title: Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy.
abstract: A novel intracellular pH-sensitive polymeric micelle drug carrier that controls the systemic, local, and subcellular distributions of pharmacologically active drugs has been developed in this study. The micelles were prepared from self-assembling amphiphilic block copolymers, poly(ethylene glycol)-poly(aspartate hydrazone adriamycin), in which the anticancer drug, adriamycin, was conjugated to the hydrophobic segments through acid-sensitive hydrazone linkers. By this polymer design, the micelles can stably preserve drugs under physiological conditions (pH 7.4) and selectively release them by sensing the intracellular pH decrease in endosomes and lysosomes (pH 5-6). In vitro and in vivo studies show that the micelles have the characteristic properties, such as an intracellular pH-triggered drug release capability, tumor-infiltrating permeability, and effective antitumor activity with extremely low toxicity. The acquired experimental data clearly elucidate that the optimization of both the functional and structural features of polymeric micelles provides a promising formulation not only for the development of intracellular environment-sensitive supramolecular devices for cancer therapeutic applications but also for the future treatment of intractable cancers with limited vasculature.
authors.affiliation: Department of Materials Science and Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Younsoo
authors.initials: Y
authors.lastname: Bae
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Shigeto
authors.initials: S
authors.lastname: Fukushima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koyama
authors.forename: Matsumura
authors.initials: M
authors.lastname: Yasuhiro
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D006835:Hydrazones / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008823:Micelles; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009928:Organ Specificity; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006835:Hydrazones; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin