Synthesis Of Polypeptide With Near Infrared Fluorescence And Its Application As Drug Delivery Agent

Polypeptide materials have been widely studied in biomedical relevant areas during recent years because it can be obtained facially and economically by one-step ring opening polymerization of amino acid N-Carboxyl-anhydride (NCA). Here in the second part of this dissertation, we prepared a novel reduction sensitive core cross-linked star polymer (CCS polymer) with a disulfide cross-linked polypeptide core and an mPEG cornea. Indomethin was physically loaded into this disulfide cross-linked nanogel to prepare a drug delivery system, and its drug release behavior was studied under both reduction-sensitive and reduction-insensitive conditions. The results showed an accelerated drug release behavior under reduction-sensitive condition.Cyanine relevant dye has been widely used for the bioimaging purpose because of its unique optical properties such as long wavelength nature and low toxicity. In the third part of this dissertation, we prepared a series of cyanine dyes with different physical structures and chemical properties. These carboxyl and alkyne-functionalized cyanine can be used to react with free amine group of polypeptide or azide functionalized polymer to prepare fluorescent polymer with near infrared fluorescence property. As a paradigm, we prepared alkyne nanogel with a disulfide cross-linked polypeptide core. Cyanine dye with azide group was then conjugated to the alkyne nanogel by Click chemistry. Anticancer drug doxorubicin was then encapsulated into the obtained NIRF nanogel, the obtained drug loade NIRF nanogel showed reduction triggered drug release behavior in the presence of10mM glutathione.Disulfide-cross-linked nanogel with near infrared fluorescence property (NIRF nanogel) was synthesized in this report. Anticancer drug doxorubicin was then encapsulated into polypeptide core of the NIRF nanogel to prepare a drug carrier with near infrared fluorescence (NIRF prodrug). In vitro drug release study of the NIRF prodrug reveals an accelerated release behavior in the presence of10mM glutathione (GSH). In vivo distribution of the NIRF nanogel and NIRF prodrug on tumor bearing nude mice shows that both of the NIRF nanogel and NIRF prodrug accumulate at tumor place at24h after tail veil injection via enhanced permeability and retention effect (EPR). Cellular uptake study of both the NIRF nanogel and NIRF prodrug shows that both of the two materials could enter cell via endocytosis. The NIRF nanogel and NIRF prodrug prepared here have the potential application for the respective purpose of cancer diagnostics and treatment.In the fifth part of this dissertation, near infrared fluorescent drug delivery system (NIRF DDS) with pH-responsive drug release ability has been designed and developed. This material was prepared by chemical conjugation of anticancer drug doxorubicin and hydrophobic aminocyanine dye to triblock copolypeptide via hydrazone and amide bond, respectively. pH sensitive drug release nature of the near infrared fluorescent polymeric drug (NIRF prodrug) was confirmed by accelerated drug release at pH of5.0via in vitro drug release experiment and a gradual drug cleavage form NIRF prodrug. Confocal laser scanning microscopic (CLSM) experiment revealed that the released drug subsequently migrated to nucleus while the polymeric residue located in cytoplast, indicating the as-prepared polymer is a candidate for theranosis of cancer.Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization has been extensively studied and widely employed for the production of polymers with various structures and functionalities. In Chapter6, a novel amphiphilic tri-block copolymer with both near infrared fluorescence and pH responsive property was prepared. Di-block copolypeptide was prepared in the first place by the sequential ring opening polymerization of ZLLys-NCA and Asp-NCA, a hydrophilic block was then attached to the copolypeptide by RFAT polymerization initiated by the thiol ester located at the chain end. NIRF prodrug was thus prepared following a similar method as documented in chapter5, the obtained NIRF has strong fluorescence in near infrared region and shows pH responsive drug release behavior.