Background: Patients with high-risk NB require intensive, multimodality therapy, but have only a 40-50% survival rate. Survivors have significant short- and long-term toxicities, so more effective, less toxic therapy is needed. Agents are being developed that target specific genes, proteins and pathways, but targeted delivery of existing agents is also promising. Here, the use of NPs as a drug delivery system is explored to increase efficacy and decrease toxicity of these agents.
Methods: A subclone of the SY5Y NB line was used for the studies. Several active agents for NB were encapsulated in pegylated-polylactide NPs, including SN38, lestaurtinib, fenretinide (4HPR), and phenylbutyrate (PBA). The efficacy of free drug versus NP-drug was evaluated on both in vitro cell proliferation and in vivo xenografts growing in nude mice.
Results: We have tested NPs with SN38 conjugated to tocopherol succinate (SN38-TS) compared to free irinotecan; NP-lestaurtinib compared to free lestaurtinib (50-200 nM), and NPs with 4HPR-PBA compared to fenretinide (1-20 µM). In the in vitro experiments, inhibition of growth with NP-drug was as or more potent than free drug at the same concentration for all the agents tested. Furthermore, at 4 hr we achieved ~100x as much SN38 in NB xenografts using NP-SN38-TS as a comparable dose of irinotecan delivered as free drug. Mice were “cured” of their NB xenografts (>180 day relapse-free survival) at a fraction of the dose of free irinotecan that produced only transient remissions. NP-lestaurtinib was also more effective than free against NB xenografts, although the lestaurtinib was not retained in NPs as long as SN38-TS. Studies are currently underway with NPs containing 4HPR-PBA, with promising early results.
Conclusions: NP encapsulation allows the targeted delivery of conventional and biological agents, which dramatically improves efficacy and decreases toxicity compared to free drug administration.