Synthesis And Controlled Release Of Environment-responsive Polymeric Anti-cancer Drugs

Currently, the polymer micellar delivery system has become a hot research due to itsunique advantages. The commonly polymeric micelles with a typical structure of ahydrophobic core and a hydrophilic shell were formed by the assembly of amphiphilicpolymers in aqueous solution. Hydrophobic drugs can enter the hydrophobic core ofthe micelles by physical embedding, chemical bonding, and electrostatic interactions,etc.. Some of the most hydrophobic materials is synthetic hydrophobic biodegradablepolymers, such as polyesters and poly(amino acids). And more hydrophilic materialsis poly(ethylene glycol)(PEG), chitosan oligosaccharide (CSO), poly(ethyleneimineamine)(PEI), poly(vinylpyrrolidone)(PVP), poly[N-(2-hydroxypropyl) methacrylam-ide](PHPMA), poly(N-isopropyl acrylamide)(PNIPAM) and so on. This paperstudies the following two kinds of responsive polymer-based drug delivery systems.1. Redox-responsive polymeric micelles with disulfide bond for drug deliveryFirstly, polycaprolactone (PCL) monomer was synthesized by ring-openingpolymerization of-CL using bis(2-hydroxyethyl)disulfde as an initiator. Then, theamphiphilic block copolymer PHPMA-PCL-SS-PCL-PHPMA was synthesized viaRAFT polymerization, wherein the disulfide bond can be selectively cleaved byreducing agents. The dialysis method was employed to prepare blank and5-fluorouracil (5-FU) loaded micelles formed form reduction-responsivePHPMA-PCL-SS-PCL-PHPMA. The critical micelle concentrations (CMC) of thecopolymers were determined by fuorescence spectroscopy with pyrene as ahydrophobic probe. The morphology and diameter of5-FU-loaded micelles werecharacterized by transmission electron microscopy (TEM) and dynamic lightscattering (DLS). The biodegradable polymeric micelles of PHPMA-PCL-SS-PCL-PHPMA can be cleaved with dithiothreitol (DTT), which is water-soluble reducingagent. The prepared polymeric micelles with disulfide bond degraded intowater-soluble polymers with pendant thiol (-SH) groups in the presence of thereducing agent DTT. These redox-responsive micelles exhibited accelerated release ofencapsulated drug in DTT containing PB buffer solution. Thus, it is easy to control therelease rate of drug from the micelles by choosing appropriate concentration of DTT. The polymeric micelles with disulfide bond could be utilized as noncytotoxic carriersfor various hydrophilic drugs, as well as be removed easily after release in thepresence of DTT.2. pH-responsive polymeric micelles with hydrazone bond for drug deliveryA diblock copolymer constituting of a poly(ethylene glycol)(PEG) and apolycaprolactone (PCL) segment, linked with a pH-responsive hydrazone bond (Hyd),was synthesized. The solvent evaporation method was employed to prepare blank and5-fluorouracil (5-FU) loaded micelles formed form pH-responsive PEG-Hyd-PCL.The critical micelle concentrations (CMC) of the copolymers were measured withpyrene fluorescent probe technique. The morphology and diameter of blank micelleswere characterized by transmission electron microscopy (TEM) and dynamic lightscattering (DLS). The encapsulation efficiency and drug-loading content wereestimated using the UV-vis spectrophotometer. The in vitro release study was furtherperformed to examine the pH-responsive drug release behavior from5-FU-loadedmicelles. In comparison to the drug release profile at normal physiological conditions(37oC, pH7.4), the5-FU-loaded micelles showed faster drug release rate at lower pH(pH5.0). This indicated that the micelles showed a pH-triggered drug release pattern.Base on the above results, it can be concluded that PEG-Hyd-PCL block copolymermicelles which respond to pH stimulus are promising smart carriers for anti-tumordrugs with the advantages of pH-triggered drug release.