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• W2884981226 abstract "Responsive polymer materials are designed to alter their properties upon exposure to physical, chemical, and biological stimuli. They have served as powerful tools in drug delivery and tissue engineering. Through the integration of functional groups, these materials are engineered to “sense” the surrounding physiological environments and enable on-demand release of encapsulated therapeutic cargos into highly specific targets. However, the physiological environment is complex, and polymer materials with single responsiveness, in some cases, cannot achieve the desired goals in drug-delivery systems. The exploitation of polymer materials responsive to multiple stimuli promises new innovations in the design of functional materials for drug delivery. We provide an overview of the recent design and applications of multi-stimuli-responsive polymer particles, films, and hydrogels. Stimuli-responsive polymer materials are powerful tools in drug delivery and tissue engineering. Because of the large variations in physiological conditions between normal microenvironments and diseased sites, polymer materials with single responsiveness may not achieve the desired goals in a complex physiological microenvironment. Instead, polymer materials responsive to multiple physical or chemical stimuli are highly desired for biomedical applications (e.g., drug delivery). In this review, we highlight recent studies in multi-stimuli-responsive materials with a specific emphasis on polymer particles, films, and hydrogels. The synthetic strategies employed to produce these responsive materials are described. Applications in drug delivery are highlighted, followed by a discussion of the current research focus and future trends. Stimuli-responsive polymer materials are powerful tools in drug delivery and tissue engineering. Because of the large variations in physiological conditions between normal microenvironments and diseased sites, polymer materials with single responsiveness may not achieve the desired goals in a complex physiological microenvironment. Instead, polymer materials responsive to multiple physical or chemical stimuli are highly desired for biomedical applications (e.g., drug delivery). In this review, we highlight recent studies in multi-stimuli-responsive materials with a specific emphasis on polymer particles, films, and hydrogels. The synthetic strategies employed to produce these responsive materials are described. Applications in drug delivery are highlighted, followed by a discussion of the current research focus and future trends. Stimuli-responsive polymer materials have been widely investigated in the field of bio-nano research for biomedical applications (e.g., drug delivery and tissue engineering).1Molina M. Asadian-Birjand M. Balach J. Bergueiro J. Miceli E. Calderón M. Stimuli-responsive nanogel composites and their application in nanomedicine.Chem. Soc. Rev. 2015; 44: 6161-6186Crossref PubMed Google Scholar, 2Wei Z. Yang J.H. Zhou J. Xu F. Zrínyi M. Dussault P.H. Osada Y. Chen Y.M. Self-healing gels based on constitutional dynamic chemistry and their potential applications.Chem. Soc. Rev. 2014; 43: 8114-8131Crossref PubMed Google Scholar, 3Purcell B.P. Lobb D. Charati M.B. Dorsey S.M. Wade R.J. Zellers K.N. Doviak H. Pettaway S. Logdon C.B. Shuman J. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.Nat. Mater. 2014; 13: 653Crossref PubMed Scopus (364) Google Scholar, 4Stuart M.A.C. Huck W.T. Genzer J. Müller M. Ober C. Stamm M. Sukhorukov G.B. Szleifer I. Tsukruk V.V. Urban M. Emerging applications of stimuli-responsive polymer materials.Nat. Mater. 2010; 9: 101-113Crossref PubMed Scopus (4521) Google Scholar Understanding the biological microenvironments is essential for the design of polymer materials that can selectively respond to biological stimuli at the organ level, under pathological conditions, and in different intracellular subcompartments. The Langer and Gu groups have recently summarized the most typical biological stimuli in the body.5Lu Y. Aimetti A.A. Langer R. Gu Z. Bioresponsive materials.Nat. Rev. Mater. 2016; 2: 16075Crossref Scopus (976) Google Scholar For example, pH values, enzyme concentrations, redox species, and glucose levels vary significantly in the microenvironments of different body parts and, therefore, can be exploited as pristine biological triggers to achieve controlled release of therapeutic molecules from drug carriers. Hence, bridging materials science and biology has advanced the design of polymer materials for biomedical applications.6Björnmalm M. Thurecht K.J. Michael M. Scott A.M. Caruso F. Bridging bio-nano science and cancer nanomedicine.ACS Nano. 2017; : 9594-9613Crossref PubMed Scopus (250) Google Scholar, 7Cui J. Probing bio-nano interactions with templated polymer particles.Chem. 2017; 2: 606-607Abstract Full Text Full Text PDF Google Scholar Recent reviews have focused on the assembly of polymer materials (e.g., polymer particles, films, and hydrogels) that are responsive to a single trigger.8Zhang Y. Yu J. Bomba H.N. Zhu Y. Gu Z. Mechanical force-triggered drug delivery.Chem. Rev. 2016; 116: 12536-12563Crossref PubMed Scopus (202) Google Scholar, 9Zhai L. Stimuli-responsive polymer films.Chem. Soc. Rev. 2013; 42: 7148-7160Crossref PubMed Scopus (158) Google Scholar, 10Karimi M. Sahandi Z.P. Baghaee-Ravari S. Ghazizadeh M. Mirshekari H. Hamblin M.R. Smart nanostructures for cargo delivery: uncaging and activating by light.J. Am. Chem. Soc. 2017; 139: 4584-4610Crossref PubMed Scopus (275) Google Scholar, 11Zhang Y.S. Khademhosseini A. Advances in engineering hydrogels.Science. 2017; 356: eaaf3627Crossref PubMed Scopus (1325) Google Scholar However, polymer materials with single responsiveness, in some cases, cannot achieve the desired goals in a complex physiological microenvironment. For example, a series of physiological and pathological barriers (e.g., mononuclear phagocyte system [MPS], non-specific distribution, cell internalization, endosome escape, multi-drug resistance) exist in organs, tissues, and cells, which leads to low drug-delivery efficiency.12Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Scopus (3846) Google Scholar, 13Liu J. Li M. Luo Z. Dai L. Guo X. Cai K. Design of nanocarriers based on complex biological barriers in vivo for tumor therapy.Nano Today. 2017; 15: 56-90Crossref Scopus (90) Google Scholar, 14Sun Q. Zhou Z. Qiu N. Shen Y. Rational design of cancer nanomedicine: nanoproperty integration and synchronization.Adv. Mater. 2017; 29Crossref Scopus (638) Google Scholar Therefore, polymer materials with rationally designed properties, including multi-stimuli responsiveness, are highly desired for biomedical applications. Here, we focus on the design, assembly, and applications of polymer particles, films, and hydrogels that are responsive to multiple stimuli, including biological and physical triggers (e.g., pH, reduction, enzyme, temperature, diol moieties, reactive oxygen species, ionic strength, shear stress, and light). We first provide an introduction to the nanoscale polymer particles mostly with dual-stimuli responsiveness and their application in drug delivery and further introduce the multi-stimuli-responsive polymer films engineered by the layer-by-layer (LbL) technique and surface-initiated polymerization method, as well as free-standing polymer films. Lastly, hydrogels with dual- and triple-stimuli responsiveness are reviewed. Our intention is to provide an overview and insight accessible to researchers (e.g., chemists, physicists, biologists, and medical scientists) active in different research fields with a special focus on exploring new directions and opportunities for the application of multi-stimuli-responsive polymer materials. For polymer particles to reach the desired sites of action, they have to go through several transport steps with multiple biological barriers, including circulation in the bloodstream, cell binding, cell internalization, and intracellular delivery.15Cui J. Richardson J.J. Bjornmalm M. Faria M. Caruso F. Nanoengineered templated polymer particles: navigating the biological realm.Acc. Chem. Res. 2016; 49: 1139-1148Crossref PubMed Scopus (106) Google Scholar Although the enhanced permeability and retention (EPR) effect can improve the accumulation of particles in tumor tissues, insufficient cell uptake and intracellular processing can limit the therapeutic efficacy. Positively charged particles facilitate cell uptake because of the electrostatic interaction with the negatively charged cell membrane, which promotes the subsequent internalization.16Cheng Z. Al Zaki A. Hui J.Z. Muzykantov V.R. Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities.Science. 2012; 338: 903-910Crossref PubMed Scopus (1073) Google Scholar However, positively charged particles could induce rapid clearance by the MPS, instability with opsonins, and serum inhibition. Meanwhile, neutrally charged and highly hydrated particles can decrease non-specific interactions and improve circulation time. Therefore, it is essential to design a system that is neutrally charged to minimize the non-specific interactions with tissues and cells while being able to convert to a positive charge at targeted sites to help the cell uptake (e.g., tumor).17Wang S. Huang P. Chen X. Hierarchical targeting strategy for enhanced tumor tissue accumulation/retention and cellular internalization.Adv. Mater. 2016; 28: 7340-7364Crossref PubMed Scopus (286) Google Scholar It is well known that pH varies significantly in different body parts from tissue to cell level. For example, the pH of plasma is around 7.4, decreases to lower than 7.0 at tumor sites, and experiences a further decrease to lower than 5.0 in late endosomes and lysosomes after cellular uptake.18Paroutis P. Touret N. Grinstein S. The pH of the secretory pathway: measurement, determinants, and regulation.Physiology. 2004; 19: 207-215Crossref PubMed Scopus (340) Google Scholar, 19Yoshida T. Lai T.C. Kwon G.S. Sako K. pH- and ion-sensitive polymers for drug delivery.Expert Opin. Drug Deliv. 2013; 10: 1497-1513Crossref PubMed Scopus (230) Google Scholar Accordingly, particles responsive to pH have been engineered via surface modification with charge convertors, which can revert the surface charge to be positive at low pH or can strip outer layers to expose positively charged inner layers at low pH. To circumvent biological barriers and trigger the drug release more efficiently, we require multi-responsive polymer particles with a hierarchical targeting strategy for the development of the next generation of nanomedicines (Figure 1).20Cheng R. Meng F. Deng C. Klok H.-A. Zhong Z. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.Biomaterials. 2013; 34: 3647-3657Crossref PubMed Scopus (1033) Google Scholar Multi-stage pH responsiveness indicates that the particles are engineered with different components, which have different sensitivity to pH changes. The Wang group reported the first example of dual pH-responsive polymer-drug particles where the conjugates were synthesized by conjugating doxorubicin (DOX) and 2,3-dimethylmaleic anhydride (DMMA) onto the copolymer of poly(ethylene glycol)-b-poly(allyl ethylene phosphate) (PEG-b-PAEP).21Du J.-Z. Du X.-J. Mao C.-Q. Wang J. Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery.J. Am. Chem. Soc. 2011; 133: 17560-17563Crossref PubMed Scopus (1000) Google Scholar The assembled polymer-drug particles could respond to the extracellular tumor pH by stripping DMMA to convert the surface charge, which promoted the drug accumulation at tumor sites and facilitated the cell internalization (Figure 2A). Furthermore, the free DOX was released in the intracellular subcompartments (e.g., endosomes and lysosomes) by cleaving the hydrazone bonds between the polymers and the drugs. Similarly, transactivator of transcription (TAT) peptides were conjugated onto the surface of polymer particles (i.e., polyethyleneimine-modified poly(β-L-malic acid), PEI-PMLA) and protected by pH-stripped PEGylation (i.e., PEG-DMMA).23Zhou Q. Hou Y. Zhang L. Wang J. Qiao Y. Guo S. Fan L. Yang T. Zhu L. Wu H. Dual-pH sensitive charge-reversal nanocomplex for tumor-targeted drug delivery with enhanced anticancer activity.Theranostics. 2017; 7: 1806-1819Crossref PubMed Scopus (62) Google Scholar When the pH decreased at the tumor sites (pH < 7), PEG-DMMA was stripped to reverse the particle surface charge from negative to positive, and TAT was exposed to enhance the cell internalization, followed by drug release at endo/lysosomal pH below 6. These particles showed improved inhibition of the tumor growth with negligible systemic toxicity. This design leads to more effective cell uptake and enhanced endo/lysosomal escape for improved drug delivery. The concentration of reducing species (e.g., glutathione [GSH]) in intracellular subcompartments (e.g., lysosomes and cytoplasm) is approximately 1,000-fold higher than that in the extracellular fluids. Therefore, the combination of pH and reduction responses into one carrier is also helpful to circumvent biological barriers for improved drug delivery. The LbL assembly has been widely used to fabricate responsive polymer films with tunable architectures and properties.24Richardson J.J. Cui J. Björnmalm M. Braunger J.A. Ejima H. Caruso F. Innovation in layer-by-layer assembly.Chem. Rev. 2016; 116: 14828-14867Crossref PubMed Scopus (571) Google Scholar This technique simply involves the alternating deposition of different interacting materials onto substrates, and the driving forces for LbL film formation range from electrostatic interactions to hydrogen bonding, charge-transfer interactions, host-guest complexes, and coordination bonding.25Cao Z.Q. Wang G.J. Multi-stimuli-responsive polymer materials: particles, films, and bulk gels.Chem. Rec. 2016; 16: 1398-1435Crossref PubMed Scopus (133) Google Scholar, 26Cui J. van Koeverden M.P. Mullner M. Kempe K. Caruso F. Emerging methods for the fabrication of polymer capsules.Adv. Colloid Interface Sci. 2014; 207: 14-31Crossref PubMed Scopus (166) Google Scholar Advantages of this technique include the possibility of all-aqueous processing, operationally simple control over the thickness of the resulting films through the number of deposition cycles, and the possibility of creating stratified films.27Richardson J.J. Björnmalm M. Caruso F. Technology-driven layer-by-layer assembly of nanofilms.Science. 2015; 348: aaa2491Crossref PubMed Scopus (1037) Google Scholar, 28Katsuhiko A. Yusuke Y. Gaulthier R. Qingmin J. Yusuke Y. Wu Kevin C.-W. Hill Jonathan P. Layer-by-layer nanoarchitectonics: invention, innovation, and evolution.Chem. Lett. 2014; 43: 36-68Crossref Scopus (896) Google Scholar Capsules with a hollow structure can be obtained when the LbL films are deposited on templated particles followed by the template removal, which has shown promising applications in drug delivery.29Liu X.Q. Picart C. Layer-by-layer assemblies for cancer treatment and diagnosis.Adv. Mater. 2016; 28: 1295-1301Crossref PubMed Scopus (73) Google Scholar, 30Chandrawati R. Chang J.Y.H. Reina-Torres E. Jumeaux C. Sherwood J.M. Stamer W.D. Zelikin A.N. Overby D.R. Stevens M.M. Localized and controlled delivery of nitric oxide to the conventional outflow pathway via enzyme biocatalysis: toward therapy for glaucoma.Adv. Mater. 2017; 29Crossref PubMed Scopus (72) Google Scholar The assembly of poly(2-diisopropylaminoethyl methacrylate) (PDPA, pKa ∼ 6.4) into multiple layers endows the capsules with pH-responsive properties given that the capsules swell at pH < 6.4 because of protonation of PDPA followed by a charge-shifting transition from a hydrophobic to a hydrophilic state.31Liang K. Such G.K. Zhu Z. Yan Y. Lomas H. Caruso F. Charge-shifting click capsules with dual-responsive cargo release mechanisms.Adv. Mater. 2011; 23: H273-H277Crossref PubMed Scopus (98) Google Scholar Both the size (swelling at pH < 6.4 and shrinking at pH > 6.4) and the surface charge of the capsules are reversible. Crosslinking of PDPA multi-layers based on a disulfide bond, which is one of the most used strategies to prepare reduction-sensitive carriers, renders degradable capsules in the presence of GSH. The degradation of the swelled capsules is much easier than that of the shrunk capsules. Thus, the synergistic effects of pH together with reduction allow for rapid and effective degradation and cargo release at extremely low GSH microenvironments (down to 0.01 mM). In addition, intracellular degradation of the PDPA capsules can be tuned by varying crosslinking density through adjusting the quantity of crosslinkers.32Liang K. Such G.K. Zhu Z. Dodds S.J. Johnston A.P.R. Cui J. Ejima H. Caruso F. Engineering cellular degradation of multilayered capsules through controlled cross-linking.ACS Nano. 2012; 6: 10186-10194Crossref PubMed Scopus (45) Google Scholar Dual pH- and reduction-sensitive drug-delivery systems have also been designed by self-assembly strategy. The Chen group reported a shell-stacked nanoparticle system via the formation of poly(L-lysine) (PLL)-based nanogels crosslinked by disulfide bonds followed by electrostatic adsorption of DMMA-modified PEG-b-PLL.33Chen J. Ding J. Wang Y. Cheng J. Ji S. Zhuang X. Chen X. Sequentially responsive shell-stacked nanoparticles for deep penetration into solid tumors.Adv. Mater. 2017; 29Crossref Scopus (315) Google Scholar The size of the obtained nanoparticles reduced from 145 nm to 40 nm and the surface charge reversed from −7.4 to 8.2 mV at acidic tumor tissues, which is due to the PEG-b-PLL release after cleaving the DMMA groups. The reduced size and positively charged surface favor the tumor accumulation and penetration, as well as the cell uptake. The disulfide crosslinking maintains the stability of the particles and prevents undesired premature drug release before the release of the stacked PEG-PLL shells, which accelerates the cleavage of disulfide bonds and intracellular drug release after cell uptake. Similar responsiveness was engineered via self-assembly of preformed polymers. Pluronic P123 was firstly conjugated with PEI via disulfide bonds and then modified with DMMA, which was used to assemble dual-responsive polymer particles.34Wang H. Li Y. Bai H. Shen J. Chen X. Ping Y. Tang G. A cooperative dimensional strategy for enhanced nucleus-targeted delivery of anticancer drugs.Adv. Funct. Mater. 2017; 27Google Scholar Acidic pH can cleave the DMMA groups to reduce the particle size and convert the surface charge from negative to positive, which helps the cell association and uptake as well as the subsequent endosome escape. The reduction microenvironment in the cytoplasm can strip PEI from particles and expose the dexamethasone-conjugated Pluronic P123, which can dilate the nuclear pores and facilitate the entry of DOX-loaded Pluronic P123 particles into the cell nuclei to improve the drug-delivery efficacy. In addition to the design of pH-stripped layers on polymer particles, Dai et al. reported self-assembled polymer micelles with a triblock copolymer composed of 2-(diisopropylamino)ethylamine-grafted poly(L-aspartic acid), 2-mercaptoethylamine-grafted poly(L-aspartic acid), and monomethoxy PEG.35Dai J. Lin S. Cheng D. Zou S. Shuai X. Interlayer-crosslinked micelle with partially hydrated core showing reduction and pH dual sensitivity for pinpointed intracellular drug release.Angew. Chem. Int. Ed. 2011; 50: 9404-9408Crossref PubMed Scopus (350) Google Scholar The micelles comprise a pH-responsive hydrated core, a disulfide crosslinked interlayer, and a PEG corona, which were used to load anti-cancer drugs (i.e., DOX), tie up the core against expansion at neutral pH, and reduce non-specific interactions, respectively. The interlayer crosslinked polymer micelles were stable and drug leakage was avoided in a neutral pH environment during blood circulation. After intracellular internalization, the micelles were disassembled by swelling the hydrated core at low pH and cleaving the disulfide bond crosslinked interlayers in endosomes or lysosomes, which induced the burst release of the loaded drugs. Instead of reducing the disulfide bonds to release the encapsulated cargo, drugs can also be released by cleaving the ester bonds used to conjugate drugs onto polymers in the presence of reducing reagents. For example, PEGylated clustered nanoparticles were fabricated by polycaprolactone (PCL) and PEG-b-PCL together with a cis-platin (Pt) prodrug-conjugated poly(amidoamine)-graft-polycaprolactone (PAMAM-g-PCL), whereby PAMAM and PCL were conjugated with 2-propionic-3-methylmaleic anhydride (CDM) (Figure 2B).22Li H.-J. Du J.-Z. Du X.-J. Xu C.-F. Sun C.-Y. Wang H.-X. Cao Z.-T. Yang X.-Z. Zhu Y.-H. Nie S. et al.Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.Proc. Natl. Acad. Sci. USA. 2016; 113: 4164-4169Crossref PubMed Scopus (549) Google Scholar At physiological pH, the PEGylated nanoparticles with a size of around 100 nm could circulate for a long time and enhance tumor accumulation based on the EPR effect. At pH < 7 at tumor sites, the clustered nanoparticles disassembled by cleaving the CDM groups and released small PAMAM/Pt prodrug conjugates. The released PAMAM/Pt prodrugs with an average size of 5 nm and increased surface charge are highly capable of penetrating tumors to reach cancer cells that are far away from the blood vessels. After cell internalization, the prodrug conjugates can be rapidly cleaved to release Pt, thus killing cancer cells and restricting tumor growth. One-step assembly of metal-phenolic networks (MPNs) has been recently proved to be a versatile method for drug-carrier engineering, owing to their pH responsiveness and negligible cytotoxicity.36Ejima H. Richardson J.J. Liang K. Best J.P. van Koeverden M.P. Such G.K. Cui J. Caruso F. One-step assembly of coordination complexes for versatile film and particle engineering.Science. 2013; 341: 154-157Crossref PubMed Scopus (1352) Google Scholar Different polyphenols and metal ions can be used as components for capsule assembly.37Guo J. Ping Y. Ejima H. Alt K. Meissner M. Richardson J.J. Yan Y. Peter K. von Elverfeldt D. Hagemeyer C.E. et al.Engineering multifunctional capsules through the assembly of metal-phenolic networks.Angew. Chem. Int. Ed. 2014; 53: 5546-5551Crossref PubMed Scopus (621) Google Scholar The difference of binding affinity between polyphenols (e.g., tannic acid [TA]) and metal ions induces various pH-disassembly profiles. MPN capsules composed of higher-valence metal ions are typically more stable under acidic pH (e.g., Zr4+ > Al3+ > Cu2+), although Fe3+ results in one of the most stable capsules probably because of its high binding affinity with polyphenols. In addition to metal ions, polyphenol can also coordinate with boronic acid to form boronate-phenolic networks (BPNs). The Caruso group has reported the assembly of BPN capsules by using TA and benzene-1,4-diboronic acid, which are responsive to acidic pH and also in the presence of exogenous competing cis-diols (e.g., glucose) (Figure 3A).38Guo J. Sun H. Alt K. Tardy B.L. Richardson J.J. Suma T. Ejima H. Cui J. Hagemeyer C.E. Caruso F. Boronate-phenolic network capsules with dual response to acidic pH and cis-diols.Adv. Healthc. Mater. 2015; 4: 1796-1801Crossref PubMed Scopus (50) Google Scholar These capsules are stable at physiological pH in vivo and can be potentially used for insulin delivery by glucose activation and anti-cancer drug delivery by acidic pH stimulus. Photothermal therapy (PTT) and photodynamic therapy (PDT) based on light irradiation have been widely used for tumor therapies, whereby the photothermal or photodynamic agents are incorporated into the drug carriers.10Karimi M. Sahandi Z.P. Baghaee-Ravari S. Ghazizadeh M. Mirshekari H. Hamblin M.R. Smart nanostructures for cargo delivery: uncaging and activating by light.J. Am. Chem. Soc. 2017; 139: 4584-4610Crossref PubMed Scopus (275) Google Scholar However, these therapeutics are still limited by rapid renal clearance and non-specific tissue distribution. Very recently, the Wang group designed a transformable polymer nanoparticle system that can minimize the interaction with the MPS and has a long circulation time (Figure 3B).39Li D. Ma Y. Du J. Tao W. Du X. Yang X. Wang J. Tumor acidity/NIR controlled interaction of transformable nanoparticle with biological systems for cancer therapy.Nano Lett. 2017; 17: 2871-2878Crossref PubMed Scopus (103) Google Scholar When the nanoparticles accumulated in the tumor sites based on the EPR effect, sheddable modifications (i.e., DMMA) on the nanoparticles were stripped in the trigger of acidic pH and then TAT peptides (i.e., YGRKKRRQRRRC-NH2) were exposed, which improved cell association and internalization. Near-infrared (NIR) light irradiation of the encapsulated IR-780 iodide promoted the DOX release loaded in the nanoparticles, thus killing the tumor cells. To introduce temperature responsiveness into polymer particles, polymers with a lower critical solution temperature (LCST) are typically used as building blocks. PNIPAM is a classical temperature-responsive material used in drug-delivery systems. PNIPAM undergoes a phase transition from a hydrophobic to a hydrophilic state when the external temperature is below the LCST of about 32°C in aqueous solution.40Schild H.G. Poly(n-isopropylacrylamide): experiment, theory and application.Prog. Polym. Sci. 1992; 17: 163-249Crossref Scopus (4672) Google Scholar, 41Katsumoto Y. Tanaka T. Sato H. Ozaki Y. Conformational change of poly(n-isopropylacrylamide) during the coil-globule transition investigated by attenuated total reflection/infrared spectroscopy and density functional theory calculation.J. Phys. Chem. A. 2002; 106: 3429-3435Crossref Scopus (221) Google Scholar, 42Liang Y. Song S. Yao H. Hu N. Triply switchable bioelectrocatalysis based on poly(n-isopropylacrylamide) hydrogel films with immobilized glucose oxidase.Electrochim. Acta. 2011; 56: 5166-5173Crossref Scopus (32) Google Scholar The reason for the phase transition is mainly the formation of hydrogen bonds between its amide groups and water molecules below the LCST. When the surrounding temperature is above the LCST, the hydrogen bonds between PNIPAM and water are disrupted, and PNIPAM collapses into a globule state, making the gel network become aggregated and hydrophobic. Chiang et al. reported pH- and temperature-responsive polymer particles partially comprising poly(acrylic acid) (PAA) and PNIPAM.43Chiang W.-H. Ho V.T. Huang W.-C. Huang Y.-F. Chern C.-S. Chiu H.-C. Dual stimuli-responsive polymeric hollow nanogels designed as carriers for intracellular triggered drug release.Langmuir. 2012; 28: 15056-15064Crossref PubMed Scopus (89) Google Scholar The drug (i.e., DOX) can be loaded below LCST because of the swelling of the polymer particles and is released slowly above the LCST. When the microenvironment pH is decreased, the extensive disruption of carboxyl groups and DOX resulting from the reduced ionization of AA residues enables the rapid release of DOX. Similarly, poly(β-aminoester) dendrimers with pH and temperature responsiveness can load drugs below LCST and allow the fast drug release in acidic intracellular subcompartments (e.g., endosomes or lysosomes).44Shen Y. Ma X. Zhang B. Zhou Z. Sun Q. Jin E. Sui M. Tang J. Wang J. Fan M. Degradable dual pH- and temperature-responsive photoluminescent dendrimers.Chem. Eur. J. 2011; 17: 5319-5326Crossref PubMed Scopus (65) Google Scholar In addition, multi-stimuli-responsive poly(vinylcaprolactam) (PVCL)-based particles were reported via a precipitation polymerization method.45Wang Y. Nie J. Chang B. Sun Y. Yang W. Poly(vinylcaprolactam)-based biodegradable multiresponsive microgels for drug delivery.Biomacromolecules. 2013; 14: 3034-3046Crossref PubMed Scopus (138) Google Scholar The temperature sensitivity of the particles can be tuned by varying the pH and the doped content of methacrylic acid (MA), whereby the LCST increases when the MA content or the pH of the solution is increased. The introduction of MA and the disulfide-bonded crosslinker N,N′-bis(acryloyl)cystamine endow the PVCL-based particles with pH and reduction sensitivities, which cause the particles to shrink at acid pH followed by their degradation in the presence of the GSH reduction reagent. The multi-responsiveness, as discussed above, is mostly based on single particles. However, for specific applications it is required to either engineer preformed particle aggregates followed by the release of single particles, or to form assemblies from single particles with biological triggers that disassemble when the microenvironment is changed. In the case of drug targeting to obstructed blood vessels, micrometer-sized poly(lactic-co-glycolic acid) (PLGA) particle aggregates were fabricated with multiple PLGA nanoparticles, which are stable in aqueous solution because of hydrophobic interactions between the nanoparticles (Figure 4A).46Korin N. Kanapathipillai M. Matthews B.D. Crescente M. Brill A. Mammoto T. Ghosh K. Jurek S. Bencherif S.A. Bhatta D. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels.Science. 2012; 337: 738-742Crossref PubMed Scopus (386) Google Scholar However, these microscale PLGA particles can break into individual nanoparticles when exposed to a high-shear-stress microenvironment (e.g., vascular narrowing caused by thrombosis) (Figure 4B). The released nanoparticles coated with thrombolytic drugs (i.e., tissue plasmino" @default.
• W2884981226 created "2018-08-03" @default.
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• W2884981226 date "2018-09-01" @default.
• W2884981226 modified "2023-10-13" @default.
• W2884981226 title "Multi-Stimuli-Responsive Polymer Particles, Films, and Hydrogels for Drug Delivery" @default.
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