Construction Of Stimuli-Responsive PEG-PCL Topological Copolymers And Their Potential Application In Triggered Release Of Anticancer Drugs

Tumor is one of the most serious diseases that threaten human health.Chemotherapy is still the main treatment for cancer therapy.Traditional polymer nanoparticle delivery systems always suffer from early leakage of drugs once being injected into the circulation of the body before reaching the tumor site.As a result,only some drugs are effective due to enhanced permeability and retention(EPR)effect.So the release process is uncontrollable,causing toxic side effects on normal tissues and organs in the body,thus,greatly limiting the application in clinical.In comparasion with normal cells,the micro environmental in tumor cells is low pH,high GSH concentration and high temperature.So the stimuli-responsive polymer micelles are considerd as an promising platform for drug delivery due to their enhanced cargo solubility,prolonged circulation time and targeted diseased tissue.In this dissertation,a series of amphiphilic copolymers with different topologies were constructed based on polyethylene glycol(PEG)and polycaprolactone(PCL)via Cu(?)-catalyzed azide-alkyne cycloaddition(CuAAC)and ring-open reaction.After introducing stimuli-responsive groups,such as disulfide bonds and acetal bonds,the amphiphilic copolymers possess stimuli-responsivity and potential in anticancer drug carriers.In chapter 2,the reduction-cleavable and swelling controllable amphiphilic conetworks(APCN)were designed and synthesized via copper(?)-catalyzed azide-alkyne cycloaddition(CuAAC)of azide terminated disulfide bonds-containing poly(?-caprolactone)(A₂macromonomer)and alkyne-terminated 4-arms polyethylene glycol(B₄ macromonomer).APCNThe amphiphilic nature enables them to be swelling in both aqueous and organic solvents.The ratio of hydrophobic and hydrophilic of as-prepared APCN was tuned by chain length of A₂ macromonomer,which give a convenience to control swelling capacity in aqueous or organic phase,respectively.The swelling ratio of APCN is up to 1100%and1450%in water and tetrahydrofuran,respectively.The degradation of most reported APCN are dependent on the diffusion of solvents and cleavage of ester and carbonate linkages.The degradation rate is slow.Most of them were observed to be completely degraded even after several days or months.But the as-prepared APCN show a rapid and controllable cleavage at a 5 mg/mL dithiothreitol concentration.The reduction-cleavable,swelling controllable and APCN are expected to possess potential in application of drug delivery systems and tissue engineering.In chapter 3,the reduction-responsive star copolymers with long-chain hyperbranched poly(?-caprolactone)(HyperMacs)core,disulfide bonds and PEG were synthesized via Cu(?)-catalyzed azide-alkyne cycloaddition(CuAAC)reaction.We design the HyperMacs structure to change the hyperbranched triazoles cavity from compact to incompact type.The HyperMacs structures hinder the PCL in crystallization and further improve the efficiency of drug packaging.The HyperMacs core was constructed from disulfide-containing AB₂-type PCL macromonomers,which possessed length-adjustable chain segments between branching points,large cavities,low degree of crystallinity.HyperMacs core shows good stability in neutral environment and unique reduction-cleavable property.After grafted with PEG,the reduction-responsive star copolymers can be self-assembled into micelles in aqueous solution.The obtained micelles exhibited much lower critical micelle concentration than their linear analogues.The reduction-responsivity from disulfide bonds makes them a promising carrier candidate for trigger release of anticancer drugs.The in vitro release results confirmed that their DOX-loaded micelles exhibited desirable reduction-triggered release performance.The cellular proliferation inhibition against HepG2 cells demonstrated that the DOX-loaded micelles showed a comparable anticancer activity with free DOX.Therefore,it can be expected that the reduction-sensitive micelles may serve as smart vehicles for intracellular delivery of anti-cancer drugs in tumor therapy.In chapter 4,reduction-responsive core-crosslinked copolymers were synthesized by Cu(?)-catalyzed azide-alkyne cycloaddition(CuAAC)reaction via“A₂+?B₃”approach.An telechelic amphiphilic B₃?macromonomer was synthesized through esterification between monomethoxy-poly(ethylene glycol)-co-poly(?-caprolactone)with tris(chloromethyl)acetic acid and was followed by azidization reaction.By CuAAC,the B₃?macromonomer was reacted with a disulfide bond-containing A₂ monomer to generate a core-crosslinked copolymers.The obtained core-crosslinked copolymers could be self-assembled into micelles in aqueous solution and its self-assembly aggregates behaviour could be tuned by controlling the ratio between PEG and PCL segments.The obtained micelles possessed much higher stability than that from linear monomethoxy-poly(ethylene glycol)-co-poly(?-caprolactone).These micelles also exhibited reduction-responsivity due to disulfide bonds.In vitro release results confirmed that their DOX-loaded micelles exhibited desirable reduction-triggered release performance.The cellular proliferation inhibition against A549 cells demonstrated that the DOX-loaded micelles showed a comparable anticancer activity with free DOX.In chapter 5,amphiphilic star copolymers(H40-star-PCL-a-PEG)with an H40hyperbranched polyester core and poly(?-caprolactone)-?-poly(ethylene glycol)copolymer arms linked with acetal groups were synthesized using ring-opening polymerization and CuAAC reaction.The acid-cleavable acetal groups between the hydrophilic and hydrophobic segments of the arms endowed the amphiphilic star copolymers with pH responsiveness.In aqueous solution,unimolecular micelles could be formed with good stability and a unique acid degradability.For the model drug of DOX,the in vitro release behavior,intracellular release and inhibition of proliferation of HeLa cells showed that the acid-cleavable unimolecular micelles with anticancer activity could be dissociated in an acidic environment and efficiently internalized by HeLa cells.Due to the acid-cleavable and biodegradable nature,unimolecular micelles from amphiphilic star copolymers are promising in applications in effective drug delivery for tumor chemotherapy.