Periodic Reporting for period 1 - NANOFLD (Nano-Technology Enabled Repositioning of Cannabinoids for Treating NAFLD)
Periodo di rendicontazione: 2022-11-01 al 2024-04-30
The project centers around addressing a pressing health concern: Nonalcoholic fatty liver disease (NAFLD) and its progression into more severe conditions like non-alcoholic steatohepatitis (NASH), which can lead to liver fibrosis, cirrhosis, and even cancer. With the rise of obesity worldwide, NAFLD has become increasingly prevalent, affecting millions of individuals and imposing significant economic burdens on healthcare systems. Currently, there is a critical gap in effective pharmacological treatments for NAFLD. The lack of specific therapies exacerbates the challenge of managing this disease, especially considering its often asymptomatic nature and the absence of consensus on optimal management strategies. Additionally, the absence of drug therapies approved by regulatory authorities like the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) underscores the urgent need for innovative solutions.
The project proposes a novel approach to target the endocannabinoid system (ECS) and cannabinoid-1 receptors (CB1Rs) in the liver, aiming to mitigate the development and progression of NAFLD. By leveraging groundbreaking nanometric drug delivery systems, the project seeks to peripheralize the action of CB1R blockers, specifically rimonabant, to minimize the risk of neuropsychiatric side effects while maximizing therapeutic efficacy. This innovative strategy holds immense promise for revolutionizing NAFLD treatment. By precisely targeting CB1Rs in the liver while avoiding central nervous system (CNS) effects, the project aims to offer a safe and effective therapeutic option for patients. This approach not only addresses the immediate need for NAFLD treatment but also holds potential for mitigating related conditions such as type 2 diabetes (T2D) and obesity, thereby alleviating the broader burden on healthcare systems.
The expected impact of the project extends beyond individual patient outcomes to encompass societal and economic benefits. By providing a novel therapeutic avenue for NAFLD, the project has the potential to reduce healthcare costs associated with managing NAFLD-related complications and improve overall public health. Moreover, by advancing personalized medicine and leveraging cutting-edge technology, the project sets a precedent for innovative approaches to tackling complex metabolic diseases, paving the way for future advancements in the field.
The project proposes a novel approach to target the endocannabinoid system (ECS) and cannabinoid-1 receptors (CB1Rs) in the liver, aiming to mitigate the development and progression of NAFLD. By leveraging groundbreaking nanometric drug delivery systems, the project seeks to peripheralize the action of CB1R blockers, specifically rimonabant, to minimize the risk of neuropsychiatric side effects while maximizing therapeutic efficacy. This innovative strategy holds immense promise for revolutionizing NAFLD treatment. By precisely targeting CB1Rs in the liver while avoiding central nervous system (CNS) effects, the project aims to offer a safe and effective therapeutic option for patients. This approach not only addresses the immediate need for NAFLD treatment but also holds potential for mitigating related conditions such as type 2 diabetes (T2D) and obesity, thereby alleviating the broader burden on healthcare systems.
The expected impact of the project extends beyond individual patient outcomes to encompass societal and economic benefits. By providing a novel therapeutic avenue for NAFLD, the project has the potential to reduce healthcare costs associated with managing NAFLD-related complications and improve overall public health. Moreover, by advancing personalized medicine and leveraging cutting-edge technology, the project sets a precedent for innovative approaches to tackling complex metabolic diseases, paving the way for future advancements in the field.
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.
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.
The project's completion has significant implications for NAFLD treatment, developing a novel drug delivery system targeting peripheral CB1Rs.
Key achievements include:
1. Innovative Delivery System: Successful development of stable PLGA-NPs loaded with rimonabant for precise liver targeting.
2. Hepatic Targeting and Safety: In vivo studies confirmed effective liver delivery while minimizing brain penetration, promising safe NAFLD treatment.
3. Pharmacokinetic Evaluations: Comprehensive PK evaluations provided insights for future clinical translation.
4. IP Strategy: Strong IP protection ensured potential commercialization and licensing agreements.
5. Commercialization Preparation: Collaboration with Yissum facilitated a robust commercialization strategy.
Potential Impacts:
1. Therapeutic Innovation: Promises to revolutionize NAFLD treatment by precisely targeting peripheral CB1Rs.
2. Commercialization Opportunities: Strong IP and industry engagement create pathways for commercial success.
3. Scientific Advancement: Advances drug delivery and cannabinoid pharmacology, enriching scientific knowledge.
Key Needs:
1. Further Research: Continued trials are essential for validating efficacy and safety.
2. Access to Resources: Funding and partnerships are crucial for scaling up and conducting trials.
3. Regulatory Compliance: Collaboration with regulatory agencies is vital for streamlined approval processes.
Key achievements include:
1. Innovative Delivery System: Successful development of stable PLGA-NPs loaded with rimonabant for precise liver targeting.
2. Hepatic Targeting and Safety: In vivo studies confirmed effective liver delivery while minimizing brain penetration, promising safe NAFLD treatment.
3. Pharmacokinetic Evaluations: Comprehensive PK evaluations provided insights for future clinical translation.
4. IP Strategy: Strong IP protection ensured potential commercialization and licensing agreements.
5. Commercialization Preparation: Collaboration with Yissum facilitated a robust commercialization strategy.
Potential Impacts:
1. Therapeutic Innovation: Promises to revolutionize NAFLD treatment by precisely targeting peripheral CB1Rs.
2. Commercialization Opportunities: Strong IP and industry engagement create pathways for commercial success.
3. Scientific Advancement: Advances drug delivery and cannabinoid pharmacology, enriching scientific knowledge.
Key Needs:
1. Further Research: Continued trials are essential for validating efficacy and safety.
2. Access to Resources: Funding and partnerships are crucial for scaling up and conducting trials.
3. Regulatory Compliance: Collaboration with regulatory agencies is vital for streamlined approval processes.