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Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury
Qingyu Zhou1, Justin Doherty2, Antonina Akk3
1Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Abstract:
Cancer treatment-induced toxicities may restrict maximal effective dosing for treatment and cancer survivors' quality of life. It is critical to develop novel strategies that mitigate treatment-induced toxicity without affecting the efficacy of anti-cancer therapies. Rapamycin is a macrolide with anti-cancer properties, but its clinical application has been hindered, partly by unfavorable bioavailability, pharmacokinetics, and side effects. As a result, significant efforts have been undertaken to develop a variety of nano-delivery systems for the effective and safe administration of rapamycin. While the efficacy of nanostructures carrying rapamycin has been studied intensively, the pharmacokinetics, biodistribution, and safety remain to be investigated. In this study, we demonstrate the potential for rapamycin perfluorocarbon (PFC) nanoparticles to mitigate cisplatin-induced acute kidney injury with a single preventative dose. Evaluations of pharmacokinetics and biodistribution suggest that the PFC nanoparticle delivery system improves rapamycin pharmacokinetics. The safety of rapamycin PFC nanoparticles was shown both in vitro and in vivo. After a single dose, no disturbance was observed in blood tests or cardiac functional evaluations. Repeated dosing of rapamycin PFC nanoparticles did not affect overall spleen T cell proliferation and responses to stimulation, although it significantly decreased the number of Foxp3+CD4+ T cells and NK1.1+ cells were observed.
Insights
Rapamycin perfluorocarbon nanoparticles show promise in preventing cisplatin-induced kidney injury. This novel delivery system improves rapamycin pharmacokinetics and demonstrates safety in preclinical models.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- Cancer treatment toxicities limit drug dosage and impact quality of life.
- Rapamycin has anti-cancer properties but faces challenges with bioavailability and side effects.
- Nanodelivery systems are being explored to improve rapamycin administration.
Purpose of the Study:
- To investigate rapamycin perfluorocarbon (PFC) nanoparticles for mitigating cisplatin-induced acute kidney injury.
- To evaluate the pharmacokinetics, biodistribution, and safety of rapamycin PFC nanoparticles.
- To assess the impact of rapamycin PFC nanoparticles on immune cell populations.
Main Methods:
- Administration of rapamycin PFC nanoparticles as a preventative measure against cisplatin toxicity.
- Pharmacokinetic and biodistribution analyses of the nanoparticle delivery system.
- In vitro and in vivo safety assessments, including blood tests, cardiac function, and T cell proliferation assays.
Main Results:
- A single preventative dose of rapamycin PFC nanoparticles mitigated cisplatin-induced acute kidney injury.
- The PFC nanoparticle system enhanced rapamycin pharmacokinetics and biodistribution.
- Rapamycin PFC nanoparticles exhibited safety in vitro and in vivo, with no observed disturbances in blood or cardiac function after single dosing. Repeated dosing affected specific T cell populations and NK1.1+ cells.
Conclusions:
- Rapamycin PFC nanoparticles represent a potential strategy to reduce chemotherapy-induced toxicity, specifically acute kidney injury.
- The nanoparticle formulation improves rapamycin delivery and safety profile.
- Further research is warranted to fully understand the immunological effects of repeated dosing.
