Nanoparticles Loaded with the BET Inhibitor JQ1 Block the Growth of Triple Negative Breast Cancer Cells In Vitro and In Vivo

Abstract

Inhibition of bromo-and extra-terminal domain (BET) proteins, epigenetic regulators of genes involved in cell viability, has been efficiently tested in preclinical models of triple negative breast cancer (TNBC). However, the use of the selective BET-inhibitor JQ1 on humans is limited by its very short half-life. Herein, we developed, characterized and tested a novel formulation of nanoparticles containing JQ1 (N-JQ1) against TNBC in vitro and in vivo. N-JQ1, prepared using the nanoprecipitation method of preformedpoly-lactid-co-glycolic acid in an aqueous solution containing JQ1 and poloxamer-188 as a stabilizer, presented a high physico-chemical stability. Treatment of MDA-MB 157 and MDA-MB 231 TNBC cells with N-JQ1 determined a significant decrease in cell viability, adhesion and migration. Intra-peritoneal administration (5 days/week for two weeks) of N-JQ1 in nude mice hosting a xenograft TNBC after flank injection of MDA-MB-231 cells determined a great reduction in the growth and vascularity of the neoplasm. Moreover, the treatment resulted in a minimal infiltration of nearby tissues. Finally, the encapsulation of JQ1 in nanoparticles improved the anticancer efficacy of this epigenetic compound against TNBC in vitro and in vivo, opening the way to test it in the treatment of TNBC.

Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors

“…The most important preparation approaches for PNs are emulsification and solvent evaporation ( Yoneki et al, 2015 ), nanoprecipitation ( Rivas et al, 2017 ; Maggisano et al, 2020 ), the supercritical anti-solvent method ( Kalani and Yunus, 2012 ), and salting-out ( Mendoza-Muñoz et al, 2012 ). The emulsification and solvent evaporation/extraction technique is the most used method for small and moderate-scale manufacturing of PNs.…”

Nanoformulation of BRD4-Degrading PROTAC: Improving Druggability To Target the ‘Undruggable’ MYC in Pancreatic Cancer

“…Small-molecule BET inhibitors such as JQ1 reduce MYC transcription but have no effect on MYC protein stability [4]. Owing to the reversible nature of binding of JQ1 to BET, as well as its short halflife, there is a need to identify molecules that would directly degrade the target BRD4 protein instead of merely inhibiting it [5,6].…”

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way

“…Unfortunately, the short half-life of JQ1 has precluded clinical studies. However, the FDA and European medicines agency (EMA) have approved polymeric biomaterials for pharmaceutical applications, and JQ1-containing nanoparticles (made of poly-lactic-co-glycolic acid) have a prolonged half-life and enhanced activity against TNBC based on in vivo and in vitro models ( Maggisano et al, 2019 ). Cells from TNBC that are BETi-resistant remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a BRD-independent manner ( Shu et al, 2016 ).…”