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Comparison of Nanogel Drug Carriers and their Formulations with Nucleoside 5′-Triphosphates

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Purpose

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.

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Abbreviations

CMC:

critical micellization concentration

CTP:

cytidine 5′-triphosphate

FBS:

fetal bovine serum

HLB:

hydrophilic–lipophilic balance

MWCO:

molecular weight cutoff

NA:

nucleoside analogs

NMP:

nucleoside 5′-monophosphate

NTP:

nucleoside 5′-triphosphate

PEG:

poly(ethylene glycol)

PEI:

polyethylenimine

PEO:

poly(ethylene oxide)

PPO:

poly(propylene oxide)

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Aknowledgments

This work was financially supported by NIH R01 grant CA102791 (S.V.V.). The authors are extremely grateful to Drs. Elena Batrakova and William Chaney for helpful discussion and Michael Jacobsen for valuable assistance in the preparation of the manuscript.

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Authors and Affiliations

  1. Center for Drug Delivery and Nanomedicine, and College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    Serguei V. Vinogradov, Ekta Kohli & Arin D. Zeman

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  1. Serguei V. Vinogradov
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  2. Ekta Kohli
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  3. Arin D. Zeman
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Correspondence to Serguei V. Vinogradov.

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Vinogradov, S.V., Kohli, E. & Zeman, A.D. Comparison of Nanogel Drug Carriers and their Formulations with Nucleoside 5′-Triphosphates. Pharm Res 23, 920–930 (2006). https://doi.org/10.1007/s11095-006-9788-5

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  • DOI: https://doi.org/10.1007/s11095-006-9788-5

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