Enhanced Intracellular Uptake of Sterically Stabilized Liposomal Doxorubicin in Vitro Resulting in Improved Antitumor Activity in Vivo

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Abstract
To investigate the correlation between the in vitro intracellular uptake and the in vivo antitumor activity of anticancer drugs delivered by sterically stabilized liposomes (SSL). Arginine-glycine-aspartic acid (RGD) peptide or RGD mimetic (RGDm) was coupled onto the surface of SSL to obtain the cell-binding carrier to facilitate the intracellular delivery of the encapsulated drugs. DOX-loaded SSL (SSL-DOX), DOX-loaded RGD-modified SSL (RGD-SSL-DOX) and DOX-loaded RGDm-modified SSL (RGDm-SSL-DOX) were prepared by lipid film dispersion followed by remote loading of DOX. The intracellular uptake of DOX from the various liposomal formulations was evaluated in vitro with melanoma B16 cells, and the pharmacokinetics, biodistribution, and antitumor activity were compared in C57BL/6 mice carrying melanoma B16 tumors. In vitro intracellular uptake of DOX by B16 cells and in vivo antitumor activity in terms of tumor growth inhibition and mice survival time prolongation for various liposomal DOX were in the following order: RGD-SSL-DOX > RGDm-SSL-DOX > SSL-DOX. The mean survival time of the mice treated with RGD-SSL-DOX, RGDm-SSL-DOX, and SSL-DOX was 55, 49, and 44 days, respectively. The three liposomal DOX formulations produced very close DOX accumulation in tumor, which is significantly higher than that of free DOX. RGD- or RGDm-SSL-DOX demonstrated prolonged circulation time similar to that of SSL-DOX, whereas they showed significantly lower DOX level in blood and remarkably higher uptake by spleen than SSL-DOX. Enhanced intracellular uptake of DOX encapsulated in SSL could produce an improved therapeutic effect for the melanoma B16 tumors. Enhancing intracellular delivery of the anticancer drugs encapsulated in SSL may be a promising strategy to improve their therapeutic efficacy for solid tumors.