title: Self-Assembled Monomethoxy (Polyethylene Glycol)-b-P(D,L-Lactic-co-Glycolic Acid)-b-P(L-Glutamic Acid) Hybrid-Core Nanoparticles for Intracellular pH-Triggered Release of Doxorubicin.
abstract: Triblock copolymers, Monomethoxy (Polyethylene glycol)-b-P(D,L-lactic-co-glycolic acid)-b-P(L-glutamic acid) (mPEG-PLGA-PGlu) with different molecular weights, were synthesized and mPEG(5k)-PLGA(20.5k)-PGlu(7.9k) were self-assembled into negatively charged nanoparticles with a hybrid core of PLGA and PGlu, and a stealth PEG shell. Because of electrostatic interaction with the negative hybrid-core, the model drug, doxorubicin (DOX), could be easily loaded into the hybrid-core nanoparticles with a high drug loading of ca. 25%. The hydrophobic interaction provided by PLGA could increase the stability of drug-loaded nanoparticles with no change in particle size for at least 3 days and only minor drug leakage (< 0.5%) in pH7.4 physiological media. Due to protonation of PGlu block in pH5.0 medium, the hybrid-core of these nanoparticles was destroyed, as shown by transmission electron microscopy, and this resulted in an increase in the pH-triggered release of DOX from 38.9% in pH7.4 release medium to 71% in pH5.0 release medium at 24 h. In vitro cytotoxicity testing involving MCF-7 and NCI-H460 cells showed that DOX-loaded nanoparticles were more cytotoxic to both types of cells than free DOX. Time-dependent cellular uptake of the drug-loaded nanoparticles was observed and at least 4 hours was required for rapid internalization through caveolinmediated endocytosis and macropinocytosis by MCF-7 cells into the endosomes where pH-trigged release of DOX from the nanoparticles occurred. The hybrid-core nanoparticles represent a potentially useful therapeutic delivery system for cationic drugs due to their high drug loading, high stability in physiological media and intracellular pH-triggered release.
authors: Helin
authors: H
authors: Xu
authors: Cuifang
authors: C
authors: Cai
authors: Jingxin
authors: J
authors: Gou
authors: Bowen
authors: B
authors: Sui
authors: Jian
authors: J
authors: Jin
authors: Hui
authors: H
authors: Xu
authors: Yu
authors: Y
authors: Zhang
authors: Lihui
authors: L
authors: Wang
authors: Yinglei
authors: Y
authors: Zhai
authors: Xing
authors: X
authors: Tang
mesh_terms: D000327:Adsorption; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003460:Crystallization / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000737:chemistry; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D011091:Polyesters; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011099:Polyglutamic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin