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Xiong XB, Ma Z, Lai R, Lavasanifar A: The therapeutic response to multifunctional polymeric nano-conjugates in the targeted cellular and subcellular delivery of doxorubicin. Biomaterials. 2010 Feb;31(4):757-68. Epub 2009 Oct 8.
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. |
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