Development and In Vitro/In Vivo Characterization of Surface-Modified Nintedanib-Loaded Nanoparticles for Enhanced Bioavailability in Chronic Kidney Disease.

Chronic kidney disease (CKD), a heterogeneous disorder with limited therapeutic options, is often complicated by drug-induced nephrotoxicity from aminoglycosides, such as gentamicin (GM). Nintedanib (NTD), a tyrosine kinase inhibitor with antifibrotic and anti-inflammatory properties, holds promise but is limited by poor solubility, low bioavailability, and potential systemic toxicity. To overcome these challenges, a nintedanib nanosuspension polymer (NTD-PNP) was developed using polycaprolactone (PCL) to improve solubility, control drug release, and maximize oral bioavailability. Physicochemical classification confirmed spherical, smooth-surfaced nanoparticles with particle sizes of 106.5-154.7 nm, ζ-potential of -1.39 to +8.86 mV, polydispersity index (PDI) of 0.139-0.384, entrapment efficiency of 28.92-70.92%, and drug loading of 19.94-47.28%. Compared with the free drug, NTD-PNPs displayed superior solubility and prolonged release kinetics. The therapeutic efficacy of NTD-PNPs was evaluated for 28 days in a gentamicin-induced CKD rat model (100 mg/kg, 21 days). Treatment with NTD-PNPs significantly reduced blood urea nitrogen and creatinine levels, indicating improved renal function. Immunohistochemical analysis further revealed downregulation of fibronectin, α-SMA, Smad3, and collagen III expression, and histopathology showed a reduction in tubular degeneration, extracellular matrix accumulation, and fibrosis. Collectively, these findings demonstrate that NTD-PNPs enhance the therapeutic index of nintedanib, offering a promising sustained-release nano formulation to mitigate CKD progression.