Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury

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.

Rapamycin Perfluorocarbon Nanoparticle Mitigates Cisplatin-Induced Acute Kidney Injury

“…The hydrophobic lipid monolayer of PFC NP could also serve as a carrier for a hydrophobic drug such as rapamycin, which can be stably dispersed and retained in the lipid monolayer of PFC NP. Our previous studies demonstrated that the pharmacokinetics (PK) of rapamycin-loaded PFC NP measured by blood content of rapamycin [ 26 ] agreed with that measured by 19 F MRS [ 76 ], which confirmed the stability of rapamycin PFC NP in circulation required to enable sustained local drug delivery. This current demonstration of therapeutic efficacy for mitigating cisplatin-induced acute kidney injury suggests a new formulation and use for an approved agent, rapamycin, to facilitate chemotherapy in patients requiring cisplatin.…”

“…Perfluorocarbon is a safe, effective, and flexible theranostic tool that has been approved for clinical use as a blood substitute [ 67 , 68 ] as well as in angioplasty [ 69 ] and retinal hemorrhage [ 70 ]. Our recently published work also demonstrated the favorable safety profile of rapamycin PFC NP [ 26 ]. PFC NP is composed of a hydrophobic PFC core and surrounding lipid monolayer [ 71 , 72 ].…”

“…Rapamycin can also suppress downstream inflammation through inhibition of mTORC1 [ 21 , 22 , 23 , 24 , 25 ]. In a previous study of mild kidney injury induced by injecting cisplatin at 10 mg/kg, we observed that rapamycin PFC NP outperformed free rapamycin in protecting renal function at 48 h [ 26 ]. Here, we sought to define the potential utility of rapamycin PFC NP in mitigating more severe acute kidney injury induced by cisplatin treatment at 25 mg/kg.…”

Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1

“…Genetic approaches using conditional knock-out of Atg5 or Atg7 in tubular cells revealed worsened AKI following cisplatin exposure in vivo [ 20 , 37 , 38 ]. Accordingly, the activation of autophagy, e.g., by rapamycin, showed a protective effect against cisplatin-induced renal deterioration [ 39 , 40 ]. Mechanistically, the protective effect of autophagy might be related to its role in mitochondrial renewal since mitochondria are particularly targeted in cisplatin toxicity [ 41 ].…”