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: 9767769
• 负责人: Levon Bostanian
• 金额: $ 10.7万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767769
• 关键词: 2 year old; 9 year old; Accounting; Address; Basic Science; Biodistribution; Biological Availability; Body Surface Area; Caco-2 Cells; Child; Childhood; Corn Oil; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Stability; Drug usage; Enzymes; Evaluation; Feedback; Fenretinide; Formulation; Fostering; Future; Gastrointestinal tract structure; Glycolic-Lactic Acid Polyester; Goals; Human; Hydrophobicity; In Vitro; Inbred BALB C Mice; Lead; Life; Lipids; Liver; Malignant Childhood Neoplasm; Methods; Molecular Weight; Morphology; Nanotechnology; Neoplasms; Neuroblastoma; Oral; Oral Administration; Organ; Particle Size; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Polymers; Polyvinyls; Population; Preparation; Process; Property; Public Health; Pyrrolidinones; Recommendation; Research Activity; Retinoids; Sympathetic Nervous System; Temperature; Testing; Toxic effect; Translational Research; United States; Weight; absorption; base; cancer diagnosis; cancer therapy; capsule; clinical translation; comparative efficacy; gastrointestinal; hydrophilicity; improved; in vivo; innovation; interdisciplinary approach; mortality; nanoemulsion; nanoparticle; pediatric patients; water solubility; zeta potential

PROJECT SUMMARY/ABSTRACT An estimated 700 children in the United States will be diagnosed with neuroblastoma in 2016, and it is the most common cancer diagnosed during the first year of life. Fenretinide, a synthetic retinoid, is the focus of long-term treatment for complete eradication of the disease. Although, fenretinide was first synthesized more than twenty years ago, the full potential benefit of the drug has yet to be achieved because of bioavailability challenges, namely, low water solubility and low cellular permeability. In the last fifteen years, attempts to improve the bioavailability of the drug using traditional methods have been unsuccessful. In our previous studies, we have formulated fenretinide as hydrophilic nanoparticles using polyvinyl pyrrolidone (PVP), as nanoemulsions, and as hydrophobic nanoparticles using poly(lactide-co-glycolide) (PLGA). Amongst the various nano- particles that were prepared, we have shown that the permeability of fenretinide through Caco-2 cells significantly increased when formulated as hydrophobic nanoparticles. In the studies described in this SC3 application, we plan to optimize these fenretinide nanoparticles using different PLGA polymers, based on molecular weight and hydrophobicity. The overall objective of this SC3 application is to identify the formulation and process parameters critical to the successful formulation of fenretinide to enhance oral bioavailability. Our central hypothesis is that encapsulation of fenretinide in hydrophobic nanoparticles can improve oral bioavailability. The following specific aims delineate the stepwise approach towards the testing of the central hypothesis. Aim 1. Preparation, characterization, and optimization of fenretinide nanoparticles. Aim 2. Evaluation of the pharmacokinetics, biodistribution, and bioactivity of fenretinide nanoparticles following oral administration in BALB/c mice. Aim 3. Evaluation of the long-term stability of fenretinide nanoparticles. These three aims are expected to have an important positive impact on the treatment of neuroblastoma. The use of the hydrophobic properties of PLGA to develop fenretinide nanoparticles with the goal of enhancing bioavailability, as proposed in this project, is highly innovative, and demonstration of enhanced oral bioavailability of fenretinide will have high potential for clinical translation to improve the treatment of neuroblastoma.

项目摘要/摘要 2016年，美国估计有700名儿童将被诊断出患有神经母细胞瘤，这是 在生命的第一年被诊断出的最常见癌症。芬列汀是一种合成类维生素类似，是 长期治疗以完全消除该疾病。虽然，首先合成了芬雷丁苷 比二十年前，由于生物利用度，该药物的全部潜在利益尚未实现 挑战，即低水溶性和低细胞渗透性。在过去的十五年中，尝试使用传统方法改善该药物的生物利用度的尝试没有成功。在我们以前的研究中， 我们使用聚乙烯基吡咯酮（PVP），纳米乳液和疏水纳米颗粒（使用聚（乳酸 - 糖 - 糖苷）（PLGA）），将fenretinide作为亲水纳米颗粒（PVP）和疏水纳米颗粒。在各种纳米中 制备的颗粒已经表明，当形式为疏水纳米颗粒时，烯丁胺通过CACO-2细胞的渗透性显着增加。在此SC3应用中描述的研究中，我们计划使用基于分子的不同PLGA聚合物优化这些芬肠丁素纳米颗粒 体重和疏水性。该SC3应用程序的总体目的是确定对成功制定芬雷丁苷的制定和过程参数，以增强口服生物利用度。我们的中心 假设是，在疏水性纳米颗粒中封装fenretinide可以改善口服生物利用度。 以下特定目的描述了测试中心假设的逐步方法。目的 1。芬雷丁素纳米颗粒的制备，表征和优化。 AIM 2。在BALB/C中口服给药后的药代动力学，生物分布和生物活性的评估 老鼠。目的3。评估烯胺纳米颗粒的长期稳定性。这三个目标应 对神经母细胞瘤的治疗有重要的积极影响。使用的使用 正如该项目中提出的那样，PLGA开发fenretinide纳米颗粒的目标是高度创新的，并且表现出增强的芬雷丁汀口服生物利用度的证明将具有很高的临床翻译潜力，可以改善神经母细胞瘤的治疗。