title: PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking.
abstract: The cytotoxicity of chemotherapeutic agents to healthy organs and drug resistance of tumor cells are believed to be the main obstacles to the successful cancer chemotherapy in the clinic. To ensure that anticancer drugs could be delivered to the tumor region, are quickly released from carriers in tumor cells and rapidly escape from endo/lysosomes, YPSMA-1-modified pH-sensitive polymeric micelles, which would be advantageous in recognizing the prostate specific membrane antigen (PSMA), were designed and fabricated for targeted delivery of paclitaxel to tumors based on the pH-sensitive diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and YPSMA-1-PEOz-PLA for treating prostate cancer. HOOC-PEOz-PLA with a critical micelle concentration of 5.0 mg L(-1) was synthesized and characterized by (1)H NMR and gel permeation chromatography. The prepared YPSMA-1-modified micelles, about 30 nm in diameter, exhibited a rapid release behavior at endo/lysosome pH and a favorable ability of fast endo/lysosome escape as observed by confocal microscopy. More importantly, we evidenced for the first time that both endosome and lysosome escape existed for pH-sensitive micelles via real time tracing using confocal microscopy, and the real time endo/lysosome escape process was also presented. The YPSMA-1-modified micelles were very effective in enhancing the cytotoxicity of paclitaxel by increasing the cellular uptake in PSMA-positive 22Rv1 cells, which was verified the correlation with PSMA expression in tumor cells by flow cytometric analysis and confocal microscopy. Moreover, the active targeting and pH-sensitivity endowed YPSMA-1-modified micelles with a higher antitumor efficacy and negligible systemic toxicity in 22Rv1 xenograft-bearing nude mice compared with unmodified micelles and Taxol®. These results suggested that the application of combining YPSMA-1 modification with pH-sensitivity to polymeric micelles may be one approach in the efficient delivery of anticancer drugs for treating PSMA-positive prostate cancers.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. yanliu@bjmu.edu.cn ll@bjmu.edu.cn.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Gao
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Li
authors.forename: Yushu
authors.initials: Y
authors.lastname: Li
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jinwen
authors.initials: J
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D011992:Endosomes / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000954:Antigens, Surface; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011073:Polyamines; D011091:Polyesters; D011108:Polymers; C511916:poly(2-ethyl-2-oxazoline); C033616:poly(lactide); C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017239:Paclitaxel