Preparation And Antitumor Effect Of Drug Loaded Poly (Amino Acid) Nanoparticles

Celestrol(CEL)is a triterpenoid broad-spectrum antitumor drug,which has obvious inhibitory effect on most tumors such as liver cancer,gastric cancer,breast cancer and so on.However,the clinical application of triptolide is limited by its poor water solubility,low oral bioavailability and the first pass effect of liver.Doxorubicin(DOX)is an anthraquinone antitumor drug with a wide antitumor spectrum.It can be used in the treatment of acute leukemia,malignant lymphoma and other tumors.Adriamycin limits its further clinical application because of its poor water solubility,low drug distribution selectivity,obvious toxic and side effects and inducing tumor drug resistance.The most effective way to improve the anti-tumor drug delivery is to use nano carriers to improve anticancer activity and reduce side effects.Poly(amino-acid)s have excellent biocompatibility and easy biodegradation.In this paper,the amphiphilic poly(ethylene glycol)-polylysine-polyphenylalanine triblock copolymer was synthesized by ring opening polymerization of amino acid-n-carboxylic anhydride(NCA)with polyethylene glycol monomethyl ether.The polyamino acid nanoparticles loaded with CEL and DOX-SS-COOH prodrug were further prepared and characterized as follows:Part Ⅰ: Polyethylene glycol poly lysine poly alanine nanoparticles CEL/mPEG-PLys-PPhe loaded with CEL were designed owing to the electrostatic interaction between the carboxyl group of CEL and the residual amino group of poly(amino acid)carries and hydrophobic force.The physical and chemical properties experiments showed that the average particle size of CEL/mPEG-PLys-PPhe nanoparticles was 260.9±4.2 nm,the zeta potential was-9.65±0.37 mV and the PDI was0.119±0.025.The drug loaded of polymer nanoparticles has good sustained-release performance.Cell uptake and apoptosis experiments showed that drug loaded nanoparticles could enhance uptake and induce tumor cell apoptosis of MCF-7 cells.In vitro antitumor experiments showed that CEL/mPEG-PLys-PPhe nanoparticles had good cytotoxicity to He La and A549 cells.Part Ⅱ: A doxorubicin derivative prodrug(DOX-SS-COOH)containing terminal carboxyl group was synthesized,and then doxorubicin loaded poly(ethylene glycol)-polylysine-polyphenylalanine nanoparticles DOX-SS-COOH/mPEG-PLys-PPhe were designed through electrostatic interaction and encapsulating the drug by hydrophobic force.The physical and chemical experiments showed that the average particle size of DOX-SS-COOH/mPEG-PLys-PPhe nanoparticles was 330.1±2.1 nm,the zeta potential was-21.35±0.31 mV,and the PDI was 0.199±0.024.Drug release experiments showed that polymer nanoparticles had pH-responsive and reduction-responsive release behavior.Cell uptake and apoptosis experiments showed that drug loaded nanoparticles could enhance uptake and induce tumor cell apoptosis of MCF-7 cells.Finally,DOX-SS-COOH/mPEG-PLys-PPhe nanoparticles showed good cytotoxicity to He La and A549 cells,ascribed to the release of the parent drug doxorubicin.