Poly(N-isopropylacrylamide)-Based Polymers: Recent Overview for the Development of Temperature-Responsive Drug Delivery and Biomedical Applications

Temperature is a widely incorporated stimulus in pharmaceutical applications because of its efficiency as a therapeutic medium; thus, substantial evidence on temperature-responsive polymer applications is reported. Poly(N-isopropylacrylamide) (PNIPAAm) is a well-established, temperature-responsive polymer that exhibits a low critical solution temperature (LCST) at ≈ 32°C, which is close to physiological temperature. Hence, they are widely used in various pharmaceutical applications, such as drug delivery with nanocarriers and thermogels. Varying the LCST for different applications can be achieved by copolymerization with other hydrophobic or hydrophilic molecules, making it a favorable smart polymer. PNIPAAm is reported to enhance drug delivery by incorporation with nanocarriers and to facilitate prolonged drug delivery, thereby avoiding the burst release of drugs in temperature-responsive hydrogels. The application of PNIPAAm is not limited to drug delivery, and it is also applied in biomedical applications such as chromatography systems and cell culture applications, where its incorporation in cell culture media enhances cell production. The unique and versatile properties of PNIPAAm render it a promising smart polymer for various functional applications. Hence, this review focuses on the diverse applications of PNIPAAm.     

Thermo‐Responsive Organic/Inorganic Hybrid Hydrogels based on Poly(N‐vinylcaprolactam)

A new type of ‘intelligent’ hydrogels has been developed in the form of organic/inorganic hybrid materials by making use of the sol‐gel technology. Poly(N‐vinylcaprolactam) (PVCL) has been incorporated in these materials for its thermo‐responsive properties. The synthesis of the hybrid hydrogels was achieved by the in situ formation of an inorganic silica phase in the presence of an aqueous solution of high molecular weight PVCL. This methodology results in the preparation of micro‐heterogeneous systems in which silica particles of nanometer dimensions act as physical cross‐links for the PVCL molecules. Hydrogen bonds between the remaining non‐condensed silanol groups and the PVCL carbonyl functions, together with physical entanglements, are responsible for the strong interactions between the organic and inorganic phases. Stress‐strain tests on highly swollen materials demonstrated that the unique structure of these thermo‐responsive hybrid hydrogels improves the mechanical stability to a great extent as compared to conventional hydrogels. Transmission measurements demonstrate that the presence of the inorganic phase does not influence the cloud point temperatures of PVCL significantly. On the other hand, the response of the reinforced hybrid hydrogels to temperature becomes less pronounced for increasing silica fractions. The reversibility of the swelling/deswelling process has been demonstrated by swelling experiments as a function of temperature.

PVCL/SiO₂ hybrid hydrogels.     

Tunable Dual‐Thermoresponsive Phase Behavior of Zwitterionic Polysulfobetaine Copolymers Containing Poly(N,N‐dimethylaminoethyl methacrylate)‐Grafted Silica Nanoparticles in Aqueous Solution

Novel thermoresponsive copolymers of zwitterionic sulfobetaine methacrylate (SBMA)‐ and N,N‐dimethylaminoethyl methacrylate (DMAEMA)‐grafted silica nanoparticles are prepared via surface‐initiated atom transfer radical polymerization. The phase behavior of these nanoparticles is investigated. The hybrid nanoparticles exhibit tunable phase transition temperature between the upper critical solution temperature (UCST) and the lower critical solution temperature (LCST) in aqueous solution. A high PSBMA content in P(SBMA‐co‐DMAEMA) copolymer in the hybrid nanoparticles leads to aggregation at low temperatures because of dominant electrostatic interactions of ionic pairs, whereas a relatively low PSBMA content in the hybrid nanoparticles results in a phase transition at high temperatures as a result of predominant hydrophobic interactions of the PDMAEMA. Interestingly, hybrid nanoparticles with a suitable molar ratio of SBMA/DMAEMA exhibit both UCST and LCST in aqueous solution, where the water‐insoluble microdomains of hybrid nanoparticles are generated by the PSBMA or PDMAEMA region depending on the temperature. The above dual‐thermoresponsive phase transition is also controllable in salt solution. A facile change in the molar content of copolymer grafted on silica nanoparticles will tune the UCST and LCST readily.

     

Refined control of thermoresponsive swelling/deswelling and drug release properties of poly(N-isopropylacrylamide) hydrogels using hydrophilic polymer crosslinkers

Thermoresponsive poly(N-isopropylacrylamide) (PNIPAm)-based hydrogels are widely investigated for their ability to alter their physical properties (e.g. dimensions, swelling/deswelling) in response to change in temperature. Despite extensive research efforts, it is still challenging to control various aspects of thermoresponsive physical properties of PNIPAm hydrogels in an efficient and comprehensive manner using conventional small molecular crosslinkers due to their limited solubility and functional groups. Herein, thermoresponsive swelling/deswelling behavior of PNIPAm hydrogels is tuned in a wide range by hydrophilic polymeric crosslinkers with varying chain lengths. The concentration and molecular weight of the poly(ethylene glycol) (PEG) crosslinker are varied to control the swelling/deswelling behavior, drug release, and lower critical solution temperature (LCST) of PNIPAm-PEG hydrogels. Compared with PNIPAm hydrogels crosslinked with a conventional small molecular crosslinker, N,N′-methylenebisacrylamide, greater degree and range of thermoresponsive swelling/deswelling as well as tunable LCST are demonstrated for PNIPAm-PEG hydrogels. In addition, more swelling-controlled PNIPAm-PEG hydrogels displayed more sustained and variable thermoresponsive drug release based on their crosslinking density, by modulating the hydrophobic transition of PNIPAm chains with hydrophilic PEG chains. In sum, various thermoresponsive properties of PNIPAm hydrogels could be controlled by hydrophilic polymeric crosslinkers, and this strategy could be applied to various hydrogel systems to control their physical properties for biomedical applications.     

Temperature‐Responsive Electrophoretic Deposition of Sulfone‐Containing Nonionic Poly(N‐isopropylacrylamide)

Recently, it has been found that nonionic aliphatic and aromatic poly(ester sulfone)s show anode selective electrophoretic behavior, and it is shown that the electrophoresis is induced by a partial charge separation of the protic solvent at the dispersion interface. In this paper, the first example of temperature‐responsive electrophoretic deposition (EPD) is reported. Electrophoresis of a nonionic sulfone‐containing poly(N‐isopropylacrylamide) [poly(NIPAM)] is performed above the lower critical solution temperature. The poly(NIPAM) is prepared via reversible addition–fragmentation chain transfer radical copolymerization of NIPAM with a sulfone‐containing methacrylate. After EPD, adhesion of human umbilical vein endothelial cells on the deposited surfaces is also demonstrated, aiming at the subsequent temperature‐sensitive detachment.     

Thermal Sensitivity of tert‐Butyloxycarbonylmethyl‐Modified Polyquats in Condensed Phase and Solubility Properties of Copolymers with N‐Isopropylacrylamide

The synthesis of the easily decomposable ionic monomer 2‐tert‐butoxy‐N‐[2‐(methacryloyl‐oxy)ethyl]‐N,N‐dimethyl‐2‐oxoethanammonium chloride ( 3 ) via thermally induced syn‐elimination of a tert‐butyl ester group was realized simply by mixing N,N‐dimethylaminoethyl methacrylate ( 1 ) and tert‐butyl chloroacetate ( 2 ) at ambient temperature without solvent. The obtained salt was polymerized via free radical polymerization. The decomposition and foaming via iso‐butene formation takes place by heating up to about 160 °C. IR, DSC, TGA, and GC/MS measurements were performed to follow this pyrolysis reaction. Furthermore, the copolymerization of 3 with N‐isopropylacrylamid (NiPAAm, 5 ) was carried out with different monomer ratios. Molar mass distributions were measured using an asymmetrical flow field‐flow fractionation (aFFFF) system. The obtained copolymers 6–10 exhibit lower critical solution temperature (LCST) behaviour in water with cloud points at different temperatures depending on the monomer ratio.

     

Parameters Affecting the Lower Critical Solution Temperature of Linear and Crosslinked Poly(N‐ethylacrylamide) in Aqueous Media

A series of linear poly(N‐ethylacrylamide) (PEA) samples varying in molar mass has been prepared by free radical polymerization in the absence and presence of a chain transfer agent and a hydrogel of PEA has been prepared using N,N‐methylenebisacrylamide (BIS) as crosslinker. The lower critical solution temperatures (LCST) of the linear polymers in water and aqueous media were determined turbidimetrically as a function of molecular weight, concentration, heating/cooling rate, and concentrations of KCl and anionic surfactant sodium dodecyl sulfate (SDS) in the aqueous solution. The corresponding LCST for the hydrogel was determined from the gravimetric swelling ratios (r). In pure water the values of LCST for linear polymer and hydrogel are 73 °C and 62 °C, respectively. The LCST of linear PEA increases with decreasing molecular weight. The swelling ratio for gels and the LCST for solutions and gels increased with the inclusion of SDS into water. The opposite effects prevailed on inclusion of KCl into water or incorporation of crosslinker. Additionally, the rates of heating/cooling play a significant role in the measured value of LCST. Hence the swelling ratio of hydrogel or the LCST can be adjusted via 1) addition of either SDS or KCl into water; 2) use of different molecular weight samples; 3) incorporation of crosslinker into polymer chain.

     

Recent results on functional polymers and macromonomers of interest as biomaterials or for biomaterial modification

Different families of functionalized polymers with potential as biomaterials, or for biomaterial modification, have been investigated. In particular, degradation studies have been performed on poly(amidoamines), a family of polymers obtained by polyaddition of amines to bisacrylamides, and endowed with heparin-complexing ability. Some new poly(amidoamines) with more resistance towards hydrolytic degradation than traditional ones have been discovered. Other ter-amino polymers deriving from the polyaddition of ter-amino functionalized bis-thiols to bis-acrylic esters, or other activated unsaturated compounds, have been studied. Their quaternarization products have been proven, in a parallel work, to act as powerful antimicrobial agents. By performing in situ the polyaddition reaction, semi-interpenetrated networks based on silicone rubber and the same polymers have been prepared. Finally, end-functionalized amphiphilic oligomers have been prepared by radical polymerization techniques, and their use for enzyme modification considered. Biomaterials (1994) 15, 1235–1241     

Hydrophilic-hydrophobic biodegradable polymers: release characteristics of hydrogen-bonded, ring-containing polymer matrices

Biodegradable hydrogen-bonded, ring-containing polymers were prepared. These included poly(enolketones) by the controlled oxidation of poly(vinyl alcohol), and poly(amide-amines) and poly(amideenamine-esters) by the reaction of diketene with diamines. These polymers had both hydrophilic and hydrophobic properties and are potentially matrix materials for the controlled release of drugs. Biomaterials (1994) 15, 1243–1247     

EPR Spectroscopy Provides a Molecular View on Thermoresponsive Dendronized Polymers Below the Critical Temperature

The nanoscopic structure of thermoresponsive dendronized polymers below the critical aggregation temperature (T_C) is revealed by CW EPR spectroscopy. At temperatures far below T_C, the water‐swollen polymers start to dehydrate and hydrophobic cavities are formed. Two different dehydration processes can be discerned, the more effective of which is observed within 4 K below T_C. The dehydration predominantly takes place at the peripheral dendritic shell, rendering it increasingly hydrophobic and eventually triggering an interchain aggregation and the formation of mesoglobules at the critical temperature. While the polymer aggregation is mainly dependent on the dendron periphery, the efficiency of the dehydration below T_C is closely related to the hydrophobicity of the dendritic core.

     

Molecular‐Recognition‐Induced Phase Transitions of Two Thermo‐Responsive Polymers with Pendent β‐Cyclodextrin Groups

PNIPAM‐based thermo‐responsive polymers with pendent β‐cyclodextrin groups were synthesized and the molecular‐recognition‐induced phase‐transition behavior of fabricated polymers was investigated. The results showed that the thermo‐sensitive PNG‐ECD and PNG‐HCD polymers could significantly recognize the guest ANS molecules, and their LCSTs in ANS aqueous solutions were lower than those in blank aqueous solution. The more ANS could be recognized by the polymer, the lower was the LCST of the polymer. The guest NS molecules had an opposite influence on the LCSTs of the PNG‐ECD and PNG‐HCD polymers, because the complexation between CD and NS slightly enlarged the hydrophilic moiety of the polymers.

     

The Dependence of the Cloud Point,Clearing Point,and Hysteresis of Poly(N‐isopropylacrylamide) on Experimental Conditions: The Need for Standardization of Thermoresponsive Transition Determinations

Inappropriately, the critical solution temperature (CST) of lower CST(LCST)‐ or upper CST(UCST)‐type thermoresponsive polymers, measured by one, individual set of conditions, is considered almost exclusively as the LCST or UCST, respectively. These are correctly the minimum or maximum, respectively, of the full phase diagrams. Because the dynamic phase transition depends on the conditions, and no standardized or widely accepted process exists for CST determination, systematic investigations are carried out with the most widely investigated poly(N‐isopropylacrylamide) (PNIPAAm) to unveil the effect of data evaluation, measurement conditions on the transmittance–temperature curves, cloud point (T _CP), clearing point (T _CL), and heating–cooling hysteresis. The unusual dependence of the fundamental hysteresis parameters, i.e., width of hysteresis (X _H) and extent of transmittance recovery (Y _H), on a broad range of conditions is revealed for the first time. On the basis of the findings, the inflection point of transmittance(absorbance)–temperature curves as T _CP and T _CL, 0.1 wt% solution, 0.2 °C min⁻¹ heating/cooling steps with 5 min equilibration between the gradual change of temperature, 488 nm wavelength to obtain data comparable to light scattering at this wavelength, and determination of X _H and Y _H are proposed as standard set of conditions.

     

Role of N-vinyl-2-pyrrolidinone on the thermoresponsive behavior of PNIPAm hydrogel and its release kinetics using dye and vitamin-B12 as model drug

Temperature-sensitive hydrogels hold great promise in biological applications as they can respond to changes in physiological temperature to produce a desired effect like controlled drug delivery. In this study, a series of poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidinone) thermosensitive hydrogels were synthesized by radical copolymerization of NIPAm with 1-vinyl-2-pyrrolidinone (NVP). By altering the initial NIPAm/NVP mole ratios, copolymers were synthesized to have their own distinctive lower critical solution temperature which was established using differential scanning calorimetry. The swelling behavior of the hydrogel was analyzed gravimetrically and it was observed that reswelling rate increases with increasing NVP mole ratio. Further characterizations of the hydrogels were performed using Fourier transform infrared spectroscopy and scanning electron microscopy. Release kinetics with respect to temperature was studied using methylene blue dye solution and vitamin B12. Kinetic modeling of the release profile revealed that the release mechanism is a non-Fickian diffusion mechanism. These results suggested that this material has potential application as intelligent drug carriers. The quantities of residual monomers in the PIV4 hydrogel were determined by HPLC method, and the results show almost complete conversion.     

Solution Behavior of Temperature‐Responsive Molecular Brushes Prepared by ATRP

Molecular brushes, with side chains consisting of two copolymers: 2‐(dimethylamino)ethyl methacrylate with methyl methacrylate, and N,N‐dimethylacrylamide with butyl acrylate were prepared by grafting‐from via atom transfer radical polymerization (ATRP). Poly(2‐(2‐bromoisobutyryloxy)ethyl methacrylate) and poly(2‐(2‐bromopropionyloxy)ethyl methacrylate) were used as macroinitiators. Dynamic light scattering (DLS) studies were performed for aqueous solutions of molecular brushes below and above the lower critical solution temperature (LCST), and an unusual concentration‐dependent LCST was observed. Due to the compact structure of molecular brushes, intramolecular collapse can occur when the average distance between molecules is much larger than the hydrodynamic dimensions of the individual macromolecules. However, if the concentration of the solution of molecular brushes is increased to the level in which the separation distance is comparable with the brush hydrodynamic dimensions, intermolecular aggregation occurs, as typically observed for solutions of linear polymers.

     

Phase separation and physical properties of PEO-containing poly(ether ester amide)s

Poly(ether ester amide) (PEEA) copolymers based on poly(ethylene glycol) (PEG), 1,4- butanediol, and dimethyl-7,12-diaza-6,13-dione-1,18-octadecanedioate (a diester-diamide monomer) were synthesized by a two-step polycondensation reaction. The obtained segmented copolymers are hydrophilic, with a water uptake of 24–340%. PEEA copolymers showed microphase separation, as observed by differential scanning calorimetry (DSC). The long spacing determined by small-angle X-ray scattering shows an increase in the hydrophilic domain size with increasing PEO content. By varying the copolymer composition, the E-modulus of PEEA could be varied between 61 and 427 MPa, with tensile strengths ranging from 12 to 39 MPa. The elongation at break can reach values up to 850%. The mechanical properties decrease with the uptake of water. However, PEEAs with a relatively low content of PEO still retain good tensile properties and are, in principle, suitable for biomedical applications.     

Block Copolymers of Methyl Vinyl Ether and Isobutyl Vinyl Ether With Thermo‐Adjustable Amphiphilic Properties

The thermo‐adjustable hydrophilic/hydrophobic properties of AB, ABA and BAB block copolymers in which A is poly(methyl vinyl ether) (PMVE) and B is poly(isobutyl vinyl ether) (PIBVE) have been investigated. The block copolymers were prepared by “living” cationic polymerization using sequential addition of monomers. The polymerizations were carried out with the system acetal/trimethylsilyl iodide as initiator and ZnI₂ as activator. The initiating system based on diethoxyethane leads to AB block copolymers whereas the initiating system based on tetramethoxypropane leads to ABA or BAB triblock copolymers. Well‐defined block copolymers of different composition with controlled molecular weights up to approx. 10 000 have been prepared. When IBVE is added to living PMVE, PIBVE‐blocks form only in the presence of an additional amount of ZnI₂, which is attributed to the fact that part of the ZnI₂ is inactive because of complex formation with PMVE. At room temperature, the combination of hydrophilic (PMVE) and hydrophobic (PIBVE) segments provides the copolymers with surfactant properties. Above the lower critical solution temperature (LCST) of PMVE, situated around 36 °C, the PMVE‐blocks become hydrophobic and the amphiphilic nature of the block copolymers is lost. The corresponding changes in hydrophilic/hydrophobic balance have been evaluated by investigation of the emulsifying properties of the block copolymers for water/decane mixtures as a function of the temperature. Below the LCST, the block copolymers have emulsifying properties similar to or better than those of the commercial PEO‐PPO block copolymers (Pluronic®). Either oil‐in‐water or water‐in‐oil emulsions can be obtained, depending on the polymer architecture and the water/decane volume ratio. The emulsifying properties are strongly reduced or completely lost above 40 °C. Emulsions obtained with a PMVE₃₆‐b‐PIBVE₅₄ block copolymer for a water/decane (v/v) ratio of 85/15 remained stable for more than six months.

50/50 and a 85/15 water/decane w/o emulsion (15 g/l) with the PMVE₃₆‐b‐PIBVE₅₄ block copolymer at 20 °C.     

Composing Well‐Defined Stimulus‐Responsive Materials Through Postpolymerization Modification Reactions

Postpolymerization modification—the installation of functional groups into a premade, reactive polymeric precursor—is emerging as an advantageous synthetic strategy toward tailored materials. In this article, the preparation of environmentally sensitive, “smart,” polymers by virtue of postpolymerization modification is presented. The underlying fundamentals of different types of stimulus‐responsiveness are highlighted with an emphasis on thermo­responsiveness, encompassing lower and upper critical solution temperature (LCST and UCST) behavior. Using a range of postpolymerization modifications as examples, properties imparted through incorporation of specific functional groups and their structure–property relations are discussed. Strategies for an appropriate choice of functionality in order to obtain well‐defined materials with custom‐made behavior are presented.

     

Block Copolymers of Vinyl Ethers as Thermo‐Responsive Colloidal Stabilizers of Organic Pigments in Aqueous Media

Summary: The colloidal stability of the aqueous dispersions of hydrophobic organic pigments, CuPc and carbon black, stabilized by a wide range of polymer structures based on alkyl vinyl ethers was studied. It was shown that, unlike the homopolymers and the random copolymers, the amphiphilic AB, ABA and BAB block copolymers of MVE with IBVE or ODVE show stabilizing activities that depend on their hydrophilic/hydrophobic balance and polymer architecture. After optimization, the colloidal stabilization is competitive with commercial PEO‐PPO block copolymers (Pluronic®). It was found that the sedimentation of the dispersions was much faster at a higher temperature, above the LCST of the PMVE‐blocks. The loss of the stabilizing activity of the block copolymers correlates with an increase of the hydrophobicity of the treated pigment surface. These properties enable the creation of colloidal dispersions with stabilities that can be tuned as a function of temperature.

Poly(methyl vinyl ether) ABA and BAB block copolymers as colloidal stabilizers of organic pigments.     

Preparation of Hierarchically Structured Amorphous Carbon Monoliths with Closed Spherical Mesopores via the Lower Critical Solution Temperature Phase Transition

Some polymer mixture systems become immiscible above a specific temperature, the so‐called lower critical solution temperature (LCST). In this work, the LCST behavior of a mixture of poly(ethylene oxide)‐block‐poly(propylene oxide)‐block‐poly(ethylene oxide) triblock copolymers and phenolic resin oligomers is observed, and the corresponding phase transition is exploited to develop a facile route to hierarchically structured carbon monoliths. Whereas evaporation‐induced self‐assembly generates hexagonal channels in the monoliths, an additional phase transition at the LCST leads to an ordered arrangement of isolated pores. The fabrication method involves annealing the gel‐phased mixture with polymeric microbeads in a 3D‐structured mold at the LCST, followed by thermosetting and a carbonization process. The LCST phase transition behavior is observed experimentally by in situ small‐angle X‐ray scattering, optical transparency measurements, differential scanning calorimetry, and infrared spectroscopy. The fundamental mechanism of the LCST phase transition is further investigated by atomistic molecular dynamics simulations.