Preparation And Application Of PH-sensitive Paclitaxel-loaded Polysialic Acid Polymeric Micelles

In recent years, to reduce the side effect of chemotherapy and enhance its bioavailability of the anticancer drugs, many drug delivery systems were developed. Among them, polymers micelles are widely investigated. Although hydrophilic materials possess various choices, the advantages of ethylene glycol are interested as hydrophilic materials. Despite improvements relative to unmodified counterparts, poly(ethylene glycol)(PEG) conjugation may not be the ideal solution for improving circulatory stability of nanoparticle carriers or free drugs.Polysialic acid(PSA), a natural, biodegradable polymer polymer for which the body possesses no receptors, has been conjugated directly to biologically active molecules to prevent premature clearance and is able to release drug at mildly acidic pH mimicking that of endosomal owing to hydrolysis of PSA. However, polysialic acid has not yet been applied to drug carrier systems.In this thesis, endosomal pH- sensitive paclitaxel-loaded polysialic acid micelles were designed and prepared for potent growth inhibition of human cancer cells in vitro. The amphiphilic copolymers was synthesized by modifying of polysialic acid. The chemical structure of polysialic acid-based amphiphilic copolymers was characterized by1H-NMR.The degree of substitution(DS) was estimated by elemental analysis. The CMC of amphiphilic PSA-U2 copolymers determined by a fluorescence spectrometry using pyrene as a probe was 0.11 mg/mL. The poorly water-soluble anticancer drug PTX was physically incorporated into PSA-U2 micelles using a nano-precipitation method. The drug loading content of PTX into PSA-U2 micelles was detected as 4.5 % and the encapsulation efficiency was 65 %. The size and morphologies of PSA-U2 and PTX-loaded PSA-U2 micelles were analyzed with Field emission scanning electron microscopy(FESEM). PSA-U2 micelles showed the nearly spherical shape. The sizes of PSA-U2 micelles ranged from 120 to 150 nm.The particle size increased when PTX was incorporated. The particle size of PTX-loaded PSA-U2 micelles ranged from 120 to 180 nm. In order to investigate the effect of pH on the drug release of PTX-loaded PSA-U2 micelles, we measured the % cumulative release under simulated physiological condition(PBS, pH 7.4), at pH 6.5 and pH 5.0 over a period of time.Results revealed that paclitaxel was released from PTX-loaded PSA-U2 micelles at acidic pH mimicking that of endosomal and few paclitaxel was released in the medium of pH 7.4 and6.5, which revealed that blank micelles had no cytotoxicity. After incubation for 72 h, the PTX-loaded micelles showed higher cytotoxicity against SGC-7901 cells(cell viability53.8 %).These pH-sensitive paclitaxel-loaded polysialic acid micelles have appeared as a highly versatile and potent platform for cancer therapy.