Synthesis And Application Of Responsive Polymer/Inorganic Nanoparticle Hybrid Assemblies

Inorganic nanoparticles have attracted much attention because of their unique properties,such as excellent luminescent properties,high photothermal conversion efficiency,and magnetic properties.Much attention has focused on introducing these inorganic nanoparticles into polymer assemblies to construct hybrid assemblies,which combine the properties of inorganic nanoparticles and polymers.They can be widely used in biological imaging,catalysis,and disease theranostics.The inorganic nanoparticle hybrid assemblies fabricated from responsive polymers,which can exhibit reversible or irreversible changes in physical properties and/or chemical structures to external stimuli have been rarely reported.Superparamagnetic iron oxide nanoparticles(SPIONs),gold nanoparticles(AuNPs),and up-conversion nanoparticles(UCNPs)are introduced into responsive polymer assemblies to construct multifunctional hybrid assemblies and their application in cancer theranostics is studied in our research work.The following sections are included in this dissertation.1.Photo-sensitive amphiphilic diblock copolymers,poly(ethylene oxide)-b-poly(2-((((2-nitrobenzyl)oxy)carbonyl)amino)ethyl methacrylate)(PEO-b-PNBOC),are used to co-assembly with hydrophobic SPIONs via an oil-in-water(O/W)emulsion and a subsequent solvent evaporation procedure,resulting in the formation of superparamagnetic iron oxide nanoparticle(SPION)-loaded hybrid nanoparticles.For hybrid nanoparticle dispersions,photo irradiation triggers cascade decaging reactions of PNBOC side chains and generation of primary amine moieties;extensive amidation reactions then occur,leading to concomitant cross-linking and a hydrophobic-to-hydrophilic transition within the cores of the hybrid nanoparticles.During this photo irradiation process,the magnetic resonance imaging(MRI)contrast of the hybrid nanoparticles are enhanced.Also anti-cancer drug,doxorubicin(DOX)is co-loaded into the hybrid nanoparticles to construct a theranostic system.More DOX release from DOX/SPION co-loaded hybrid nanoparticles under UV light irradiation.Thus the stability of the hybrid nanoparticles,the MRI contrast,and drug release rate can be regulated synchronously.2.Reversible addition-fragmentation chain transfer(RAFT)polymerization is employed to synthesize diblock copolymers of PNBOC-b-PMALA and PEO-b-PMALA,where MALA is synthesized by condensation of lipoic acid and hydroxyethyl methacrylate.Gold nanoparticle(AuNP)surface is functionalized with PEO-b-PMALA and PNBOC-b-PMALA diblock copolymer chains via cooperative multidentate binding interactions between AuNP surface and PMALA segments.For amphiphilic gold nanoparticles(AuNPs)with a diameter of 3 nm,AuNP hybrid vesicles with diameter of?160 nm and?320 nm are obtained though slow water addition and nanoprecipitation self-assembly method,respectively.And for AuNPs with a diameter of 13 nm,AuNP hybrid vesicles with a dimeter of?190 nm and hybrid nanotubes are obtained,respectively.These AuNP hybrid vesicles and hybrid nanotubes all exhibit photo-induced chemical cross-linking and hydrophobicity-to-hydrophilicity transition within AuNP hybrid bilayers.AuNP hybrid vesicles fabricated from amphiphilic AuNPs(3 nm in diameter)have been used as an X-ray computed tomography(CT)contrast agent.And drug-loaded AuNP hybrid vesicles fabricated from amphiphilic AuNPs(13nm in diameter)have been used for combined photothermal therapy and chemotherapy.More efficient to kill tumor cells within this drug-loaded AuNP hybrid vesicles due to its long acting photothermal therapy and sustained drug release after 410 nm light irradiation.AuNP hybrid nanotubes are used as a catalysis for p-nitrophenol reduction.3.Amphiphilic diblock copolymers,P(DMA-co-Eos)-b-PCPTM,are synthesized though reversible addition-fragmentation chain transfer(RAFT)polymerization,where DMA,Eos,and CPTM are N,N-dimethylacrylamide,4-vinylbenzyl2-(2,4,5,7-tetrabromo-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoate,and reduction-cleavable camptothecin(CPT)prodrug monomer,respectively.Hydrophobic oleic acid-stabilized UCNPs(NaYF4:Yb/Er)and the diblock copolymer are dispersed and disolved in chloroform,respectively.An oil-in-water(O/W)emulsion and a subsequent solvent evaporation procedure is used to construct up-conversion nanoparticle(UCNP)hybrid polymer assemblies.After optimization experimental conditions,UCNP hybrid vesicles are obtained.Under980 nm laser irradiation,energy transfer between UCNPs and photosensitizer occur,resulting in excitation of the photosensitizer to produce singlet oxygen.At the same time,up-conversion fluorescence can be also used for cellular imaging.After UCNP hybrid vesicles being endocytosed by cancer cells,singlet oxygen generated by laser irradiation promotes the hybrid vesicles escape from endolysosomes to cytosol,where the reductive environment triggers the rapid release of CPT.Finally,these UCNP hybrid vesicles show potent ability to kill tumor cells.4.The effect of only using photodynamic therapy(PDT)for cancer treatment is limited due to hypoxic microenvironment of tumor tissue.Combined reversible addition-fragmentation chain transfer(RAFT)polymerization and polymer post-modification method,near-infrared photosensitizer is attached to the amphiphilic block polymer side chain through redox-responsive disulfide bond moiety.Assemblies fabricated from this polymer exhibit photothermal therapy to photodynamic therapy transition in a reductive microenvironment.We also copolymerize CPTM to this polymer which further enhance the treatment effect.By changing the bonding mode between the photosensitizer and the polymer main chain,we also fabricate polymersomes which is capable of crosslinking mode transition in a reductive microenvironment.This process can be used to regulate the permeability of the vesicle bilayer in addition to the aforementioned therapy mode transition.