Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma

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.

Lipoproteins and lipoprotein mimetics for imaging and drug delivery

“…Drug toxicity in normal prostate and ovarian epithelial cell lines was reduced in the HDL-drug formulation compared to drug alone. Similar work has been reported, with HDL loaded with fenretinide,[165] a retinoid derivative, and doxorubicin. [166, 167] In both cases, encapsulation of the drug in HDL enhanced cytotoxicity of neuroblastoma and hepatocellular carcinoma cells, respectively, while reducing off-target effects in healthy, normal cells.…”

“…In a recent report, Lacko et al sequestered the poorly water soluble drug valrubicin into spherical HDL. [74, 165] This drug loaded HDL had significantly increased toxicity against SR-B1 expressing ovarian and prostate cancer cell lines, compared to valrubicin alone. Drug toxicity in normal prostate and ovarian epithelial cell lines was reduced in the HDL-drug formulation compared to drug alone.…”

High-density lipoproteins for therapeutic delivery systems

“…Using similar approaches, Sabnis, et al have formulated the chemotherapeutic valrubicin into spherical rHDLs 73 , as well as fenretinide, a retinoid, potentially useful in neuroblastoma. 74 …”

Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery

“…BLT-1 has been shown to inhibit the function of the SR-B1 receptor, while circulating HDL competes with the rHDL nanoparticles and thus has been shown to interfere with the drug uptake from the rHDL nanoparticles. 34,[50][51][52] When the PC-3 cells were pre-incubated with BLT-1 and human HDL, respectively, and subsequently treated with rHDL-SPION and rHDL-SPION-valrubicin nanoparticles, the uptake of iron was reduced by almost 90%, indicating that the mechanism of iron uptake was specific and likely dependent on the SR-B1 receptors. These data are also consistent with earlier findings regarding the release of the drug payload to cancer cells and tumors from the rHDL nanoparticles.…”

“…These data are also consistent with earlier findings regarding the release of the drug payload to cancer cells and tumors from the rHDL nanoparticles. 34,42,52 Stability studies showed that 60%-65% of the iron remained within the nanoparticles after 48 hours of incubation, indicating that encasement of SPIONs and valrubicin within rHDL provided a stable environment that has the potential to remain longer in the circulation than conventional nonencapsulated drugs. Free drugs generally exit the circulation within a few hours.…”