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: 8338306
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338306
• 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. PUBLIC HEALTH RELEVANCE: The current SC3 project will promote the basic and translational research in nanotechnology and novel drug delivery. This research activity will foster innovative and interdisciplinary approaches essential to improve public health by providing possible treatments for cancer.

描述（由申请人提供）：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，这种肿瘤患者的预后有所改善，但由于疾病的致命复发，总体5年生存率仍低于60%。然而，致命性复发的发生率可以通过增加创新疗法来消除残留疾病来降低。要彻底根除残留疾病，需要在早期进行长期治疗。 芬维A胺是一种合成类维生素A，是完全根除该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，芬维A胺作为儿童神经母细胞瘤长期治疗的潜力受到口服给药后水溶性差和生物利用度差的限制。 本项目的总体目标是开发芬维A胺纳米颗粒。中心假设是芬维A胺的生物利用度将由于小的尺寸而显著增强。 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逐步检验中心假设的方法。具体目标1.纳米颗粒制剂的制备。将分别使用实验室纳米喷雾干燥器和高压均质器制备两种不同的纳米颗粒制剂。具体目标2。纳米颗粒的表征。具体目标3。体外药物释放的评价。具体目标4。芬维A胺的肠渗透性评价 使用Caco-2细胞模型。 在我们看来，拟议的研究是创新的，因为文献中没有使用纳米喷雾干燥器或高压均质器生产芬维A胺纳米颗粒的报道。我们预计，芬维A胺的生物利用度将通过其纳米颗粒形式的制剂来提高，因此，将需要较低剂量的药物来达到治疗血浆浓度。降低药物剂量还将降低不良副作用的发生率并提高患者的依从性。 拟议的项目将帮助首席研究员发展他在纳米技术和药物纳米颗粒配方方面的技能。这将有助于他提高他的出版记录，从而加强他提交竞争性赠款申请的能力。 拟议的项目还将通过与该大学卓越中心项目资助的培训计划合作，增加少数民族学生对研究的接触，该项目要求导师是参与研究的教员。 公共卫生相关性：目前的SC 3项目将促进纳米技术和新型药物输送的基础和转化研究。这项研究活动将促进创新和跨学科的方法，通过提供可能的癌症治疗方法来改善公众健康。