Oral paclitaxel solubilized and bioenhanced by food compound for cancer therapy

描述（由申请人提供）：紫杉醇（PTX）药物紫杉醇（Taxol）和Abraxane(r)目前通过静脉（IV）输注给药。将IV转为口服PTX为癌症患者提供了巨大的优势，包括最大限度地减少或消除输注过程和辅料引起的副作用（例如，恶心，过敏反应）和显著的成本节约。然而，口服PTX药物由于低吸收和配制辅料的潜在胃肠道毒性而受到影响。Abraxane(r)在白蛋白中结合PTX，这使得它不适合口服给药，而紫杉醇(r)形式的PTX不能被充分吸收以实现治疗生物利用度。我们最近的实验表明，使用从蔓越莓植物中分离出来的一种食品成分——蔓越莓苷（RUB），可以提高其溶解度和渗透性。初步结果表明，RUB通过形成水溶性纳米粒子（以下简称NANO-PTX）使PTX具有溶解性。NANO-PTX可以冻干成粉末，可以在生理盐水、胃液和肠液中完全重组。纳米PTX的渗透性系数可以预测65%的肠道吸收，而裸PTX几乎是不透水的。纳米- ptx对包括乳腺癌在内的几种人类癌细胞的细胞毒性完全维持。经灌胃给药后，纳米- ptx靶向肿瘤，引起肿瘤坏死。口服给药的雌性大鼠血浆中检测到NANO-PTX， PTX水平为IC50的50倍。这些初步结果是令人鼓舞和支持口服PTX药物。然而，由于其新新性，RUB作为一种可能具有抑制外排泵附加益处的增溶赋形剂从未被使用过，而且NANO-PTX的口服生物利用度和功效也从未得到证实。我们建议使用R21机制来探索口服PTX药物的潜力，有四个具体目标：1)提高NANO-PTX的效率，使目前由300 mg RUB溶解的6.0 mg/mL可以减少到60 mg，增强5倍；2)测定纳米ptx对啮齿动物的毒性和口服生物利用度；3)确定NANO-PTX在异种移植肿瘤小鼠模型中的口服疗效；4)探索纳米ptx和Pgp外排转运体之间可能相互作用导致吸收增强的潜在机制。如果结果提供了概念证明，它将为研究有前途的口服PTX治疗人类乳腺癌和其他类型癌症的药物奠定基础，因为与研究企业所探索的相比，增溶/生物增强赋形剂是一种安全问题最小的食品化合物。

DESCRIPTION (provided by applicant): 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.