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

Danielle Soberman,David T Guerrero,Ivan S Alferiev,Venkatadri Kolla,Ferro Nguyen,Peng Guan,Ilia Fishbein,Garrett M Brodeur,Michael Chorny,Blake B Pressly

doi:10.3390/ijms23031752

Abstract

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological 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 orthotopic, 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) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.

Highlights

Neuroblastoma (NB), a neural crest-derived malignancy of the sympathetic nervous system, is the most common and deadly extracranial solid tumor of childhood
Present in the prodrug form), the release medium samples collected from NP[SN22-TOx]
Broad-spectrum therapeutics, such as topoisomerase I inhibitors of the camptothecin family currently used in the clinic as a first-line treatment [46], continue to yield poor results in patients with high-risk NB due to rapid clearance, non-specific biodistribution leading to dose-limiting adverse effects [19,20,47], and drug resistance acquired in the course of treatment [8,11]

Summary

Introduction

Neuroblastoma (NB), a neural crest-derived malignancy of the sympathetic nervous system, is the most common and deadly extracranial solid tumor of childhood. It accounts for 6–10% of all childhood cancers, and 12–15% of deaths from cancer in children [1]. Despite major improvements in the cure rates for other pediatric cancers, little progress has been made in patients with aggressive forms of NB. Many high-risk patients have advanced, metastatic tumors at diagnosis, and their disease often progresses relentlessly, demonstrating no durable response to treatment. Amplification of the MYCN oncogene encoding a transcription factor N-Myc is present in 18–20% of all NBs [4], and is a high-risk feature predicting low chemosensitivity and poor therapeutic response [5]

Methods

Results

Conclusion