Study Of Stimuli-responsive Polymer Anticancer Drugs

Cancer is the main cause of premature death in humans, although it has beenchanged in the clinical detection methods to improve the civic awareness, the rate ofcancer is rising. Essentially, the cancer is a disease caused by uncontrolled cell growth,due to participate in the balance of cell proliferation and cell death gene mutation,making the organization’s balance disrupted. Currently, the main measures to cure ofcancer as follows: chunks tumor resection followed by radiation therapy orchemotherapy way to kill residual cancer cells.Small molecule natural products are mainly used for the synthetic drugs.However the synthetic drugs have some defectives: low targetable or non-targetable.Polymeric drug, protein drug and polymer micelles drug tend to accumulate at thetumor site due to their enhanced permeation and retention (EPR) effect, thus couldreduce their toxic and side effect in normal tissue. It is caused a great deal of attentionin the field of chemistry and medicine during the past four decades.The thesis consists of two chapters as follows:1. The rhodamine B monomer containing disulfide bond MA-MAOHD-RHB,was synthesized by the reaction of the carboxyl group activated rhodamine B and2-(methacryloyl)oxyethyl-2’-hydroxyethyl disulfide. Amphiphilic block copolymerspoly(HPMA)-MA-MAOHD-RHB2was prepared via RAFT polymerization. Themonomer MA-MAOHD-RHB and copolymers were characterized by1HNMR. Themicelles formed by poly(HPMA)-MA-MAOHD-RHB in a mixture of methanol andH2O (5:1by volume) based on the hydrophobic poly(MA-MAOHD-RHB) cores andhydrophilic HPMA shells. In the presence of dithiothreitol (DTT), the disulfide bondwas fractured from polymer chains and the rhodamine B entered into the solution. Astime increases, the fluorescence intensity in the solution was gradually increased.Amphiphilic block copolymer micelles containing disulfide bond showed very goodstimuli-responsive, and could potentially be used as a pharmaceutical carrier forcontrolled drugs delivery.2. Poly(HPMA)-(MA-PNP)-SMZ was successfully synthesized andcharacterized as dual targeting drug delivery system. Poly (HPMA)- (MA-PNP)-SMZ containing an acid-sensitive hydrazine bond. In the normal humanbody fluid (pH=7.4), the hydrazine bond of poly(HPMA)-(MA-PNP)-SMZ is stable;while in tumor site (pH=4.5-6.9), the hydrazine bond is hydrolyzed to release smallmolecule drug4-[Bis-(2-chloroethyl)amino]benzaldehyde. Drug releasing rate fromcopolymers was investigated in PBS at pH4.0,5.0and7.4, respectively. The resultsshowed that only20%of4-[Bis-(2-chloroethyl)amino]benzaldehyde could bereleased at pH=7.4in120hours. At pH=4and5, drug releasing becomes faster andthe release rate at pH=4is higher than that of at pH=5. There is an obvious burstreleasing in the first15hours, then the release rate is slowly down. It is illustrated thatpoly (HPMA)-(MA-PNP)-SMZ is an acid-sensitive drug carriers.