Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models

Abstract

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblas-toma (NB) patients do not survive. Without significant improvements in delivery strategies, anti-cancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically mean-ingful results in the settings of disseminated, recurrent, or refractory disease. By enhancing phar-macological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of ortho-topic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demon-strate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydro-phobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.