Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 1, Issue 8, Pages 646-655Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.5b00025
Keywords
endosomal pH-sensitive lipids; histidinylated cationic amphiphiles; cancer cell selective cytoxicity; anti-cancer liposomes; mitochondrial membrane depolarization
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Funding
- Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi [CSC-0302, BSC-0123]
- CSIR-Mayo Clinic Collaborative Research Fund [MLP-0018]
- Council of Scientific & Industrial Research
- University Grant Commission, Government of India, New Delhi
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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 Box 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.
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