Synthesis And Properties Of Ph/Redox Responsive Star Polypeptides For Controlled Drug Delivery

The structure, physical and chemical properties of responsive polymers change according to the external environmental stimulis. Responsive polymers as controlled drug delivery materials can response to the signal stimulation of diseased region to control drug release, improve drug efficacy and reduce side effects. Thus, we design and synthesis of pH and redox responsive star polypeptides based on high biocompatibility amino acids. Meanwhile, we also investigate physicochemical properties, mechanism of drug loading, controlled release properties and cell toxicity of star polypeptides.Firstly, the amino acid-N-carboxylic acid anhydride were synthesized from the corresponding amino acid. The chemical structures of amino acid-N-carboxylic acid anhydride and intermediates were characterized by 1H NMR and FT-IR. Then, hexamethyldisilazane (HMDS) initiated the sequential ring opening polymerization (ROP) of amino acid-N-carboxylic acid anhydride, and the protecting groups were removed to obtain star polypeptides based on poly(L-glutamic acid)-poly(phenylalanine-cystine). The results of GPC, DLS, NMR, FT-IR and elemental analysis demonstrated polypeptides with star structure, and star polypeptdes can self-assembly to form 50nm micelles. The star polypeptides have pH and redox response. With pH of the micelles solution decreased, the size and Zeta potential of star polypetides micelles increased to 1506nm and -2.6mV. In the reductive environment, the size of star polypetides micelles increased from 80nm to 216nm due to the core structure of star polypetides micelles dissociated.Doxorubicin (DOX) and Resveratrol (RES) were chosen as model drugs to investigatethe drug ability and in vitro release of star polypeptides. The drug loading content can be controlled by tunning the composition of the star polypeptides. With the hydrophobic proportion increasing, the drug loading content of DOX decreased and the drug loading content of RES increased. The mechanism of drug loading demonstrated that DOX and RES were loaded into star polypeptides through electrostatic and hydrophobic interaction. In vitro drug release experiments indicated that star polypeptides micelles have pH and redox response. With pH decreased from 7.4 to 5.5, the 72h cumulative release of DOX increased to 50%and the 72h cumulative release of RES decreased to 20%. With DTT concentration increased from OmM to 10mM, release of DOX and RES were significantly accelerating, and 72h cumulative release exceeded 40% and 80%. Finally, the 72h cumulative release of DOX and RES reached 83% and 64% at pH 5.5 and DTT lOmM mimic to intracellular environment.The results of cytotoxicity showed that star polypeptides have low biotoxicity and interact well with cells. The cell viabilities of HeLa and MCF-7 were up to 80% at all the concentrations up to 500mg L-1. Meanwhile, drug loaded micelles can effectively inhibit the proliferation of tumor cells, and the cytotoxicity of DOX and RES loaded micelles exceeded free DOX and DOX loaded micelles. These results demonstrated that there exist synergistic antitumor effect between DOX and RES.