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The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

ABSTRACT: Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents.

SUBMITTER: Tsume Y

PROVIDER: S-EPMC3942691 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

Tsume Yasuhiro Y Borras Bermejo Blanca B Amidon Gordon L GL

Pharmaceuticals (Basel, Switzerland) 20140127 2

Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the ...[more]

PMID: 24473270

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Project description:The spread of Zika virus (ZIKV) infection across the USA and various countries in the last three years will not only have a direct impact on the U.S. health care system but has caused international concerns as well. The ultimate impact of ZIKV infection remains to be understood. Currently, there are no therapeutic or vaccine options available to protect those infected by ZIKV. The drug ivermectin (IVM) was found to be a viable agent for the prevention of transmission of ZIKV. Ivermectin is unstable in the presence of water and does not remain in adequate concentration in the human bloodstream to be effective in treatment for ZIKV. Biodegradable nanoparticles would aid in the delivery of ivermectin by providing a high enough concentration of drug and ensuring the drug is gradually released to maintain an appropriate level in the body. The overall goal of this study was to develop and optimize an orally administrable nanoformulation of IVM which can circulate in the blood for a long period for efficient delivery. To achieve the goal, we synthesized and optimized a synthetic nanoformulation of IVM for oral use which can cross the intestinal epithelial barrier to enter the bloodstream. Our studies documented that when delivered with the synthetic nanoparticle (NP), IVM can be accumulated in the blood at a higher concentration and preliminary studies highlighted that NP delivered IVM has the ability to target nonstructural 1 protein of ZIKV. For potential clinical relevance, long-term storable formulation of IVM-nanoparticle in dry powder state for inclusion in a capsule form and cryoprotectant containing frozen forms revealed promising findings. Further, our preliminary in vitro studies documented that ivermectin crosses the placental barrier, thus making it unsafe for the pregnant ZIKV population, whereas the ivermectin-loaded nanoparticle did not show any significant placental barrier crossing, thus indicating its potential suitability for such population. We envision that this work will fill a great unmet need by developing safer and more effective therapies for the treatment of viral infections, including ZIKV.

Dataset Information

The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

Publications

The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs.

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