Introduction and Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment, often caused by the action of permeability glycoprotein (P-gp) efflux pumps which reduce drug accumulation in cancer cells. To develop and optimize a nanoformulation of Irinotecan using excipients known for their P-gp inhibitory potential, aiming to overcome MDR in cancer therapy.

Methods: Nanoparticles were prepared and optimized employing a 3-factor, 2-level factorial design focusing on hydroxypropyl methylcellulose (HPMC) concentration and the number of preparation cycles. Particle size, polydispersity index (PDI), and entrapment efficiency were evaluated. Characterization was performed using Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD) to confirm molecular dispersion. In vitro P-gp inhibition was assessed in Caco-2 cells with ELISA analysis, and in vivo efficacy was evaluated through pharmacokinetic studies in rats.

Results: The optimized Irinotecan nanoparticles exhibited a particle size of 201 nm, PDI of 0.100, and entrapment efficiency of 91%. DSC and XRD confirmed the molecular dispersion of the drug within the freeze-dried nanoparticles. In vitro studies demonstrated significant P-gp inhibition, with the nanoformulation requiring nearly half the concentration to achieve similar effects compared to the free drug. In vivo studies showed enhanced P-gp inhibition, indicated by improved maximum plasma concentration (Cmax) values.

Conclusion: Excipients-based Irinotecan nanoparticles effectively inhibit P-gp activity, providing a promising nanoformulation strategy to overcome multidrug resistance in cancer treatment.