condition in the stomach so that the drug can be absorbed	⁶⁹

3.5 Challenges

In spite of many proof-of-concept articles clinical effectiveness of stimuli responsive polymeric system is not fully established yet. For instance, higher molecular weight of stimuli responsive polymers are generally more effecting in delivering the drugs at their cellular targets, but as to date, they are hardly biodegradable and excretion from the body is questionable.⁷⁰ The problem of biodegradability also faced specifically for pH responsive polymer. Therefore further research involving in vivo cytotoxicity, biodegradability and pathway of distribution need to be done to solve this problem so that this polymer can be practically useful in clinical setting.⁷¹ The most preferable route of administration which is oral may be exploited extensively for the application of pH responsive polymer as the main advantage can be controlled release of the drugs.⁷² Besides, gastrointestinal tract (GIT) comprises with wide range of pH from oral cavity until the large intestine which makes it really fits for the application for this type of polymer. The major challenges need to overcome by these smart polymers to become clinically effective include biodegradability, biocompatibility and excretion from body system³⁴.

4 CONCLUSION:

This review summarizes important aspects on stimuli responsive polymer emphasizing on pH responsive polymeric drug delivery and some of its potential applications. There are many enteric coated oral formulations in market which releases the drug in intestine at basic pH. However other than oral delivery or enteric coated delivery, stimuli sensitive system for other targeted drug delivery is rare. Thus, the comprehensive studies from the choice of polymer until the effectiveness of delivering the drugs need to be more advanced as the drugs such as biopharmaceuticals or biomolecular are generally complex in nature. Ensuring safety and efficacy of stimuli sensitive system is crucial for being approved by regulatory bodies. However with new types of biomaterials or bio-composite synthesis it can be hoped that pH responsive or other stimuli responsive polymeric drug delivery system would overcome the challenges to developing clinically effective site specific or targeted newer drug delivery systems.

5 ACKNOWLEDGEMENT:

Partial financial support to arrange the resources for writing this article has been provided by the fundamental research grant scheme from Ministry of Higher Education Malaysia (FRGS/17-006-0572).

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Received on 11.06.2018 Modified on 20.08.2018

Research J. Pharm. and Tech 2018; 11(11): 5115-5122.

DOI: 10.5958/0974-360X.2018.00934.4