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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要预计 2016 年美国将有 700 名儿童被诊断出患有神经母细胞瘤，生命第一年诊断出的最常见癌症。芬维A胺是一种合成类维生素A，是目前关注的焦点长期治疗才能彻底根除疾病。虽然，芬维A胺是最先合成的二十多年前，由于生物利用度的原因，该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。在过去十五年中，使用传统方法提高药物生物利用度的尝试并未成功。在我们之前的研究中，我们使用聚乙烯吡咯烷酮 (PVP) 将芬维A胺配制为亲水性纳米颗粒、纳米乳液，以及使用聚丙交酯乙交酯 (PLGA) 配制为疏水性纳米颗粒。其中各种纳米通过对所制备的颗粒进行观察，我们发现，当配制为疏水性纳米颗粒时，芬维A胺通过 Caco-2 细胞的渗透性显着增加。在此 SC3 申请中描述的研究中，我们计划使用不同的 PLGA 聚合物，基于分子重量和疏水性。该 SC3 应用的总体目标是确定对成功配制芬维A胺以提高口服生物利用度至关重要的配方和工艺参数。我们的中央假设将芬维A胺封装在疏水性纳米颗粒中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胺纳米颗粒的制备、表征和优化。目的 2. 评价芬维A胺纳米颗粒口服后在 BALB/c 中的药代动力学、生物分布和生物活性老鼠。目的 3.评估芬维A胺纳米颗粒的长期稳定性。这三个目标预计将对神经母细胞瘤的治疗具有重要的积极影响。利用疏水特性正如本项目中提出的那样，PLGA 开发芬维A胺纳米颗粒的目的是提高生物利用度，具有高度创新性，并且证明芬维A胺口服生物利用度的增强将具有很大的临床转化潜力，以改善神经母细胞瘤的治疗。