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H-gemcitabine: a new gemcitabine prodrug for treating cancer.

ABSTRACT: In this report, we present a new strategy for targeting chemotherapeutics to tumors, based on targeting extracellular DNA. A gemcitabine prodrug was synthesized, termed H-gemcitabine, which is composed of Hoechst conjugated to gemcitabine. H-gemcitabine has low toxicity because it is membrane-impermeable; however, it still has high tumor efficacy because of its ability to target gemcitabine to E-DNA in tumors. We demonstrate here that H-gemcitabine has a wider therapeutic window than free gemcitabine.

SUBMITTER: Dasari M

PROVIDER: S-EPMC4011667 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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H-gemcitabine: a new gemcitabine prodrug for treating cancer.

Dasari Madhuri M Acharya Abhinav P AP Kim Dongin D Lee Seungjun S Lee Sungmun S Rhea Jeanne J Molinaro Ross R Murthy Niren N

Bioconjugate chemistry 20121226 1

In this report, we present a new strategy for targeting chemotherapeutics to tumors, based on targeting extracellular DNA. A gemcitabine prodrug was synthesized, termed H-gemcitabine, which is composed of Hoechst conjugated to gemcitabine. H-gemcitabine has low toxicity because it is membrane-impermeable; however, it still has high tumor efficacy because of its ability to target gemcitabine to E-DNA in tumors. We demonstrate here that H-gemcitabine has a wider therapeutic window than free gemcit ...[more]

PMID: 23237198

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Project description:The treatment of pancreatic cancer with gemcitabine is hampered by its rapid metabolism in vivo, the dense stroma around the tumor site which prevents the drug from reaching the cancerous cells and drug resistance. To address these challenges, this study describes the preparation of a retinoid prodrug of gemcitabine, GemRA (gemcitabine conjugated to retinoic acid), and its formulation into a nanoparticulate system applicable for pancreatic cancer treatment. Retinoic acid targets stellate cells which are part of the stroma and can thus augment the delivery of gemcitabine. GemRA dissolved in dimethylsulfoxide presented efficacy towards PANC-1 (human) and mT4 (mouse) pancreatic cancer cell lines but its poor solubility in aqueous solution affects its applicability. Thus, the preparation of the nanoparticles was initially attempted through self-assembly of GemRA, which resulted in the formation of unstable aggregates that precipitated during preparation. As a result, encapsulation of the drug into micelles of polyethylene glycol-retinoic acid (PGRA) amphiphilic conjugates was accomplished and resulted in successful incorporation of GemRA into nanoparticles of ca. 33 nm by dynamic light scattering and 25 nm by transmission electron microscopy. The nanoparticles had good stability in aqueous media and protected gemcitabine from the enzymatic action of cytidine deaminase, which converts gemcitabine to its inactive metabolite upon circulation. Cellular uptake of the nanoparticles by PANC-1 cells was confirmed by fluorescence spectroscopy and flow cytometry. Treatment of PANC-1 cells in vitro with the prodrug-loaded nanoparticles resulted in a significant reduction in cell viability (IC50 ca. 5 μM) compared to treatment with gemcitabine (IC50 > 1000 μM). The ability of the GemRA-loaded nanoparticles to induce cellular apoptosis of treated PANC-1 cells was ascertained via a TUNEL assay suggesting these nanoparticles are effective in pancreatic cancer treatment.

Dataset Information

H-gemcitabine: a new gemcitabine prodrug for treating cancer.

Publications

H-gemcitabine: a new gemcitabine prodrug for treating cancer.

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