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Efficacy of a novel integrin‐targeted anti‐c‐Myc nanotherapy against multiple myeloma in mice (1054.11)
Author(s) -
Soodgupta Deepti,
Pan Dipanjan,
Hu Grace,
Sen Pan Angana,
Yang XiaoXia,
Prochownik Edward,
Lanza Gregory,
Tomasson Michael
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1054.11
Subject(s) - prodrug , in vivo , integrin , multiple myeloma , chemistry , apoptosis , pharmacology , in vitro , viability assay , cancer research , cell , biology , biochemistry , immunology , microbiology and biotechnology
The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC‐MAX dimerization is limited by poor efficacy. We first sought to test the efficacy of a novel MYC‐MAX dimerization inhibitor prodrug. Treatment of three MM cell lines (mouse and human) with a lipase‐labile prodrug inhibitor of MYC‐MAX dimerization (MI1‐PD) decreased cell viability more than parent drug MI1 on an equimolar basis and increased apoptosis. However, MI1‐PD is hydrophobic, limiting translation to in vivo use. To overcome this challenge, we next determined if the efficacy of MI1‐PD could be improved by delivery in nanoparticles targeted to MM‐specific integrins. Integrin‐targeted, MI1‐PD‐containing nanoparticles inhibited growth and induced apoptosis compared to control nanoparticles without drug, or without integrin‐targeting. Binding and efficacy of nanoparticles correlated with integrin expression in target cells. A mouse model of MM was used to assess in vivo efficacy of nanoparticle‐bound MI1‐PD, with survival used as the primary endpoint. In vivo, administration of nanoparticle‐bound MI1‐PD conferred significant survival benefit versus untreated controls (52 days vs. 29 days, p=0.001). Our results suggest the feasibility of an improved integrin‐targeted nanotherapy approach to disrupt MYC‐MAX dimerization using a lipase‐labile prodrug. Grant Funding Source : This work was supported by the Department of Defense Grant Award # W81XWH1110446