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/文摘