Comparison of nanogel drug carriers and their formulations with nucleoside 5'-triphosphates.
OBJECTIVE
The aim of the study is to synthesize and characterize nanogel carriers composed of amphiphilic polymers and cationic polyethylenimine for encapsulation and delivery of cytotoxic nucleoside analogs 5'-triphosphates (NTPs) into cancer cells.


METHODS
Nanogels were synthesized by a novel micellar approach and compared with carriers prepared by the emulsification/evaporation method. Complexes of nanogels with NTP were prepared; particle size and in vitro drug release were characterized. Resistance of the nanogel-encapsulated NTP to enzymatic hydrolysis was analyzed by ion-pair high-performance liquid chromatography. Binding to isolated cellular membranes, cellular accumulation and cytotoxicity were compared using breast carcinoma cell lines CL-66, MCF-7, and MDA-MB-231. In vivo biodistribution of the 3H-labeled NTP encapsulated in different types of nanogels was evaluated in comparison to the injected NTP alone.


RESULTS
Nanogels with a particle size of 100-300 nm in the unloaded form and less than 140 nm in the NTP-loaded form were prepared. An in vitro release of NTP was >50% during the first 24 h. Nanogel formulations ensured increased NTP drug stability against enzymatic hydrolysis as compared to the drug alone. Pluronic-based nanogels NG(F68), NG(F127), NG(P85), and NGM(P123) demonstrated 2-2.5 times enhanced interaction with cellular membranes and association with various cancer cells compared to NG(PEG). Among them, NG(F68) and NG(F127) exhibited the lowest cytotoxicity. Injection of nanogel-formulated NTP significantly modulated the drug accumulation in different mouse organs.


CONCLUSIONS
Nanogels composed of Pluronic F68 and P123 were shown to display certain advanced properties compared to NG(PEG) as a drug delivery system for NTP analogs. Formulations of nucleoside analogs in active NTP form with these nanogels will improve the delivery of these cytotoxic drugs to cancer cells and the therapeutic potential of this anticancer chemotherapy.
Vinogradov
Serguei V
SV
Center for Drug Delivery and Nanomedicine, and College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. vinograd@unmc.edu
Kohli
Ekta
E
Zeman
Arin D
AD
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003570:Cytidine Triphosphate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D000080385:Nanogels; D036103:Nanotechnology; D011060:Poloxalene / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D013678:Technology, Pharmaceutical; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004337:Drug Carriers; D000080385:Nanogels; C422648:pluronic block copolymer p85; C413692:polyethylene glycol polyethyleneimine nanogel; C464484:pluronic block copolymer P123; D011092:Polyethylene Glycols; D003570:Cytidine Triphosphate; D011094:Polyethyleneimine; D011060:Poloxalene