Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma

Abstract

Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P < 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P < 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4–targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs. NT/ND: 28 days, P < 0.05 and T/D 20: 52 days vs. NT/ND: 29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach.

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

“…Utilizing this information, we evaluated nanoparticle-mediated drug delivery targeted against integrin αvβ3. We recently developed phospholipid/polysorbate-80 micelle nanoparticles (MPs, ~12.5 nm) for their small size and unique mechanism of “contact-facilitated drug delivery” (29); in the present study, we demonstrate that integrin αvβ3-targeted micelle nanoparticles (αvβ3-MPs) carrying the chemotherapeutic docetaxel reduce bone metastases and tumor-associated bone destruction more effectively than free-docetaxel. Collectively, we demonstrate that αvβ3 is a tumor target on breast cancer bone metastases and provide support for safer, more effective therapies against this often incurable disease by targeting integrin αvβ3.…”

“…Phospholipid/polysorbate 80 micelle nanoparticles (MPs) were prepared as a microfluidized suspension of 20% (v/v), combining polysorbate tween 80 (Sigma Aldrich, Inc.) with a 2.0% (w/v) of a surfactant comixture, and 1.7% (w/v) glycerin in pH 6.5 carbonate buffer, as previously described (29). Optionally, the surfactant comixture included 2.28mol% of docetaxel-prodrug (DTX-PD), and/or 0.15mol% of αvβ3-targeted quinolone nonpeptide coupled to phosphatidylethanolamine-PEG2000, with the remaining mol% lecithin.…”

“…The nanoparticle-targeting quinolone nonpeptide specific for integrin αvβ3 was originally developed by Bristol-Myers Squibb Medical Imaging (US patent 6,511,648 and related patents) and coupled to phosphatidylethanolamine-PEG2000, as previously described (29). The quinolone nonpeptide was initially characterized as the 111 In-DOTA conjugate RP478 and cyan 5.5 homologue TA145 (33).…”

Multimodal Imaging and Theranostic Application of Disease-Directed Agents

“…However, their clinical translation is still far-reaching. Better understanding of biological and biophysical obstacles encountered by these agents is necessary [11,12,14,22,72,77,78]. For the readers, this introductory chapter will illustrate a presentation of the advancements related to this field and the biological obstacles encountered, which we hope will stimulate more studies to tune these technologies for translational and clinical applications.…”

Concepts to Target MYC in Pancreatic Cancer

“…These data might be explained by the inappropriate pharmacokinetics of 10058-F4 observed in vivo (36). However, recent data demonstrate that such problems can be solved, and a nanoparticle-based delivery of a 10058-F4 prodrug was demonstrated to improve survival in an in vivo model for multiple myeloma (37). Although direct MYC inhibitors are far from being clinically tested, especially the abovementioned Mycro3 study argues that direct MYC inhibitors should be further developed, improved and tested in PDAC.…”