Activities Performed and Main Achievements:
The project embarked on a journey to develop a nanometric drug delivery system targeting the endocannabinoid system, specifically cannabinoid-1 receptors (CB1Rs), in the liver. Several trials were conducted, exploring various polymers, lipids, and surface-active agents, alongside different methods of nanoparticle (NP) formulation. These efforts were driven by the goal of efficiently entraping rimonabant in nanometric drug delivery systems while preventing its penetration into the brain.
After careful experimentation, a breakthrough was achieved using a single emulsion evaporation approach. This method enabled the creation of stable biodegradable polymeric nanoparticles based on Poly (lactic-co-glycolic acid) (PLGA) with high loading capacity and encapsulation efficiency of rimonabant. These PLGA-NPs were designed to be taken up by circulating macrophages, which ferry them directly to the liver.
Upon administration to mice, these novel nanoparticles demonstrated remarkable pharmacokinetic properties. Notably, they exhibited significantly low levels of rimonabant in the brain compared to free rimonabant, confirming the successful mitigation of CNS-related side effects. Moreover, high levels of rimonabant were found in the liver, indicating effective hepatic targeting.
Further studies delved into the intrahepatic distribution of rimonabant-loaded nanoparticles, aiming to elucidate their fate at the cellular level. Flow cytometry analysis revealed the uptake of fluorescently labeled nanoparticles by hepatocytes and non-parenchymal cells (NPCs) in the liver. Immunofluorescence studies confirmed the co-localization of nanoparticles within hepatocytes and Kupffer cells (KCs), providing insights into their cellular interactions.
In-depth pharmacokinetic evaluations were conducted to assess the systemic fate of rimonabant-loaded nanoparticles following various routes of administration. Subcutaneous (SC), intravenous (IV), intraperitoneal (IP), and per os (PO) routes were explored to determine optimal delivery strategies. These studies yielded crucial data on tissue distribution, drug concentrations, and pharmacokinetic parameters, informing future clinical translation efforts.
Overall, the project successfully achieved its scientific aims, culminating in the development of a novel nanometric drug delivery system with promising therapeutic potential for nonalcoholic fatty liver disease (NAFLD) and related metabolic disorders. These achievements lay the groundwork for future clinical translation and commercial development, offering new hope for patients affected by these challenging conditions.
