The paclitaxel (PTX) drugs, Taxol(r) and Abraxane(r), are currently administered by intravenous (IV) infusion. Converting IV to oral for PTX offers great advantages to cancer patients, including the minimization or elimination of infusion-procedure- and excipients-induced side effects (e.g., nausea, hypersensitivity reactions) and significant cost savings. However, an oral PTX medication suffers due to low absorption and potential gastrointestinal toxicity from formulating excipients. Abraxane(r) conjugates PTX in albumin, which renders it unsuitable for oral administration, whereas PTX given in Taxol(r) form cannot be absorbed sufficiently for therapeutic bioavailability. Our recent experiments demonstrate some promise for enhancing the solubility and permeability using rubusoside (RUB), a food ingredient isolated from the Rubus plant. Preliminary results showed that RUB enabled the solubility of PTX by forming water-soluble nanoparticles (hereafter NANO-PTX). NANO-PTX can be lyophilized to a powder, which can be completely reconstituted in saline, gastric, and intestinal fluids. NANO-PTX attained a permeability coefficient that predicts 65% intestinal absorption whereas the naked PTX is nearly impermeable. Cytotoxicity of NANO-PTX against several human cancer cells including breast was completely maintained. When orally gavaged to tumor mice, NANO-PTX targeted the tumor and caused necrosis. In orally dosed female rats, NANO-PTX was detected in the plasma with a PTX level 50 times IC50. These preliminary results are encouraging and supportive of an oral PTX medication. However, RUB as a solubilizing excipient with possible added benefit of inhibiting efflux pump has never been used due to its novelty, and the oral bioavailability and efficacy of NANO-PTX have never been demonstrated. We propose to use the R21 mechanism to explore the potential of an oral PTX medication with four specific aims: 1) improve NANO-PTX efficiency so the current 6.0 mg/mL solubilized by 300 mg RUB can be reduced to 60 mg, a 5-fold enhancement;2) determine the toxicity and oral bioavailability of NANO-PTX in rodents;3) define efficacy of NANO-PTX by oral administration in a xenografted tumor mouse model;and 4) explore the underlying mechanism for enhanced absorption resulting from possible interaction between NANO-PTX and Pgp efflux transporter. If the outcome provides proof of concept, it will set the stage for investigations of promising oral PTX medication for human breast and other types of cancer as the solubilizing/bioenhancing excipient is a food compound with minimal safety concerns compared to what has been explored in the research enterprise.

Public Health Relevance

Paclitaxel is a very potent natural chemotherapeutic agent but it can only be given intravenously. Converting IV to oral for cancer therapy can make it more available clinically, but low oral bioavailability as a result of low solubility and permeability i an obstacle. In addition to low oral bioavailability, excipients that formulate paclitaxel often cause gastrointestinal toxicity. Formulating paclitaxel with a food ingredient would reduce potential toxicity and the enhanced permeability would increase potential bioavailability and efficacy. Our preliminary results demonstrated these potential advantages but require the exploratory and developmental investigations requested in this R21 project. Success in demonstrating efficacy and safety could advance oral paclitaxel as a viable therapy for breast and other types of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Developmental Therapeutics Study Section (DT)
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Fu, Yali
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Louisiana State University Agricultural Center
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Baton Rouge
United States
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Liu, Zhijun; Zhang, Fang; Koh, Gar Yee et al. (2015) Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles. Anticancer Drugs 26:167-79