Abstract A119: Nanocarriers with a camptothecin-mitocan co-drug suppress tumor growth and extend survival in models of chemosensitive and chemoresistant neuroblastoma
Authors: Guerrero David , Alferiev Ivan S. , Nguyen Ferro , Guan Peng , Kolla Venkatadri , Soberman Danielle , Fishbein Ilia , Levy Robert J. , Brodeur Garrett M. , Chorny Michael 
Published: August 2018

Abstract
Background: Neuroblastoma (NB) ranks as the most common solid tumor in infants and is responsible for 15% of all childhood cancer deaths. Chemotherapeutics used as a first-line treatment in high-risk NB patients are inherently toxic and ultimately ineffective. High-risk NB patients have &lt;50% survival rate, and a particular challenge is posed by a group of “ultrahigh”-risk patients who show no response to therapy. With the goal of developing a clinically viable treatment strategy for high-risk NB, this study focused on an experimental approach integrating novel mutual prodrugs (co-drugs) and biodegradable nanocarriers. Nanocarrier-mediated co-drug delivery is designed to take advantage of enhanced accumulation and retention of sub-100 nm-sized nanoparticles (NP) in the tumor, followed by controlled release and in situ activation of the co-drug. Toward this goal, we developed a series of reversibly hydrophobized co-drugs exhibiting stable encapsulation in NP and activated hydrolytically to produce in one step 1) a potent camptothecin analog that inhibits topoisomerase I (SN-38) and 2) a pro-oxidant “helper” agent of a redox-silent tocol family of mitocans acting on the mitochondrial respiratory chain of cancerous cells. The effectiveness of co-drug loaded NP was evaluated in vitro and in orthotopic models of MYCN-amplified, chemosensitive, and drug-resistant NB. Methods and Results: A series of SN38-tocol conjugates constructed with progressively increasing hydrolytic activation rates were synthesized in high yields via direct coupling of the components. Co-drug loaded biodegradable NP (average size: 85±36 nm) were formulated using a nanoprecipitation approach adapted for producing sub-100 nm-sized nanocarriers. In comparative in vitro studies, a co-drug designed with a phenolic ester linkage was found to be most effective, achieving profound and sustained growth inhibition of MYCN-amplified NB cells, both chemo-naïve and chemoresistant (IMR-32 and BE(2)-C cells derived at diagnosis and during relapse after chemotherapy, respectively) under conditions modeling different levels of exposure experienced by NB cells within the tumor. Phenolic carbonate and aliphatic ester designs were notably less efficient. In an in vivo model of chemosensitive disease (IMR-32 orthotopic xenograft), nanocarriers with phenolic ester co-drug administered over 4 weeks (10 mg/kg, once a week) induced tumor regression and completely inhibited tumor growth over a 26-week period. This co-drug/nanocarrier formulation tested against chemoresistant NB (BE(2)-C orthotopic xenograft) potently suppressed tumor growth and extended animal survival up to 7 weeks, in comparison to irinotecan, which was only marginally effective (event-free survival of 3 weeks vs. 2 weeks in "no treatment" and drug-free NP groups). Conclusions: Camptothecin-mitocan co-drugs can be rationally designed and optimized to enhance their performance in the context of nanocarrier-based therapy of aggressive NB. The co-drug/nanocarrier combination strategy, whose feasibility and effectiveness against both chemosensitive and drug-resistant NB was demonstrated in the present preclinical studies, holds promise as a new therapeutic strategy for high-risk NB as well as for other solid tumors currently lacking effective treatment options.
Citation Format: David Guerrero, Ivan S. Alferiev, Ferro Nguyen, Peng Guan, Venkatadri Kolla, Danielle Soberman, Ilia Fishbein, Robert J. Levy, Garrett M. Brodeur, Michael Chorny. Nanocarriers with a camptothecin-mitocan co-drug suppress tumor growth and extend survival in models of chemosensitive and chemoresistant neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A119.