Treatment of Graft Vascular Disease with paclitaxel-loaded lipid nanoparticles: effects on inflammatory markers and plasma lipids, functional aspects of HDL, and serum MicroRNAs

Abstract

In previous studies, we demonstrated that lipid nanoparticles with a lipid structure similar to low-density lipoprotein (LDL), termed LDL-like nanoparticles (LDE), accumulate in transplanted rabbit hearts. When rabbits with cardiac transplants, a model of graft vascular disease (GVD), were treated with the chemotherapeutic agent paclitaxel associated with LDE, there was a notable reduction in coronary artery stenosis and preservation of vessels, alongside a marked reduction in the inflammatory process, a central cause in the genesis of GVD. Previously, it had been shown in patients with advanced cancer and aortic atheromas that LDE-paclitaxel formulation drastically reduces the toxicity of this drug, making it well-tolerated and safe. GVD is the leading cause of heart transplant failure, and currently, no effective treatment for the disease is available. The aforementioned results in rabbits with cardiac transplants and the safety of LDE-paclitaxel demonstrated in clinical studies led us to propose the use of LDE-paclitaxel in treating patients with cardiac transplants and GVD. In a project already approved by the Ethics Committee, treatment will be evaluated using intravascular ultrasound (IVUS) imaging, performed before treatment initiation, one month after, and one year after treatment initiation. In addition to imaging studies, an in-depth study of factors causing or exacerbating GVD, such as the inflammatory process and disturbances in lipid metabolism, as well as factors related to circulating microRNAs, is necessary. PRIMARY OBJECTIVE: Evaluate the effect of LDE-paclitaxel treatment on serum concentrations of inflammatory markers and circulating microRNAs, and on HDL functionality in patients with GVD. SECONDARY OBJECTIVE: Correlate data on inflammatory markers and microRNAs with radiological imaging data obtained from patients. METHODS: Prospective, single-center, double-blind, randomized, placebo-controlled study. Twenty patients with GVD will be allocated in a 1:1 ratio to either the LDE-paclitaxel treatment group or the placebo group (treated with LDE solution without paclitaxel). Patients will receive treatment every 3 weeks for 18 weeks (total of 6 three-week cycles) with paclitaxel associated with LDE at a dose of 175 mg/m2 of body surface area, administered via 120-minute intravenous infusion. Serum concentrations of inflammatory markers and circulating microRNAs will be determined before treatment, one month after the last dose, and one year after treatment initiation. (AU)