Formulation of Fenretinide Nanoparticles for Enhanced Bioavailability

芬维A胺纳米颗粒的制剂可增强生物利用度

• 批准号: 8699223
• 负责人: Levon Bostanian
• 金额: $ 10.85万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699223
• 关键词: Adverse effects; Applications Grants; Basic Science; Biological Availability; Biological Products; Caco-2 Cells; Cancer Patient; Cell Line; Cell membrane; Cell model; Childhood; Classification; Data; Development; Differential Scanning Calorimetry; Disease; Dosage Forms; Dose; Drug Delivery Systems; Drug Formulations; Electron Microscope; Evaluation; Exhibits; Faculty; Fenretinide; Fostering; Funding; Human; In Vitro; Incidence; Innovative Therapy; Intestines; Laboratories; Literature; Malignant Neoplasms; Mentors; Methods; Microscopy; Minority; Modeling; Morphology; Nanotechnology; Neoplasms; Neuroblastoma; Oral; Oral Administration; Particle Size; Patients; Permeability; Pharmaceutical Preparations; Plasma; Preparation; Principal Investigator; Property; Public Health; Publications; Recurrent disease; Relapse; Reporting; Research; Research Activity; Research Design; Residual Tumors; Retinoids; Scanning; Solubility; Staging; Students; Sympathetic Nervous System; System; Testing; Therapeutic; Training Programs; Translational Research; Universities; Work; X ray diffraction analysis; absorption; base; cancer therapy; capsule; compliance behavior; improved; in vitro activity; in vivo; innovation; interdisciplinary approach; member; nano; nanoparticle; novel; outcome forecast; particle; pressure; programs; skills; therapeutic effectiveness; water solubility

DESCRIPTION (provided by applicant): Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most common malignant tumor in childhood. In recent years, prognosis for patients with this neoplasm has improved, but the overall 5- year survival is still less than 60% because of fatal relapses of the disease. However, the incidence of fatal relapses can be reduced by adding innovative therapy to eradicate the residual disease. Complete eradication of the residual disease requires long-term treatment during the early stages. Fenretinide, a synthetic retinoid, is the focus of long-term treatment for complete eradication of the disease. The drug has been successfully tested for antitumor activity in vitro and in vivo. However, the potential of fenretinide as a long-term treatment for childhood neuroblastoma is limited by its poor water solubility and poor bioavailability following oral administration. The overall objective of this project is to develop fenretinide nanoparticles. The central hypothesis i that the bioavailability of fenretinide will be significantly enhanced due to the small size of the nanoparticles and their enhanced ability to penetrate cell membranes. The following four specific aims delineate the step-wise approach towards the testing of the central hypothesis. Specific Aim 1. Preparation of nanoparticle formulations. Two different nanoparticle formulations will be prepared using a laboratory nanospray dryer and a high pressure homogenizer, respectively. Specific Aim 2. Characterization of the nanoparticles. Specific Aim 3. Evaluation of the in vitro drug release. Specific Aim 4. Evaluation of the intestinal permeability of fenretinide using a Caco-2 cell model. The proposed research is innovative, in our opinion, because there are no reports in the literature of using the Nano Spray Dryer or high pressure homogenizer to produce nanoparticles of fenretinide. We expect that the bioavailability of fenretinide will be enhanced by its formulation in the form of nanoparticles, and as a result, lower doses of the drug will be needed to achieve therapeutic plasma concentrations. Lowering the drug dose will also reduce the incidence of adverse side effects and enhance patient compliance. The proposed project will help the principal investigator develop his skills in nanotechnology and the formulation of nanoparticles of drug substances. It will help him enhance his publication record and, therefore, strengthen his ability to submit competitive grant applications. The proposed project will also increase the exposure of minority students to research by working in conjunction with a training program funded by the Center of Excellence program at the university, which requires the mentor to be a faculty member involved in research.

描述(申请人提供)：神经母细胞瘤是一种交感神经系统肿瘤，是儿童第二常见的恶性肿瘤。近年来，该病患者的预后有所改善，但由于该病的致命复发，总体5年生存率仍不到60%。然而，通过增加根除残留疾病的创新疗法，可以减少致命复发的发生率。彻底根除残留病需要在早期阶段进行长期治疗。芬维甲胺是一种合成的维甲酸，是彻底根除这种疾病的长期治疗的重点。该药物已成功地在体外和体内进行了抗肿瘤活性测试。然而，非维甲酸作为儿童神经母细胞瘤长期治疗的潜力受到其较差的水溶性和口服后较差的生物利用度的限制。该项目的总体目标是开发非维甲酸纳米粒。中心假设一，芬维甲素的生物利用度将显著提高，因为 纳米颗粒及其增强的穿透细胞膜的能力。以下四个具体目标描述了检验中心假设的循序渐进的方法。具体目标1.纳米粒制剂的制备。两种不同的纳米颗粒配方将分别使用实验室纳米喷雾干燥器和高压均质器来制备。具体目标2.纳米颗粒的表征。具体目的3.体外释药评价。特定目的4.非维甲酸的肠道通透性评价 使用Caco-2细胞模型。在我们看来，这项拟议的研究是创新的，因为在文献中没有使用纳米喷雾干燥器或高压均质器来生产芬维替尼纳米粒的报告。我们预计，非维甲酸的生物利用度将通过其纳米颗粒的形式得到提高，因此，实现治疗性血浆浓度需要较低剂量的药物。降低药物剂量还将减少不良反应的发生率，提高患者的依从性。拟议的项目将帮助首席研究人员发展他在纳米技术和药物物质纳米颗粒配方方面的技能。这将帮助他提高他的出版记录，从而增强他提交竞争性拨款申请的能力。拟议中的项目还将通过与该大学卓越中心项目资助的一个培训项目合作，增加少数族裔学生接触研究的机会。该培训项目要求导师是参与研究的教职员工。