Oral paclitaxel solubilized and bioenhanced by food compound for cancer therapy

用于癌症治疗的食品化合物溶解和生物增强的口服紫杉醇

基本信息

批准号：
8512674
负责人：
ZHIJUN LIU
金额：
$ 18.26万
依托单位：
LOUISIANA STATE UNIV AGRICULTURAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-17 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512674
关键词：
Abraxane Adverse effects Albumins Alkaloids Antineoplastic Agents Biological Availability Biological Factors Blood Circulation Breast Camptothecin Cancer Patient Cost Savings Cremophor Data Development Diterpenes Dose Drug Formulations Encapsulated Epithelium Etoposide Excipients Exploratory/Developmental Grant Face Female Food Glycolates Glycosides Human Hypersensitivity Infusion procedures Inhibitory Concentration 50 Intestinal Absorption Intestines Intravenous Intravenous infusion procedures Investigation Life Lignans Liposomes Liquid substance Malignant Neoplasms Metabolism Micelles Modeling Mus Nature Nausea Necrosis Oral Oral Administration Outcome Paclitaxel Permeability Pharmaceutical Preparations Pharmacologic Substance Plants Plasma Podophyllotoxin Powder dose form Preparation Property Protein Binding Rattus Reaction Research Rodent Safety Saline Solubility Staging Stomach Structure Taxane Compound Therapeutic Time Topoisomerase II Toxic effect Type I DNA Topoisomerases Water Xenograft Model absorption analog base cancer cell cancer therapy cancer type chemotherapeutic agent copolymer cytotoxicity docetaxel efflux pump gastrointestinal improved intestinal epithelium irinotecan malignant breast neoplasm malignant mouth neoplasm monolayer mouse model nano nanoparticle nanoparticulate reconstitution research study success taxane tumor tumor xenograft water solution

项目摘要

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.

描述（由申请人提供）：目前通过静脉输注（IV）输注来管理紫杉醇（PTX）药物，紫杉醇（R）和Abraxane（R）。将IV转换为PTX的口服为癌症患者带来了很大的优势，包括最小化或消除输液过程和赋形剂诱导的副作用（例如，恶心，超敏反应）以及可节省大量成本。但是，由于赋形剂的吸收率低和潜在的胃肠道毒性，口服PTX药物受到了损坏。白蛋白中的Abraxane（R）偶联PTX，这使其不适合口服给药，而紫杉醇（R）形式中给出的PTX不能充分吸收以用于治疗性生物利用度。我们最近的实验证明了使用Rubusoside（Rub）（一种从Rubus植物中分离出来的食品成分）来增强溶解度和渗透性的希望。初步结果表明，通过形成水溶性纳米颗粒（以下称纳米PTX），摩擦可以使PTX的溶解度。纳米-PTX可以冻干到粉末，可以在盐水，胃液和肠道中完全重构。纳米PTX达到了一个预测65％肠道吸收的渗透系数，而裸ptx几乎不可渗透。纳米-PTX对包括乳房在内的几个人类癌细胞的细胞毒性完全保持了。当口服口服到肿瘤小鼠时，纳米-PTX靶向肿瘤并引起坏死。在口服剂量的雌性大鼠中，在PTX水平50倍IC50的血浆中检测到纳米-PTX。这些初步结果令人鼓舞和支持口服PTX药物。然而，由于其新颖性，从未使用过抑制抑制外排泵的溶解剂量，并且从未证明过口服生物利用度和纳米PTX的疗效。我们建议使用R21机制探索具有四个特定目的的口服PTX药物的潜力：1）提高纳米PTX效率，因此当前的6.0 mg/ml通过300 mg摩擦溶解的效率可以减少到60 mg，5--增强倍数； 2）确定纳米PTX在啮齿动物中的毒性和口服生物利用度； 3）通过口服给定异种肿瘤小鼠模型来定义纳米-PTX的功效； 4）探索纳米PTX和PGP外排转运蛋白之间可能相互作用引起的增强吸收的基本机制。如果结果提供了概念证明，它将为调查人类乳腺癌和其他类型的癌症的有希望的口服PTX药物奠定基础研究企业。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles.

DOI：
10.1097/cad.0000000000000173
发表时间：
2015-02
期刊：
Anti-cancer drugs
影响因子：
2.3
作者：
Liu Z;Zhang F;Koh GY;Dong X;Hollingsworth J;Zhang J;Russo PS;Yang P;Stout RW
通讯作者：
Stout RW