Fabrication And Application Of Reduction-degradable Poly (L-succinimide) Nanomicelles Produgs Carriers

Polymeric nanomicelle is a kind of amphiphilic compound with an average size of100nm and become one of international research hotspots. Hydrophobic drugs can be entrapped into the inner core by hydrophobic interaction, electrostatic effect or H-bond action, so as to improve their solubility, bioavailability, reduce cytotoxcity as well as endow passive targeting properity. Disulfide bond is a sort of special chemical bond who will break spontaneously in reduction environment in hunman body. The preparation of reduce-sensitive nanomicelle prodrug combined disulfide bonds has become one of key reseaches worldwidely. Cell permeate peptide (CPP) is a kind of small molecule polypeptide who can carry the hydrophobic drug that is about100times of CPP molecular weight into the cells without any side effect to the host. The nanomicelle with CPP linked will restrain the drug resistance due to long time medication. The major works of this paper is focused on the design and synthesis of nanomicelle drug delivery system with the disulfide bonds and CPP combined, and the characterization of structures, drug release, cytotoxcity as well as cellular uptake in vitro. The details are given as follows.Chapter1:IntroductionIn recent years, the biodegradable polymer nanomicelles as an anti-cancer drug carrier have been paid lots of attention in the field of medical. Small molecular drugs, has high anti-cancer activity although, the shortcomings such as water insoluble, high side effects, restrict their clinical applications. The properties of high solubility in water, controlled release, passively targeting, biodegradable, reduced toxicity, removed drug restraint were fulfilled by introducing the disulfide bonds and CPP into the preparation of polymeric nanomicelle. This chapter elaborated the development of nanomicelle, disulfide bond, CPP, as well as the design thought of this paper.Chapter2:Fabrication and characterization of6-mercaptopurine nanomicellesThe amino-acid derivatives of poly (ethylene glycol)(mPEG-SS-NH2) and2-(pyridyldithio)-ethylamine (PDA) were successively grafted to the main chain of poly (L-succinimide)(PSI) to get the product mPEG-SS-NH-g-PAsp-PDA.6-mercaptopurine was used to exchange the PDA from the side chain of PSI through thiol-disulfide exchange reaction to obtain the target product mPEG-SS-NH-PAsp-MP. It will form nanomicelle in phosphoric acid buffer solution (PBS) by self-assembly. The structures of the products were characterized by’H NMR, and the nature of the polymeric nanomicelle to was determined by fluorescence spectra, UV-vis, DLS, TEM, GPC method.Chapter3:Fabrication and characterization of CPP nanomicellesThe five-member rings of PSI were gradually opened by mPEG-SS-NH2, PDA, and dopamine (DA) to prepare the product mPEG-SS-NH-g-PAsp-DA. CPP was used to exchange the PDA from the side chain of PSI through thiol-disulfide exchange reaction to obtain the target product mPEG-SS-NH-PAsp-DA-CPP. It will form nanomicelle in PBS by self-assembly. The structures of the products were evaluated by1H NMR, DLS, GPC, fluorescence microscope and so on.