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.
The current SC3 project will promote the basic and translational research in nanotechnology. This research activity will foster innovative and interdisciplinary approaches to the application of nanotechnology to drug delivery. This is essential to improve public health by providing possible oral treatments for cancer.
| Ledet, Grace A; Graves, Richard A; Glotser, Elena Y et al. (2015) Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles. Int J Pharm 479:329-37 |
| Graves, Richard A; Ledet, Grace A; Nation, Cedric A et al. (2015) Effect of squalane on mebendazole-loaded Compritol® nanoparticles. J Biomater Sci Polym Ed 26:868-80 |
| Graves, Richard A; Ledet, Grace; Nation, Cedric A et al. (2015) An ultra-high performance chromatographic method for the determination of artemisinin. Drug Dev Ind Pharm 41:819-24 |
| Graves, Richard A; Ledet, Grace A; Glotser, Elena Y et al. (2015) Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide. Eur J Pharm Sci 76:1-9 |
