In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5381-5381
Abstract:
Background: While it is well known that MYC oncoprotein drives multiple myeloma (MM) pathogenesis, the development of several small-molecule inhibitors of the c-MYC/MAX interaction has been limited by rapid systemic metabolism, poor bioavailability and the inability of the drug to reach inhibitory concentrations in the tumor. Objective: The goal of this study was to develop and deliver an effective VLA-4-targeted Sn 2 lipase-labile Myc-inhibitor nanotherapy. Experimental Methods: A novel Sn 2 phosphatidylcholine-cMyc-Max antagonist prodrug (M1-PD) was designed, synthesized, characterized and evaluated in vitro and in vivo. In vitro, titrated free M1-PD was compared to free Myc-antagonist in human MM cell lines (H929 and U266) and mouse MM (5TGM1). M1-PD was incorporated into two lipid-based nanoparticle genera ( & lt;20nm and ∼200nm) that were functionalized for MM targeting using a peptidomimetic VLA-4-lipid ligand. The nanoparticles were physico-chemically characterized and evaluated for their relative pharmacokinetics in vivo. Effectiveness of the two VLA-4-targeted M1-PD nanotherapies were evaluated in MM cell cultures, correlated with VLA-4 expression levels, and then studied in C57BL/KaLwRij mice with metastatic 5TGM1. Results: Bioactivity of free M1-PD was several orders magnitude more potent that the free cMyc antagonist in cell culture. Binding and efficacy of M1-PD nanoparticles correlated with integrin expression in target cells. VLA-4-M1-PD nanoparticles ( & lt;20nm and ∼200nm) equivalently inhibited MM cell growth in vitro compared to controls. In C57BL/KaLwRij mice with metastatic 5TGM1, VLA-4-MI1-PD 20nm micelles conferred significant survival benefit (T/D) over the 20nm targeted no drug (T/ND) or untreated controls (NT/ND) (52 days vs. 29 days, p=0.001) and versus the 200nm VLA-4-MI1-PD nanocolloid and its controls. Conclusion: These finding support the feasibility of a new VLA-4-directed nanotherapy to deliver lipase-labile cMyc prodrug to disrupt MYC-MAX dimerization and improve MM survival. Citation Format: Deepti Soodgupta, Dipanjan Pan, Grace Cui, Angana Senpan, Xiaoxia Yang, Samuel A. Wickline, Edward V. Prochownik, Katherine N. Weilbaecher, Michael H. Tomasson, Gregory M. Lanza. VLA-4 targeted nanoparticles deliver a cMYC-MAX prodrug antagonist extends survival a metastatic myeloma mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5381. doi:10.1158/1538-7445.AM2014-5381
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-5381
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
