Synthesis And Properties Of Multiply Responsive Miktoarm Star Copolymers

Synthesis and properties of stimuli-responsive polymers have attracted much attention inmaterials science recently. Among families of functional polymers, stimuli-sensitiveaggregates that respond to various stimuli such as temperature, pH, light, redox can notonly maximize the drug efficacy and minimize side effects but realize on-demand drugdosing, and thus they can hold great potential for clinical medicine and oncology. However,most of aggregation systems were fabricated by amphiphilic block copolymers, and reportson smart systems based on multicomponent miktoarm star copolymers remain limited thusfar. At present, it is very urgent to synthesize smart miktoarm stars and explore theirversatile properties in materials science. This study aims at synthesis and properties ofstimuli-responsive star polymers by “living”/controlled polymerization techniques andhighly efficient linking reactions, in which dually and multiply sensitive ABC, AB2C2andABCDE star copolymers were prepared, and their structure-property relationships andpotential applications in smart drug delivery systems were investigated. The main contentsare listed as follows.First, the research in Part1aimed at synthesis and properties of novel5-armPEG(PCL)2(PNIPAM)2(S1) and PEG(PCL)2(PAA)2(S3) star terpolymers, and theiraggregates formed by a single star or mixed stars were efficiently used for loading andrelease of doxorubicin (DOX) upon dual and triple stimuli. The AB2C2star terpolymershad two disulfide moieties and poly(ethylene glycol)(PEG, A), poly(ε-caprolactone)(PCL,B), poly(N-isopropylacrylamide)(PNIPAM, C1), poly(tert-butyl acrylate)(PtBA, C2), andpoly(acrylic acid)(PAA, C3) segments.2-((2-((2-hydroxymethyl-2-(pent-4-ynoyloxy)methyl)propionyloxy)ethyl)disulfanyl)ethyl4-cyano-4-(phenylcarbonothioylthio)pentanoate(HCP) was synthesized and used as a multifunctional agent for ring-openingpolymerization of ε-caprolactone, RAFT chain extension polymerization ofN-isopropylacrylamide (NIPAM) and tert-butyl acrylate (tBA) to generate BC-type diblockcopolymers. Terminal diazide functionalized poly(ethylene glycol)(PEG-(N3)2) andalkyne-mid-functionalized PCL-b-PNIPAM and PCL-b-PtBA copolymers were subjected to copper(I)-mediated azide-alkyne cycloaddition (CuAAC) reaction to generatePEG(PCL)2(PNIPAM)2(S1) and PEG(PCL)2(PtBA)2(S2) star terpolymers, and followedby selective hydrolysis to obtain PEG(PCL)2(PAA)2(S3) star. The results given by1HNMR and GPC-MALLS revealed that the resultant star copolymers had well-definedstructures, controlled molecular weight and relatively low polydispersity (PDI=1.08-1.15).Polymeric aggregates and coaggregates including normal micelles, multicompartmentmicelles, and vesicles were obtained by (co)assembly of S1and S3stars in aqueoussolution. In the presence of external stimuli, remarkably enhanced release kinetics wasnoted, and the maximum increment of cumulative release from various aggregates at48hcould reach up to218%(S1micelles),136%(S3micelles), and212%(mixed aggregates).Various polymeric aggregates had a great potential as controlled delivery vehicles due totheir reasonable drug loading efficiency and stimuli-adjustable drug release properties.Second, the research in Part2aimed at synthesis and properties of novel miktoarmPEG-PCL-PNIPAM star terpolymer with cleavable disulfide and acetal linkages.2-((2-((2-Hydroxymethyl-2-((4-oxo-4-(prop-2-yn-1-yloxy)butanoyl)oxy)methyl)propionyloxy)ethyl)disulfanyl)ethyl4-cyano-4-(phenylcarbono thioylthio)pentanoate (HPP) wassynthesized and used to prepare PCL-b-PNIPAM copolymer. On this basis, CuAACbetween acetal and azide functionalized PEG (PEG-acetal-N3) and alkyne-mid-functionalized PCL-b-PNIPAM was performed to synthesize well-defined triply responsivePEG-PCL-PNIPAM star terpolymer. Self-assembly was used to to form Indocynine Green(ICG) and DOX encapsulated multi-sensitive star aggregates (abbreviated as I/D MSSA).The I/D MSSA system allows image-guided drug delivery and real-time monitoring of theaccumulation of the drug in the tumor since ICG is a NIR-sensitive dye and DOX is achemotherapy drug. When dual or triple stimuli were applied, there are obvious alterationsin drug release kinetics, reflecting smart drug delivery and targeting therapy effect.Antitumor activities of the I/D MSSA system at the cellular level were also studied, and theresults demonstrated the combination of the thermal effect of ICG and DOX chemotherapycan effectively promote tumor cell apoptosis. This smart system has a great potential inclinical trials.Last, the research in Part3aimed at controlled synthesis and properties of ABCDE starquintopolymers with cleavable disulfide and o-nitrobenzyl ester moieties. The integratedutilization of ring-opening polymerization (ROP), reversible addition-fragmentation chain transfer (RAFT) process, and azide-alkyne cycloaddition reaction was used to constructmultiply responsive5-arm ABCDE star quintopolymers, in which multifunctional agentsHCP and NOP were used for synthesis of alkyne and disulfide-functionalized PLLA-b-PM(BC) and alkyne and o-nitrobenzyl ester functionalized PCL-b-PNIPAM (DE). Themiktoarm stars are composed of poly(ethylene glycol)(A), poly(L-lactide)(B),poly(tert-butyl acrylate)(C1), poly(diisopropylamino)ethyl methacrylate (PDPA, C2),poly(ε-caprolactone)(D), poly(N-isopropylacrylamide)(E). As evidenced from1H NMRand GPC-MALLS, the resultant stars, namely, PEG-PLLA-PtBA-PCL-PNIPAM (Q1),PEG-PLLA-PDPAEMA-PCL-PNIPAM (Q2) and PEG-PLLA-PAA-PCL-PNIPAM (Q3),possessed well-controlled molecular weight, low polydispersity, and precise composition.These star copolymers could exhibit multiple responsiveness to temperature, reduction, UVradiation and CO2(or pH), and they could be degraded into4-arm ABDE and3-arm ABDstar copolymers with stimuli-triggered cleavage of C and E segments. Upon externalstimuli, DOX and Nile Red (NR) loaded aggregates could afford adjustable release kinetics,and thus they had a great potential as controlled delivery vehicles.In summary, this study was primarily focused on continuous development of efficientapproaches to the synthesis of novel miktoarm star copolymers with cleavable moieties andstimuli-responsive segments. On this basis, their physicochemical properties, self-assemblybehaviors, and drug loading and release properties were investigated. Our study allowsfacile synthesis of multicomponent star copolymers, which further accelerates thedevelopment of advanced polymer synthesis. Meanwhile, cleavable linkages and sensitivesegments were introduced into star copolymers via macromolecular design, andstimuli-triggered drug delivery properties were investigated, which provides a practical andreliable basis towards biomedical applications.