Kidney Selective Bcl2 Inhibitor Delivery Improves Fibrosis Treatment

Kidney fibrosis is one of the deadliest diseases. Kidney fibrosis often goes undiagnosed due to the absence of symptoms until the disease progresses to advanced stages, at which point dialysis or kidney transplant becomes the only viable options. Despite the significant morbidity and mortality associated with kidney fibrosis, there is currently no treatment available that efficiently and effectively addresses the condition. This study aims to develop a nanoparticle-mediated therapeutic modality targeting kidney fibrosis, anticipating improved therapeutic outcomes. We have modified a poly(lactic-co-glycolic acid) (PLGA) nanoparticle to link with angiotensin 2 targeting peptide (AT2 peptide) that targets and bind with angiotensin targeting 2 receptor (AT2R) and loaded with the Bcl-2 inhibitor (Navitoclax/Navi), to carry the payload to the site of action efficiently and specifically. Navi induces apoptosis by inhibiting the anti-apoptotic protein Bcl2. The therapeutic efficacy of various Navi formulations was investigated by both in vitro and in vivo models and compared to a group treated with Fasudil, a Rho-kinase inhibitor. A significant reduction of the Bcl2 expression and an upregulation of apoptosis were observed in the group of mice treated with targeted nanoparticle (TNP/Navi) when compared to free Navi or nontargeted formulation (NP/Navi), using immunohistochemistry and molecular biology techniques. A significant reduction in α-SMA and CTGF was observed in the TNP/Navi group for both in vitro and in vivo models that demonstrates an obvious indication of therapeutic potential of the developed formulation. Conservation of normal kidney morphology and less collagen deposition in the kidney treated with TNP/Navi further consolidates that AT2R targeted nanoparticle-mediated apoptosis upregulation has the potential to reverse the pathology of kidney fibrosis.