Apoptotic cascade inspired lipid nanovesicles show synergism with encapsulated paclitaxel in chemoresistant colon carcinoma.
Inspired from the apoptotic cascade, we developed phosphatidylserine (PS)-based proapoptotic lipid nanovesicles, capable of bypassing drug resistance and exhibiting synergistic anticancer activity with encapsulated paclitaxel in chemoresistant human colon adenocarcinoma (HCT-15).


METHODS
Nanovesicles were developed and evaluated both in vitro and in vivo for their proapoptotic activity, synergism with encapsulated paclitaxel and ability to bypass drug resistance.


RESULTS
110 ± 7 nm sized nanovesicles were found to be proapoptotic and synergistic with paclitaxel, and bypassed drug resistance. The formulation, with synergistic inputs from PS and paclitaxel, downregulated Ki-67 and inhibited angiogenesis leading to apoptosis by activating caspase-3 and downregulating Bcl-2, resulting in DNA fragmentation. The nanovesicles, while increasing the systemic circulation time of paclitaxel by 6.9-fold reduced systemic toxic effects of paclitaxel and were found to be nonimmunogenic.


CONCLUSIONS
These results suggest the therapeutic potential of PS-based proapoptotic nanovesicles encapsulating paclitaxel in chemoresistant human colon carcinoma.
Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Nitin
N
Joshi
Thanigaivel
T
Shanmugam
Atul
A
Deshmukh
Rinti
R
Banerjee
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry; D050997:Nanomedicine; D036103:Nanotechnology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D010718:Phosphatidylserines / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D000972:Antineoplastic Agents, Phytogenic; D053769:Nanocapsules; D010718:Phosphatidylserines; D017239:Paclitaxel
colon carcinoma; drug resistance; lipid nanovesicles; paclitaxel; phosphatidylserine; proapoptotic