Enhanced Intratumoral Delivery of SN38 as a Tocopherol Oxyacetate Prodrug Using Nanoparticles in a Neuroblastoma Xenograft Model

Purpose: Currently, <50% of high-risk pediatric solid tumors like neuroblastoma (NB), can be cured, and many survivors experience serious or life-threatening toxicities, so more effective, less toxic therapy is needed. One approach is to target drugs to tumors using nanoparticles, which take advantage of the enhanced permeability of tumor vasculature. Experimental Design: SN38, the active metabolite of irinotecan (CPT-11), is a potent therapeutic agent that is readily encapsulated in polymeric nanoparticles (NPs). Tocopherol oxyacetate (TOA) is a hydrophobic mitocan that was linked to SN38 to significantly increase hydrophobicity and enhance NP retention. We treated NBs with SN38-TOA NPs and compared the efficacy to the parent prodrug CPT-11 using a mouse xenograft model. Results. NP treatment induced prolonged event-free survival (EFS) in most mice, compared to CPT-11. This was shown for both SH-SY5Y and IMR-32 NB xenografts. Enhanced efficacy was likely due to increased and sustained drug levels of SN38 in the tumor compared to conventional CPT-11 delivery. Interestingly, when recurrent CPT-11-treated tumors were retreated with SN38-TOA NPs, the tumors transformed from undifferentiated NBs to maturing ganglioneuroblastomas. Furthermore, these tumors were infiltrated with Schwann cells of mouse origin, which may have contributed to the differentiated histology. Conclusion. NP delivery of SN38-TOA produced increased drug delivery and prolonged EFS compared to conventional delivery of CPT-11. Also, lower total dose and drug entrapment in NPs during circulation should decrease toxicity. We propose that NP-based delivery of a rationally designed prodrug is an attractive approach to enhance chemotherapeutic efficacy in pediatric and adult tumors.

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