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

• 批准号: 8384971
• 负责人: ZHIJUN LIU
• 金额: $ 15.08万
• 依托单位: LOUISIANA STATE UNIV AGRICULTURAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384971
• 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

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.

描述（由申请人提供）：紫杉醇（PTX）药物Taxol（r）和Abraxane（r）目前通过静脉（IV）输注给药。将IV转换为口服PTX为癌症患者提供了很大的优势，包括最小化或消除输注程序和赋形剂诱导的副作用（例如，恶心、超敏反应）并显着节省成本。然而，口服PTX药物由于低吸收和来自配制赋形剂的潜在胃肠道毒性而受到影响。Abraxane（r）在白蛋白中结合PTX，这使其不适合口服给药，而以Taxol（r）形式给予的PTX不能被充分吸收以获得治疗生物利用度。我们最近的实验表明，使用从悬钩子属植物中分离的食品成分甜茶苷（RUB）来增强溶解性和渗透性是有希望的。初步结果显示，RUB通过形成水溶性纳米颗粒（下文称为NANO-PTX）来实现PTX的溶解性。NANO-PTX可以冻干成粉末，其可以在盐水、胃液和肠液中完全重构。NANO-PTX达到预测65%肠吸收的渗透系数，而裸PTX几乎是不可渗透的。NANO-PTX对包括乳腺癌在内的几种人类癌细胞的细胞毒性完全保持。当经口灌胃给肿瘤小鼠时，NANO-PTX靶向肿瘤并引起坏死。在经口给药的雌性大鼠中，在血浆中检测到NANO-PTX，PTX水平50倍IC 50。这些初步结果是令人鼓舞的，并支持口服PTX药物。然而，由于其新奇，RUB作为具有抑制外排泵的可能附加益处的增溶赋形剂从未被使用，并且NANO-PTX的口服生物利用度和功效从未被证明。我们建议使用R21机制来探索口服PTX药物的潜力，其具有四个特定目的：1）提高NANO-PTX效率，使得当前由300 mg RUB溶解的6.0 mg/mL可以减少到60 mg，增加5倍; 2）确定NANO-PTX在啮齿动物中的毒性和口服生物利用度; 3）在异种移植肿瘤小鼠模型中通过口服施用确定NANO-PTX的功效;以及4）探索由NANO-PTX与Pgp外排转运蛋白之间的可能相互作用引起的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，因为增溶/生物增强赋形剂是一种食品化合物，与研究企业中探索的相比，安全性问题最小。 公共卫生相关性：紫杉醇是一种非常有效的天然化疗药物，但只能通过静脉注射给药。将IV转化为口服用于癌症治疗可以使其在临床上更可用，但是由于低溶解度和渗透性导致的低口服生物利用度是一个障碍。除了口服生物利用度低之外，配制紫杉醇的赋形剂常常引起 胃肠道毒性将紫杉醇与食物成分一起配制将降低潜在的毒性，并且增强的渗透性将增加潜在的生物利用度和功效。我们的初步结果证明了这些潜在的优势，但需要在这个R21项目中要求的探索性和发展性研究。成功证明有效性和安全性可以推动口服紫杉醇作为乳腺癌和其他类型癌症的可行疗法。