Abstract
Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (NB) (HRNB). The long term survival rates of HRNB in the United States are still only 30–50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment. Current chemotherapy regimens also have a serious limitation due to off target toxicity. In the present work, we evaluated the potential application of reconstituted high density lipoprotein (rHDL) containing fenretinide (FR) nanoparticles as a novel approach to current NB therapeutics. The characterization and stability studies of rHDL-FR nanoparticles showed small size (<40 nm) and high encapsulation efficiency. The cytotoxicity studies of free FR vs. rHDL/FR toward the NB cell lines SK-N-SH and SMS-KCNR showed 2.8- and 2-fold lower IC50 values for the rHDL encapsulated FR vs. free FR. More importantly, the IC50 value for retinal pigment epithelial cells (ARPE-19), a recipient of off target toxicity during FR therapy, was over 40 times higher for the rHDL/FR as compared to that of free FR. The overall improvement in in vitro selective therapeutic efficiency was thus about 100-fold upon encapsulation of the drug into the rHDL nanoparticles. These studies support the potential value of this novel drug delivery platform for treating pediatric cancers in general, and NB in particular.
Highlights
Neuroblastoma (NB) is one of the most frequently diagnosed tumors in pediatric patients
We evaluated the potential application of reconstituted high density lipoprotein containing fenretinide (FR) nanoparticles as a novel approach to current NB therapeutics.The characterization and stability studies of rHDL-FR nanoparticles showed small size (
Because of its high octanol-water coefficient (XlogP), All-trans-retinoic acid (ATRA) was considered to be an appropriate candidate to be transported by the rHDL drug delivery system and a model for the incorporation of FR
Summary
Neuroblastoma (NB) is one of the most frequently diagnosed tumors in pediatric patients. A stratification strategy for NB cases has emerged based on established clinical and biological criteria as a basis for designing effective therapeutic regimens for the specific forms of the disease [2]. According to this strategy, approximately 40% of NB patients are classified as having the high risk form of the disease (HRNB) [2, 3]. Extensive pre-clinical and early clinical trials for treatment of NB have focused on small-molecule inhibitors targeting specific genetic pathways, implicated in the proliferation of NB cells These include the insulin-like growth factor I receptor (IGF-IR), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and Akt [9,10,11,12,13]. Despite recent advances in the development of anti-cancer agents and the use of multi-modal therapeutics for the treatment of HRNB the morbidity and mortality in this group of patients remains high [3,4,5, 17]
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