Formulation of Fenretinide Nanoparticles for Enhanced Bioavailability

项目摘要/摘要 据估计，2016年美国将有700名儿童被诊断出神经母细胞瘤，而且 在生命的第一年被诊断出的最常见的癌症。芬维替尼，一种合成的维甲酸，是 长期治疗可彻底根除该病。虽然，芬维替尼首先合成的更多 20多年前，由于生物利用度的原因，该药物的全部潜在好处尚未实现 挑战，即低水溶性和低细胞渗透性。在过去的15年里，使用传统方法提高药物的生物利用度的尝试都没有成功。在我们之前的研究中， 我们用聚乙烯吡咯烷酮(PVP)将芬维替尼制成亲水纳米粒，用聚丙交酯-乙交酯共聚物(PLGA)制成纳米乳剂，并将其制成疏水纳米粒。在各种纳米材料中- 在制备的纳米颗粒中，我们已经表明，当以疏水纳米颗粒的形式配制时，非维甲酸通过Caco-2细胞的渗透性显著增加。在SC3应用中描述的研究中，我们计划使用不同的PLGA聚合物来优化这些非维甲酸纳米粒，基于分子 重量和疏水性。这一SC3应用的总体目标是确定对成功配制芬维替尼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 假设将非维甲酸包裹在疏水纳米粒中可以提高口服生物利用度。 以下具体目标描述了对中心假设进行检验的逐步方法。目标 1.非维甲酸纳米粒的制备、表征及优化目的2.评价口服非维甲酸纳米粒在BALB/c小鼠体内的药代动力学、生物分布和生物活性 老鼠。目的3.评价非维甲酸纳米粒的长期稳定性。这三个目标预计将 对神经母细胞瘤的治疗有重要的积极影响。疏水特性的使用 PLGA开发非维甲酸纳米粒以提高生物利用度为目标，这一项目具有很高的创新性，非维甲酸口服生物利用度增强的示范将具有很高的临床转化潜力，以改进神经母细胞瘤的治疗。

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.