Oral paclitaxel solubilized and bioenhanced by food compound for cancer therapy

说明(申请人提供)：紫杉醇(PTX)药物紫杉醇(R)和亚伯拉欣(R)目前通过静脉(IV)输注给药。PTX将静脉注射改为口服给癌症患者带来了巨大的好处，包括最大限度地减少或消除了输液程序和赋形剂引起的副作用(例如恶心、过敏反应)，并显著节省了成本。然而，口服PTX药物由于吸收低和配方辅料潜在的胃肠道毒性而受到影响。Abraxane(R)与PTX在白蛋白中结合，这使得它不适合口服，而以紫杉醇(R)形式给出的PTX不能被充分吸收，从而达到治疗的生物利用度。我们最近的实验表明，使用从悬钩子属植物中分离出来的一种食品成分Rubusoside(RUB)，可以提高其溶解性和渗透性。初步结果表明，RUB通过形成可溶于水的纳米颗粒(以下简称纳米PTX)来提高PTX的溶解度。纳米PTX可以冷冻干燥成粉末，可以在生理盐水、胃液和肠液中完全重组。纳米PTX的渗透系数可预测65%的肠道吸收，而裸PTX几乎不透。纳米PTX对包括乳腺在内的几种人类癌细胞的细胞毒性完全保持不变。当口服给肿瘤小鼠时，纳米PTX靶向肿瘤并导致坏死。在经口给药的雌性大鼠中，在血浆中检测到纳米PTX，其水平是IC50的50倍。这些初步结果是令人鼓舞的，并支持口服PTX药物。然而，由于其新颖性，RUB作为一种可能具有抑制外排泵作用的增溶辅料从未被使用过，纳米PTX的口服生物利用度和有效性也从未被证明过。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)提高纳米PTX的效率，使目前由300 mg RUB增溶的6.0 mg/mL可减少到60 mg，提高5倍；2)确定纳米PTX在啮齿动物身上的毒性和口服生物利用度；3)在小鼠移植瘤模型中确定纳米PTX的疗效；以及4)探索纳米PTX与PGP外流转运体可能相互作用导致吸收增强的潜在机制。如果这一结果提供了概念证据，它将为研究有前景的口服PTX药物治疗人类乳腺癌和其他类型的癌症奠定基础，因为与研究企业探索的药物相比，这种增溶/生物增强辅料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.