title: Active targeting co-delivery system based on pH-sensitive methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K for enhanced cancer therapy.
abstract: In this paper, we successfully synthesized folate-modified pH-sensitive copolymer methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K (mPEG2K-PCL4K-PGA1K-FA), which could form the polymeric assembly in an aqueous solution, for co-delivering hydrophilic drugs doxorubicin hydrochloride (DOX) and verapamil hydrochloride (VER) (FA-poly(DOX+VER)). Since VER was an effective P-glycoprotein inhibitor, the combination of DOX and VER could reverse the multidrug resistance efficiently and enhance the therapeutic effect. Therefore, the inhibition ratios of MCF-7/ADR resistant cancer cell treated by FA-poly (DOX+VER) were almost more than 30% higher than those of FA-polyDOX after 48h and 72h. Furthermore, the conjugation of FA could lead the co-delivery systems actively targeting into the FA receptor over-expressing cancer cells in addition to the passive accumulation of the assembly in tumor tissues. Importantly, the prepared mPEG2K-PCL4K-PGA1K-FA assembly showed high pH-sensitive property, which made the drugs mostly released in tumor tissue (acid environment) than in physiological environment (neutral environment). In summary, the as-prepared co-delivery system FA-poly(DOX+VER) demonstrated a high efficiency in reversing the multidrug resistance and targeting FA receptor to improve the anticancer effect of DOX in MCF-7/ADR resistant cells.
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors.forename: Nuannuan
authors.initials: N
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors.forename: Chunzhi
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China. Electronic address: yuxialuan@sdu.edu.cn.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Key Lab of Colloid & Interface Chemistry, Shandong University, Ministry of Education, 250100, PR China.
authors.forename: Aixin
authors.initials: A
authors.lastname: Song
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Yunmei
authors.initials: Y
authors.lastname: Song
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Garg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000737:chemistry*; D014700:Verapamil / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D011091:Polyesters; C016240:polycaprolactone; D011099:Polyglutamic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; D014700:Verapamil
keywords: Active targeting; Co-delivery system; Enhanced cancer therapy; Multidrug resistance reversal; pH-sensitive