title: The therapeutic response to multifunctional polymeric nano-conjugates in the targeted cellular and subcellular delivery of doxorubicin.
abstract: The purpose of this study was to develop polymeric nano-carriers of doxorubicin (DOX) that can increase the therapeutic efficacy of DOX for sensitive and resistant cancers. Towards this goal, two polymeric DOX nano-conjugates were developed, for which the design was based on the use of multi-functionalized poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles decorated with alphavbeta3 integrin-targeting ligand (i.e. RGD4C) on the micellar surface. In the first formulation, DOX was conjugated to the degradable PEO-b-PCL core using the pH-sensitive hydrazone bonds, namely RGD4C-PEO-b-P(CL-Hyd-DOX). In the second formulation, DOX was conjugated to the core using the more stable amide bonds, namely RGD4C-PEO-b-P(CL-Ami-DOX). The pH-triggered drug release, cellular uptake, intracellular distribution, and cytotoxicity against MDA-435/LCC6(WT) (a DOX-sensitive cancer cell line) and MDA-435/LCC6(MDR) (a DOX-resistant clone expressing a high level of P-glycoprotein) were evaluated. Following earlier in vitro results, SCID mice bearing MDA-435/LCC6(WT) and MDA-435/LCC6(MDR) tumors were treated with RGD4C-PEO-b-P(CL-Hyd-DOX) and RGD4C-PEO-b-P(CL-Ami-DOX), respectively. In both formulations, surface decoration with RGD4C significantly increased the cellular uptake of DOX in MDA-435/LCC6(WT) and MDA-435/LCC6(MDR) cells. In MDA-435/LCC6(WT), the best cytotoxic response was achieved using RGD4C-PEO-b-P(CL-Hyd-DOX), that correlated with the highest cellular uptake and preferential nuclear accumulation of DOX. In MDA-435/LCC6(MDR), RGD4C-PEO-b-P(CL-Ami-DOX) was the most cytotoxic, and this effect correlated with the accumulation of DOX in the mitochondria. Studies using a xenograft mouse model yielded results parallel to those of the in vitro studies. Our study showed that RGD4C-decorated PEO-b-P(CL-Hyd-DOX) and PEO-b-P(CL-Ami-DOX) can effectively improve the therapeutic efficacy of DOX in human MDA-435/LCC6 sensitive and resistant cancer, respectively, pointing to the potential of these polymeric micelles as the custom-designed drug carriers for clinical cancer therapy.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Xiong
authors.forename: Zengshuan
authors.initials: Z
authors.lastname: Ma
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D051379:Mice; D008823:Micelles; D008962:Models, Theoretical; D049329:Nanostructures / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D011091:Polyesters / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C458722:polyethylene oxide-polycaprolactone copolymer; D004317:Doxorubicin