title: Polymeric micelle for tumor pH and folate-mediated targeting.
abstract: Novel pH-sensitive polymeric mixed micelles composed of poly(L-histidine) (polyHis; M(w) 5000)/PEG (M(n) 2000) and poly(L-lactic acid) (PLLA) (M(n) 3000)/PEG (M(n) 2000) block copolymers with or without folate conjugation were prepared by diafiltration. The micelles were investigated for pH-dependent drug release, folate receptor-mediated internalization and cytotoxicity using MCF-7 cells in vitro. The polyHis/PEG micelles showed accelerated adriamycin release as the pH decreased from 8.0. When the cumulative release for 24 h was plotted as a function of pH, the gradual transition in release rate appeared in a pH range from 8.0 to 6.8. In order to tailor the triggering pH of the polymeric micelles to the more acidic extracellular pH of tumors, while improving the micelle stability at pH 7.4, the PLLA/PEG block copolymer was blended with polyHis/PEG to form mixed micelles. Blending shifted the triggering pH to a lower value. Depending on the amount of PLLA/PEG, the mixed micelles were destabilized in the pH range of 7.2-6.6 (triggering pH for adriamycin release). When the mixed micelles were conjugated with folic acid, the in vitro results demonstrated that the micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake. In addition, after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity. This approach is expected to be useful for treatment of solid tumors in vivo.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Suite 318, Salt Lake City, UT 84108, USA.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Kun
authors.initials: K
authors.lastname: Na
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry*; D006639:Histidine / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry; D008027:Light; D008823:Micelles; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D011956:Receptors, Cell Surface; D012542:Scattering, Radiation; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008823:Micelles; D011108:Polymers; D011956:Receptors, Cell Surface; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C033223:polyhistidine; D019344:Lactic Acid; D006639:Histidine; D004317:Doxorubicin; D005492:Folic Acid