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.

项目总结/摘要 据估计，2016年美国将有700名儿童被诊断患有神经母细胞瘤， 最常见的癌症是在出生后的第一年诊断出来的。芬维A胺是一种合成类维生素A， 长期治疗以彻底根除疾病。虽然芬维A胺首次合成更多 二十多年前，由于生物利用度的问题，这种药物的全部潜在益处尚未实现。 挑战，即低水溶性和低细胞渗透性。在过去的15年中，使用传统方法提高药物生物利用度的尝试一直不成功。在我们以前的研究中， 我们已经使用聚乙烯吡咯烷酮（PVP）将芬维A胺配制成亲水性纳米颗粒、纳米乳液和使用聚（丙交酯-共-乙交酯）（PLGA）配制成疏水性纳米颗粒。在各种各样的纳米- 通过比较制备的纳米颗粒，我们已经表明，当配制成疏水纳米颗粒时，芬维A胺通过Caco-2细胞的渗透性显著增加。在本SC 3申请中描述的研究中，我们计划基于分子生物学特性，使用不同的PLGA聚合物优化这些芬维A胺纳米颗粒。 重量和疏水性。本SC 3申请的总体目标是确定成功配制芬维A胺以提高口服生物利用度的关键处方和工艺参数。我们的中央 假设芬维A胺在疏水纳米颗粒中包封可以提高口服生物利用度。 以下具体目标描述了检验中心假设的逐步方法。目的 1.芬维A胺纳米粒的制备、表征及优化。目标2.芬维A胺纳米粒在BALB/c小鼠体内的药代动力学、生物分布和生物活性评价 小鼠目标3.芬维A胺纳米粒的长期稳定性评价。预计这三个目标将 对神经母细胞瘤的治疗有重要的积极影响。疏水特性的应用 PLGA开发芬维A胺纳米粒的目的是提高生物利用度，如本项目所提出的，是高度创新的，证明芬维A胺的口服生物利用度提高将具有很高的临床转化潜力，以改善神经母细胞瘤的治疗。