Abstract 375: SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors

Abstract

Purpose: Anthracyclines effectively treat many pediatric cancers, but their use is limited by cardiotoxicity and new approaches to mitigate anthracycline-induced cardiac damage are urgently needed. Nanoparticle drug delivery is one solution to maintain anticancer efficacy while mitigating both acute and long-term cardiac complications. Additionally, novel treatments are needed to improve cure rates in certain cancer diagnoses that have not seen advancements in decades, particularly Ewing Sarcoma (EWS). Experimental Design: We investigated the use of a self-assembling micelle structure composed of myristic acid conjugated to an Apo-A1 mimetic 5A peptide, termed Myr5A nanoparticles (Myr5A NPs). These nanoparticles are transported into cells via the cholesterol scavenger receptor class B type-1 (SR-B1). Doxorubicin (DOX) and the Myr5A NP cannot form a stable micelle due to the hydrophilic nature of DOX, which results in preferential binding to the peptide shell, as opposed to the hydrophobic core. To favor micelle stability, we opted to use the novel, highly hydrophobic anthracyclines valrubicin and AD198 to test the nanoparticle delivery system. The potency of these anthracyclines encapsulated in Myr5A NPs were evaluated in human EWS cell lines with high and low SR-B1 expression via MTT assay. Additionally, 5 mg/kg intraperitoneal injections were administered weekly to 4-week-old wild type C57BL6/J mice and immune compromised homozygous null forkhead box N1 mice (Foxn1null/null mice) over 5 weeks, to assess by echocardiography, acute and long-term cardiac dysfunction. Results: Treatment with Myr5A-encapsulated AD198 and Myr5A-encapsulated valrubicin significantly inhibited EWS cell proliferation at concentrations comparable to conventional anthracyclines. Moreover, compared to unencapsulated valrubicin and AD198, encapsulation resulted in a lower IC50 in EWS lines with higher SR-B1 surface expression. By 19 weeks of age, DOX-treated C57BL6/J mice exhibited significantly decreased ejection fraction (EF) compared to PBS control and Myr5A-encapsulated anthracyclines (p<0.05). Additionally, an increase in Left Ventricular Mass (LVM) was observed in all groups except DOX by 19 weeks (p<0.05). Lastly, DOX-treated Foxn1null/null mice showed diminished survival rate compared to all treatment groups, and similar results to C57BL6/J mice in EF and LVM. Conclusions: Our results indicate that AD198 and valrubicin, when encapsulated in Myr5A NPs, induce minimal cardiac dysfunction while maintaining antitumor efficacy in EWS tumors. Myr5A NP drug delivery may be a viable option for the treatment of high SR-B1 expressing tumors with a decreased risk of acute and long-term cardiac complications. Future studies will evaluate the drug potency in non-cancer cell lines, such as cardiac fibroblasts and myocytes, and the effects of Myr5A-encaspulated anthracyclines on EWS xenografts and other pediatric tumors. Citation Format: Kathryn Crouch, Logan Davis, Nirupama Sabnis, Alexander Pertsemlidis, Laura Rutledge, James Graham, Jason Yustein, Gregory J. Aune. SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 375.