Use of paclitaxel carried in lipid nanoparticles to treat aortic allograft transplantation in rats

Abstract

Objectives The aim of this study was to test whether lipid core nanoparticles loaded with paclitaxel (LDE-PTX) protect rat aortic allograft from immunological damage. Methods Fisher and Lewis rats were used differing in minor histocompatibility loci. Sixteen Lewis rats were allocated to four-animal groups: SYNG (syngeneic), Lewis rats receiving aorta grafts from Lewis rats; ALLO (allogeneic), Lewis rats receiving aortas from Fisher rats; ALLO+LDE (allogeneic transplant treated with LDE), Lewis rats receiving aortas from Fisher rats, treated with LDE (weekly injection for 3 weeks); ALLO+LDE-PTX (allogeneic transplant treated with LDE-PTX), Lewis rats receiving aortas from Fisher rats treated with LDE-PTX (4 mg/kg weekly for 3 weeks). Treatments began on transplantation day. Results Thirty days post-transplantation, SYNG showed intact aortas. ALLO and ALLO+LDE presented intense neointimal formation. In ALLO+LDE-PTX, treatment inhibited neointimal formation; narrowing of aortic lumen was prevented in ALLO and ALLO+LDE. LDE-PTX strongly inhibited proliferation and intimal invasion by smooth muscle cells, diminished 4-fold presence of apoptotic/dead cells in the intima, reduced the invasion of aorta by macrophages and T-cells and gene expression of pro-inflammatory tumour necrosis factor-alpha (TNFα), interferon gamma (IFNγ) and interleukin-1 beta (IL-1β). Conclusions LDE-PTX was effective in preventing the vasculopathy associated with rejection and may offer a potent therapeutic tool for post-transplantation.

Use of paclitaxel carried in solid lipid nanoparticles to prevent peritoneal fibrosis in rats

“…In our study, as expected, the induction of fibrosis in rats promoted the increase of gene expression of the pro-fibrotic markers fibronectin, FSP-1, TGF-β, SMAD3 and VEGF, that favours angiogenesis and thereby assists the perfusion of the newly formed fibrotic tissue [12,13,19]. It is noteworthy that LDE-PTX treatment pronouncedly diminished the gene expression of all those molecular factors, thus interfering with diverse mechanisms of fibrogenesis.…”

“…It is remarkable that, when associated with LDE, PTX toxicity is practically diminished: the 50% lethal dose (LD50) of LDE-PTX is roughly tenfold higher than that of conventional PTX [16]. Observable toxicity was nearly absent in experimental animal models of atherosclerosis [18,31], cancer [16,32], heart [33], and aorta [19] transplantation, in mice, rats, rabbits and monkeys [34]. In clinical trials enrolling patients with advanced cancers [17,20,21] and cardiovascular disease [22], no clinical or laboratorial toxicities were observed at the 175 mg/m 2 body surface triweekly dose used in those studies.…”

“…The ability of LDE to drastically reduce the toxicity of PTX was shown not only in studies in experimental animals [16,18,19], but also in patients with advanced cancers [17,20,21] and patients with cardiovascular disease [22]. LDE-PTX association was shown stable in the bloodstream of animals and human patients and the pharmacological action is enhanced by this formulation compared with the commercial formulation of PTX in which this agent is carried with Cremophor EL [16].…”

Bases celulares e efeitos do tratamento com metotrexato associado a nanopartículas lipídicas sobre as alterações cardiovasculares da endotoxemia induzida por LPS em ratos

“…Esse efeito pode estar relacionado ao papel controverso do receptor A3 de adenosina em sua contribuição para a resposta inflamatória, sendo capaz de diminuir apoptose de células inflamatórias e, por outro lado, capaz de diminuir TNF-α, IFN-γ e IL-12, pela via de sinalização celular da via de quinases ERK 1/2 (Salvatore et al, 2000). Em alguns de nossos estudos anteriores, a LDEMTX reduziu a expressão de citocinas pró-inflamatórias em modelos experimentais (Barbieri et al, 2017;Bulgarelli et al, 2013;Pepineli et al, 2021). No entanto, os resultados aqui apresentados não foram suficientes para descrever uma relação entre a modulação de processo inflamatório e a melhora da função cardíaca nos animais LPS-LDEMTX, sendo necessário realizar estudos adicionais para esta compreensão, como a análise de expressão de microRNAs envolvidos na regulação da expressão gênica e inibição da tradução proteica destas interleucinas.…”