Abstract
AbstractPolymeric micellar drug delivery systems (MDDSs) of core-shell architecture based on amphiphilic AB diblock or ABA triblock copolymers possess numerous advantages. They improved solubility and bioavailability of hydrophobic drugs that were poorly soluble or insoluble in water. Micelles with biocompatible hydrophilic shell exhibited low uptake by the reticuloendothelial system even if they had a nonbiocompatible core and hydrophobic core significantly protect the incorporated drug . Additionally, polymeric micelles with nano-scale could avoid the recognition by MPS or RES and they prolonged the circulation time in blood. In this study, polymeric micelle with environmental stimuli-sensitive properties such as thermo-sensitive properties and pH-sensitive properties were prepared for used in drug delivery. Polymeric micelles were self-assembled from diblock and triblock copolymers in aqueous solution, respectively. Amphiphilic block copolymers with hydrophilic block segment of poly(2-ethyl-2-oxazoline)(PEtOz) and biodegable aliphatic polyester segment of poly(L-lactide)(PLLA) were synthesized from cationic ring-opening polymerization.This study proposes a new delivery system, which was potentially useful for targeted drug delivery, and rapidly changes the micelle structure in response to changes in intracellular pH. Following intravenous administration, polymeric micelles were accumulated in tumor tissue by EPR effect, and then taken up to cells via endocytosis process. The pH value of endosomal comportments were decreased from 7.4 to 5 because protons are pumped into the vesicles. From our design, the micellar structures can stabilized to preserve hydrophobic drug(Doxorubicin, Dox) under physiological conditions(pH7.4) and selectively release the drugs by sensing the intracellular pH change in endosomes and lysosomes(pH 4~5).The micelles were self-assembled from PEtOz-PLLA diblock amphiphilic copolymers and PLLA-PEtOz-PLLA triblock amphiphilic copolymers, respectively. The hydrophobic anticancer drug could be entrapped into the hydrophobic core resign of micelles. The characterizations, pH-sensitive properties, micellar stability were determinated by dynamic light scanning(DLS). Additionally, critical micellar concentration(CMC) and structure changed properties of micelle were determinated by fluorescence spectrum.The mean diameters of micelles were all less than 200 nm and exhibited low polydispersity index. The drug loading level of Doxorubicin(DOX) incoporated into the PEtOz/PLLA triblock polymeric micelles can be as high as 30 % . The drug loading level of Doxorubicin(DOX) incoporated into the PEtOz/PLLA diblock polymeric micelles can be as high as 25 % . At 37℃, the cumulated released rate of Dox from PEtOz/PLLA diblock polymeric micelle at pH5.0 was about 35 % in the initial 3 hour. On the other hand, both micelles exhibit less drug relesed at pH7.4, indicating that micelles were stabilized in physiological conditions. In use of the method of MTT assay, we could confirm the inhibiting proliferation of HeLa by the releasing anticancer drug and effective therapy to cancer in vitro.In conclusion, PEtOz /PLLA block copolymers possessed the advantages of environmental sensitivity, biodegradability and lower cytotoxicity, that were suitable for used in drug delivery, especially for cancer therapy. The drug released behaviors of micelles incorpotated with Dox were excellent either in buffer solution or in intracellular endosomal compartment. The result of CLSM observation indicated the release of drug successfully released in the acidic organelles due to the deformation of the micelle structure. As the results, these micelles loaded anticancer drug(Dox) have great potential for application in drug delivery system, especially for used in intracellular drug delivery .Keywords: Poly(2-ethyl-2-oxazoline)(PEtOz), Poly(L-lactide)(PLLA), block polymer, micelle, core-shell, stimuli-sensitive, biodegable, self-assembly, endocytosis process.,cancer therapy, intracellular drug delivery