The stimuli sensitive polymers have proved its applicability in forming hydro-gels [1], drug delivery[2] and target specificity[3]. Some stimuli sensitive polymers occur in nature likeeg, chitosan, cellulose, xyloglucan and many of them are routinely synthesized like, poly(N-isopropylacrylamide) (PNIPAAm) and co-polymers of PNIPAAm[4]. Nature has designed complex structures in response to various external stimuli. For example, the nano-composite structure of collagen fibrils in sea cucumber alters stiffness of its inner dermis[5]. This alteration of connective tissue is reversible, which acts as a defense mechanism[6, 7].
Capadona etal.,synthesized a chemo-responsive polymeric nano-composite structure, which mimics the response of collagen fibrils when exposed to similar physiological conditions. This polymeric nano-composite is based on ethylene oxide-epichlorohydrin copolymer on to which rigid nanofiber network of cellulose was assimilated [8].
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Structure of cellulose whiskers, ethylene oxide-epichlorohydrin and polyvinyl acetate matrix polymer. Cellulose whiskers was isolated from tunicate cellulose pulp by sulfuric acid hydrolysis[9].Study of nanocompositeisbased on a rubber like ethylene oxide–epichlorohydrin (1:1) copolymer (EO-EPI) into which arigid cellulose nanofiber network was assimilated [9].
Naturally derived stimuli sensitive polymers have inherent properties like biocompatibility, efficient degradation of byproducts and specific biological interactions, these polymers have limitations like limited availability, batch to batch variation resulting in composition, poor mechanical strength as compared to synthetic stimuli sensitive polymers. Naturally derived stimuli sensitive polymers like chitosan, a polysaccharide, which is not stimuli sensitive but could be made stimuli sensitive by mixing with glycerophosphate, other examples are cellulose derivatives like methyl cellulose, hydroxypropylmethyl cellulose[10]. A list of naturally derived stimuli sensitive polymers along with chemical structures is mention in table 1.
1.1 Stimuli responsive polymers
Synthetic polymers have proved there applicability as therapeutic agent in drug delivery. These polymers showbetter pharmacokinetic property with greater ability for tissue targeting. The synthetic polymershows response when stimulated by external stimuli hence, they are called smart polymer or stimuli responsive polymer [15]. The stimuli-responsive polymer works on the principle of identification, evaluation of external signal and then by changing its structural conformation[16].These stimuli are classified as physical (temperature, light, electrical field), chemical (pH,ion, redox)[17], and biological responses.This results in change in a conformation, alteration in partition coefficient or solubility, drug release or more than one change at same time[18].
Physical responsive polymers
Some polymers respond to physical stimuli like temperature, light, electrical field, magnetic field,etc.Polymers which become insoluble on heating, have lower critical solution temperature (LCST) like, PNIPAM [19], and those which become soluble on heating have upper critical solution temperature (UCST) like, poly (2-phenyl-2-oxazoline) (PPhOx) [20].
Temperature sensitive polymers
Thermo-responsive polymers utilize small changein temperature to cause macroscopic alteration in polymer material [21]. Various types of thermo-responsive fluorescent polymers like a) PNIPAAmb) PNIPAAm-fluorescent labeled c)PNIPAAm-co-butyl methacrylate-fluorescent labeled, a hydrophobic co-polymer butyl methacrylate (BMA) was used to lower LCST to a precise temperature d) PNIPAAm-co-DMAPAAm-fluorescent labeled] (Figure. 2), N,N-dimethylaminopropylacrylamide(DMAPAAm) causes increase in LCST throughhydrophilization of polymeric chain,where synthesized, which shows thermo selective cellular uptake, enables determination of normal and pathological cell[21].
Light sensitive polymers
The light sensitive polymers undergo photochromism, in which, an reversible chemical transformation occurs between two isomeric forms of same structure after absorption of light[22]. Absorption of light leads to photochromism which results alteration in absorption spectra[23]. Pericyclic reaction, dissociation process, cis-trans isomerization, electron transfer(oxidation-reduction) and intramolecular hydrogen transfer or group transfer are the mechanisms involved in it[24]. A reversible contraction and expansions in shape and volumes of photochromic light crystal elastomers (LCE) in response to light stimulation.These LCE filmscontainpoly(siloxane) as main chain and cross-linkedchromo-thermicazobenzene, this film was placed on solid support, which helps maintaining temperature to 85°c.
1.1.2 Chemical responsive polymers
Polymer which exhibits change in configuration or which responds to chemical stimuli like pH, ion and other stimuli are known as chemical responsive polymers like, poly(methylacrylate)[25].
1.1.2.1 pH responsive polymers
pH responsive polymers contain pendant reactive groups which when are cross-linked with other polymer forming hydrogel shows response to stimulus like pH [25]. In recent years, muchwork has been exploredon co-polymerization of pH and temperature sensitive monomers[17, 26]. Graft co-polymers were synthesized to show temperature and pH sensitivity. A side chain temperature sensitive polymer (Figure 4.), the amino terminal ofNIPAAm was graftedon a carboxyl group of pH sensitive backbone polymer, like poly(acetic acid) (PAAc), in the presence of dicyclohexylcarbodiimide (DCC) and methanol byusing coupling method[26].
Stimuli sensitive polymer-dye conjugation
Dyes or indicatorsare used to sense or react to particular stimuli like pH and temperature [27]. Some indicator changes color in H+ and OH– ion solution due to which they are use as pH sensitive dyes and those which changes color by deflection in temperature are use as temperature sensitive dyes [27]. A list of thermo-chromic polymer-dye conjugations are shown in table 2.
The novel chromogenic polymer gel network was synthesized by mixing poly(alkoxy) derivative with bromothymol blue, which yields transparent green gel (Figure 5.), at 33°c, green gel turns intolight yellow gel with gradual increase in temperature[29]. In table 2, list of different chromogenic polymer gel networks arementioned.Poly(alkoxy) gel network was used to form complex with other dyes like, nitrazin yellow, where, color of gel network changes from blue to green. Similarly, for chlorophenol red, where color changes from red to yellow PVA-borax-cresol, phenol substituted dye (cresol) was conjugated with PVA-borax complex to obtain thermochromic hydrogel. Other example, PVA-borax-2,6-diphenyl-4-(2,4,6-triphenylpyridinio)phenolate (DTPP) forms reversible thermochromic hydrogel.
Such system shows color change and increase in absorption by a gradual increase of temperature. The absorption spectrum of DTPP explains dependency of absorbance on temperature causes bathochromic shift of absorption maximum [28].
InBorax-PVA-DTPP network,DTPP was embedded in PVA-borax gel matrix, boric acid is cross linked to PVA polymer that is, borate ions reacts with hydroxyl group present on PVA to form monodiol-borate complex and didiol-borate complex [30].
Another example of gel containing dye composed of two polymers (PVA and polyether) includes addition of zwitterionicsurfactant, which is a dipolar surfactant,was selected to avoid strong ionic interaction with anionic dye. This surfactant, like, sulfobetain forms aggregates above its critical micelle concentration therefore, it can influence U.V-absorption spectra of a water soluble dye like phenol red as shown in [31].
The dye can also be conjugated with dendrimer to enhance imaging applications and for metal ion probing[32]. For example, generation 5 poly(amidoamine) [G5(PAMAM)] dendrimercontaining 128 surface sites which can incorporate 0 to7 dyes like, 6-carboxytetramethylrhodamine succinimdyl ester (TAMRA), fluorescein. Acetylation yields complete conjugate of dendrimer and dye [33].
nano sized stimuli sensitive polymers have been proved to show response to external signaling [34]. pH sensitive system was prepared by the combination of two modified pH sensitive indicator dyes like, N-fluoresceinylacrylamide (FA), and N-acrylamide-N?-rhodamine B thiourea (Rh B) (Figure. 11).These two functional monomeric dyes were copolymerized with acrylamide and methylenebis(acrylamide) in w/o micro-emulsion to form dye conjugated poly(acrylamide nanoparticles [35]. Synthesis ofN-fluoresceinylacrylamide- N-acrylamide-NE?-rhodamine B thiourea (FA-Rh B)copolymerized nanoparticles. The two functional monomeric dyes FA and Rh Bwere co-polymerized with acrylamide and methylenebis acrylamide in w/o micro-emulsion [35].
Fluorescence emission spectra of polyacrylamide nanoparticle conjugated with fluorescein and rhodamine dye. The fluorescence emission intensity of Rh B remains unchanged with increasing pH whereas that of FA increases.
An amine functionalized RAFT co-polymer poly {N-(2-hydroxypropyl) methacrylamide-b–N-[3-(dimethylamino)propyl] methacrylate} {poly (HPMA258–b-DMAPMA13)} was labeled by fluorescent dye like, 6-(fluorescein-5-carboxamido)hexanoic acid, succinimidyl ester (5-SFX) using anhydrous DMF along with triethanolamine which catalysis the reaction [36]. The primary amine of poly(HPMA258-b-DMAPMA13) is more reactive than tertiary thiol group this allows conjugation of 5-SFX with poly(HPMA258-b-DMAPMA13).
?-cyclodextrinis cyclic oligosaccharide [37], which has been proved for large number of applications like, increasing solubility [38], detection of compounds [39], immobilization of toxic compounds [40], drug release [41] etc. Some dyes were conjugated in complexing agent like an azo dye inside ?-cyclodextrincavity.Azo dye like methyl red indicator shows color change from yellow to red as pH decreases, this is because of the protonation of azo group (Figure 14.). Methyl red (MR) shows yellow color when complexes with ?-CD even in acidic pH 4.The complex was formed in dimethylacetoamide by using an condensing agent like, dicyclohexylcarbodiimide, it becomes useful in detection of neutral species which will act as guest inside MR-?-CD complex and will replace MR, which changes its color to red [42].
Role of polymer-dye conjugation in cellular uptake
Cellular uptake consist of endocytosis process in which extracellular compounds are captured by plasma membrane forming vesicles. Along with endocytosis there are other methods like, receptor mediated pathway, phagocytosis and micro-pinocytosis[43].
The plasma membrane of a eukaryotic cell has a barrier which allows small and uncharged molecules to pass through it[44].The nano sized polymers, despiteplasma membrane barrier, can irreversibly interact with lipid membraneby insertion of dangling side chains into the hydrophobic region of cell, which can be explained by molecular dynamics[45].Polymer like 2-methcryloyloxyethyl phosphorylcholine (MPC) was copolymerized with n-butyl methacrylate (BMA) forming poly(MPC-co-BMA)[46],thecovalentlylabeledrhodamine Btopoly(MPC-co-BMA) (rhoPMB)was synthesized using free radical polymerization method with perbutyl-ND as an initiator.RhoPMB30 was distributed inside live HepG2 cell (a human hepatocellular liver carcinoma cell line).
Natural polymer is applicable in biomedical, environmental science and agricultural field like, hydrophobically modified glycol chitosan (HGC) that can form stable nanoparticles. HGC shows prolonged blood circulation period when the particle size is controlled. It accumulates selectively inside tumor cell when administered systemically [47] and applicable in delivering various therapeutic agents like, peptides, genes and small anticancer drugs [43].
The polymer conjugate probes are applicable for penetration inside the membrane of tumor cell for treatment[48], detection[49] or diagnosis[50, 51].
Further study for the conjugation ofpolymer and pH sensitive dye to form a reusable system which will sense or exhibit color change at different pH ranges.
