Design Of Novel Doxorubicin Polymeric Prodrug And Study On Its Auto-accelerating Release Behavior

At present,polymeric prodrugs are important drug delivery systems?DDS?that has shown tremendous advantages in cancer treatment.However,the covalent bond used to link the anticancer drug is not stable enough under normal physiological conditions,and this may result in serious toxic and side effects.At the same time,the slower breakage rate of the covalent bonds?especially disulfide bonds?in the tumor microenvironment reduces the rate of drug release,so that the drug cannot accumulate enough concentration to kill cancer cells in a short time.Therefore,a prodrug design strategy not only reduce drug leakage,but also accelerate drug release is needed to improve anti-cancer efficacy and reduce toxic and side effects.In addition,fluorescent substances can be introduced into the drug delivery system to design the responsive nano-diagnostics.The changes of the fluorescence intensity of the nano-diagnostics after drug release in the tumor microenvironment can achieve real-time in situ monitoring of tumor tissues,which provides a new technique for the diagnosis and treatment of cancer,and exhibites huge application potential.Therefore,this thesis focuses on the design of polymer prodrugs with automatic accelerated release function and its application in the integration of tumor diagnosis and treatment.This research mainly includes five sections as follows:1.A serial new polymer doxorubicin prodrugs PEG-P?GMA-CBA?_n-DOX with different hydrophobic segments are synthesized and self-assemble into core-shell nanoparticles.As the hydrophobic block increases,the drug content of the prodrug gradually raises and the particle size gradually becomes larger.Since the structure of the prodrug changes from a hydrophobic block to a semi-hydrophobic block during the release of DOX,the self-accelerating release mechanism can be triggered.These nano-prodrugs all exhibits the characteristics of pH-triggered rapid release of DOX.PEG-P?GMA-CBA?₅₁-DOX polymer prodrug nanoparticles can effectively deliver DOX to the nucleus,and show stronger anti-tumor effect for HepG 2 cells than DOX,which is considered to be an excellent drug delivery system.2.Poly?2-?diisopropylamino?ethyl methacrylate??PDPA?cationic block is introduced into the polymer prodrug through continuous RAFT polymerization as the second switch for pH-sensitive prodrugs to prepare the core-shell-corona PEG₄₃-b-PDPA₆₅-b-PFPMA₃₆-DOX prodrug,and the effects of PDPA on drug release behavior is studied.Compared with the core-shell structure PEG₄₃-b-PFPMA₃₆-DOX prodrug,the core-shell-corona structure prodrug of PEG₄₃-b-PDPA₆₅-b-PFPMA₃₆-DOX micelles exhibits a faster drug release rate in the tumor cell microenvironment;while in physiological media,the drug leakage rate is lower.3.Two redox-sensitive polymer prodrugs are designed.A reduction-sensitive prodrug PEG₄₃-PPDSM₄₃-DOX is obtained through RAFT polymerization and thiol exchange reaction,which reveals a lower release under physiological conditions,but a lower release rate in the simulated tumor cell conditions.In order to improve the release rate of the reduction-sensitive prodrug,the single-trigger double-switch prodrug PEG₄₃-PDPA₃₅-P?MAL-DOX?₃ containing PDPA block is synthesized through continuous RAFT polymerization,the release rate of the prodrug in the simulated tumor cell environment is significantly improved,and ultra-low leakage is achieved in the normal physiological environment.Both prodrugs can be endocytosed by the cells and shows the effect of treating cancer.4.A functional diblock copolymer PPEGMA₄₂-b-PFPMA₁₂₂ is synthesized by RAFT polymerization,then carbon quantum dots?CDs?and DOX are introduced to prepare a crosslinked nano-therapeutic agent of PPEGMA₄₂-b-PFPMA₁₂₂-?CDs?-DOX with tumor cell microenvironment triggered DOX release and real-time imaging functions.The nano-diagnostic agent can not show fluorescence in the simulated normal physiological medium due to the simultaneous static quenching and dynamic quenching mechanisms;however in the simulated tumor cell microenvironment,CDs and DOX releases due to the pH-induced Schiff base bond rupture,and the strong fluorescence of CDs is recovered.Meanwhile,the carboxyl and amino groups on CDs and the disintegration of crosslinked structures automatically accelerate the drug release in the tumor microenvironment.5.A functional polymer containing naphthalimide?NAP?fluorophore is obtained by RAFT polymerization to construct the nano-prodrug diagnostic agent PPEGMA₂₀-PNAP₈-DOX based on intramolecular fluorescence resonance energy transfer?FRET?mechanism.During the drug release process,the diffusion of hydrogen ions is promoted to accelerate the release rate of DOX due to the release of DOX and re-assembly of the polymer.In addition,this prodrug only displays DOX fluorescence due to the intramolecular FRET effect.With the release of DOX,the FRET phenomenon disappeares and the fluorescence of PPEGMA₂₀-PNAP₈ is recovered.Compared with DOX,this prodrug also shows a significantly enhanced antitumor effect on HepG 2cells.The good biocompatibility,pH stimulus response,and changes in FRET signal during drug release of the polymer prodrug nano-diagnostic agent reveal great application potential in the field of controlled release of anticancer drugs and real-time fluorescence imaging of tumor tissues.