Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines.
The therapeutic efficiency of anticancer nucleoside analogues (NA) strongly depends on their intracellular accumulation and conversion into 5'-triphosphates. Because active NATP cannot be directly administrated due to instability, we present here a strategy of nanoencapsulation of these active drugs for efficient delivery to tumors. Stable lyophilized formulations of 5'-triphosphates of cytarabine (araCTP), gemcitabine (dFdCTP), and floxuridine (FdUTP) encapsulated in biodegradable PEG-cl-PEI or F127-cl-PEI nanogel networks (NGC and NGM, respectively) were prepared by a self-assembly procedure. Cellular penetration, in vitro cytotoxicity, and drug-induced cell cycle perturbations of these nanoformulations were analyzed in breast and colorectal cancer cell lines. Cellular accumulation and NATP release from nanogel was studied by confocal microscopy and direct high-performance liquid chromatography analysis of cellular lysates. Antiproliferative effect of dFdCTP nanoformulations was evaluated in human breast carcinoma MCF7 xenograft animal model. Nanoencapsulated araCTP, dFdCTP, and FdUTP showed similar to NA cytotoxicity and cell cycle perturbations. Nanogels without drugs showed very low cytotoxicity, although NGM was more toxic than NGC. Treatment by NATP nanoformulations induced fast increase of free intracellular drug concentration. In human breast carcinoma MCF7 xenograft animal model, i.v. dFdCTP-nanogel was equally effective in inhibiting tumor growth at four times lower administered drug dose compared with free gemcitabine. Active triphosphates of NA encapsulated in nanogels exhibit similar cytotoxicity and cell cycle perturbations in vitro and faster cell accumulation and equal tumor growth-inhibitory activity in vivo at much lower dose compared with parental drugs, illustrating their therapeutic potential for cancer chemotherapy.
ENS-CNRS UMR 5239 UFR Lyon-Sud, Oullins, France.
Carlos M
CM
Galmarini
Galya
G
Warren
Ekta
E
Kohli
Arin
A
Zeman
Anton
A
Mitin
Serguei V
SV
Vinogradov
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001085:Arabinofuranosylcytosine Triphosphate / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D015179:Colorectal Neoplasms / Q000473:pathology*; D003561:Cytarabine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D000080385:Nanogels; D009705:Nucleosides / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000378:metabolism*; D011094:Polyethyleneimine / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D011122:Polyphosphates / Q000378:metabolism*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004337:Drug Carriers; D000080385:Nanogels; D009705:Nucleosides; D011108:Polymers; D011122:Polyphosphates; C413692:polyethylene glycol polyethyleneimine nanogel; D003561:Cytarabine; D003841:Deoxycytidine; D001085:Arabinofuranosylcytosine Triphosphate; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; C005692:triphosphoric acid; D000093542:Gemcitabine