Engineered breast tumor targeting peptide ligand modified liposomal doxorubicin and the effect of peptide density on anticancer activity

• Published in: Biomaterials Vol. 34; no. 16; pp. 4089 - 4097
• Main Authors: Shahin, Mostafa, Soudy, Rania, Aliabadi, Hamidreza M, Kneteman, Norman, Kaur, Kamaljit, Lavasanifar, Afsaneh
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-05-2013
• Subjects: Active targeting; Advanced Basic Science; Amino Acid Sequence; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Body Weight - drug effects; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Death - drug effects; Cell Line, Tumor; Dentistry; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Delivery Systems; Female; Ligands; Mice; Mice, SCID; Molecular Sequence Data; Peptide density; Peptides - chemistry; Peptides - pharmacology; Protein Engineering; Stealth liposomes; Targeting peptide; Tissue Distribution - drug effects; Treatment Outcome; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Targeting peptide; Active targeting; Breast cancer; Peptide density; Doxorubicin; Stealth liposomes
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2013.02.019

Abstract 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 0.3 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.