Journal
BIOMATERIALS
Volume 34, Issue 16, Pages 4089-4097Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.02.019
Keywords
Breast cancer; Targeting peptide; Active targeting; Stealth liposomes; Doxorubicin; Peptide density
Funding
- Alberta Cancer Foundation (ACF)
- Canadian Institutes of Health Research (CIHR)
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This study aimed to develop actively targeted liposomal formulations of doxorubicin (DOX) using an engineered breast tumor targeting peptide ligand, p18-4 (WxEAAYQrFL). Towards this goal, stealth liposomes bearing different molar ratios of p18-4 peptide (1.5 and 03 peptide/total lipid mol %), namely HD and LD liposomes, were successfully prepared. The effect of p18-4 peptide modification and density on breast cancer cell uptake, selective cytotoxicity as well as inhibition of tumor growth and the tissue disposition of encapsulated DOX in breast tumor xenograft models in mice were assessed. The results showed a 2.4 and 5 folds decrease in the IC50 of HD liposomes in MDA-MB-435 and MCF-7 breast tumor cells, respectively. Although LD liposomes showed less (1.6 and 2.2 folds) decrease in the IC50 of DOX in the same breast cancer cell lines, they were more selective in their cytotoxic effect and uptake towards breast cancer over normal breast epithelial cells, MCF10A. Evaluation of the anticancer activity in NOD-SCID mice bearing MDA-MB-435 xenografts after receiving six i.v. injections of 2.5 mg/kg/week DOX equivalent showed a superior anticancer activity for LD liposomal DOX compared to HD and unmodified liposomal formulations. Mice treated with LD liposomal DOX illustrated 4.8 folds reduction in the mean relative tumor volume compared to non-targeted DOX liposomes. This was despite similar tumor accumulation of DOX as part of LD liposomes compared to that for unmodified liposomes 24 h following the last injection. In contrast, HD liposomes showed decreased DOX accumulation in the tumor and preferential uptake by liver and spleen. Treatment with unmodified and LD liposomes did not have any adverse impact on the activity level and mean body weight of live animals during the study period. In conclusion, surface modification of liposomal DOX with engineered p18-4 peptide at an optimum density can improve the antitumor efficacy and selectivity of liposomal DOX. (c) 2013 Elsevier Ltd. All rights reserved.
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