Examples of Tumor Growth Inhibition Properties of Liposomal Formulations of pH-Sensitive Histidinylated Cationic Amphiphiles

• Published in: ACS biomaterials science & engineering Vol. 1; no. 8; pp. 646 - 655
• Main Authors: Garu, Arup, Moku, Gopikrishna, Gulla, Suresh Kumar, Pramanik, Dipankar, Majeti, Bharat K, Karmali, Priya P, Shaik, Haseena, Sreedhar, Bojja, Chaudhuri, Arabinda
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.08.2015
• Subjects: endosomal pH-sensitive lipids; anti-cancer liposomes; histidinylated cationic amphiphiles; cancer cell selective cytoxicity; mitochondrial membrane depolarization
• ISSN: 2373-9878; 2373-9878
• DOI: 10.1021/acsbiomaterials.5b00025

Herein we report on the unexpected cancer cell selective cytotoxicities of the liposomal formulations of aspartic and glutamic acid backbone-based four novel lipids with endosomal pH-sensitive head-groups and aliphatic n-hexadecyl & n-octadecyl hydrophobic tails. Surprisingly, although the formulations killed cancer cells efficiently, they were significantly less cytotoxic in non-cancerous healthy cells. Importantly, intratumoral administration of the liposomal formulations efficiently inhibited growth of melanoma in a syngeneic C57BL/6J mouse tumor model. Western Blotting experiments with the lysates of liposomes treated cancer cells revealed that liposomes of lipids 1–4 induce apoptosis selectively in cancer cells presumably by releasing cytochrome c from depolarized mitochondria and subsequent activation of caspases 3 & 9, upregulation of Bax and down regulation of Bcl-2. In summary, the present report describes for the first time tumor growth inhibition properties of the liposomal formulations of endosomal pH-sensitive histidinylated cationic lipids under both in vitro and systemic settings.