Gemcitabine-based therapy for pancreatic cancer using the squalenoyl nucleoside monophosphate nanoassemblies

• Published in: International journal of pharmaceutics 2015-03, Vol.482 (1-2), p.38-46
• Main Authors: Maksimenko, Andrei, Caron, Joachim, Mougin, Julie, Desmaële, Didier, Couvreur, Patrick
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Deoxycytidine kinase; Female; Gemcitabine; Humans; Ki-67 Antigen - drug effects; Mice; Nanoassemblies; Nanomedicine - methods; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Nanoparticles - ultrastructure; Neoplasm Invasiveness; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Prodrugs - administration & dosage; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Squalene - administration & dosage; Squalene - analogs & derivatives; Squalene - chemistry; Squalene - pharmacology; Squalene - therapeutic use; Squalenoyl prodrug; Xenograft Model Antitumor Assays
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2014.11.009

[Display omitted] Gemcitabine is currently the most effective agent against advanced pancreatic cancer. However, the major therapeutic hurdles using gemcitabine include rapid inactivation by blood deaminases and fast development of cell chemoresistance, induced by down-regulation of deoxycytidine kinase or nucleoside transporters. To overcome the above drawbacks we designed recently a novel nanomedicine strategy based on squalenoyl prodrug of 5′-monophosphate gemcitabine (SQdFdC-MP). This amphiphilic conjugate self-organized in water into unilamellar vesicles with a mean diameter of 100nm. In this study the antitumor efficacy of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models have been investigated. Cell viability assays showed that SQdFdC-MP NAs displayed higher antiproliferative and cytotoxic effects, particularly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC-MP NAs decreased significantly the growth (∼70%) of human MiaPaCa2 xenografts, also preventing tumor cell invasion, whereas native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. These results correlated with a reduction of Ki-67 antigen and the induction of apoptosis mediated by caspase-3 activation in tumor cells. These findings demonstrated the feasibility of utilizing SQdFdC-MP NAs to make tumor cells more sensitive to gemcitabine and thus providing an efficient new therapeutic alternative for pancreatic adenocarcinoma.