Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

Abstract

OBJECTIVE:The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis.METHODS:This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed.RESULTS:The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group.CONCLUSION:Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Targeted Delivery of Bioactive Molecules for Vascular Intervention and Tissue Engineering

“…These qualities are determined by the nanoparticle size ( Walkey et al, 2012 ; Tan et al, 2013 ), surface properties ( Walkey et al, 2012 ), particle geometry ( Tan et al, 2013 ), shear stress and flow rate in the blood vessel ( Klingberg et al, 2015 ), and drug release kinetics ( Panyam and Labhasetwar, 2004 ). Many different materials have been used for fabricating drug-eluting nanoparticles, including synthetic polymers [reviewed in ( Wang et al, 2016 )], lipoproteins [reviewed in ( Damiano et al, 2013 ; Harisa and Alanazi, 2014 )], lipids ( Shiozaki et al, 2016 ), and metals ( Weakley et al, 2011 ). Different materials and design criteria may be needed depending on the type of drug to be released, and the intended target of the nanoparticle.…”

“…Intravenously injected lipid nanoparticles loaded with the drug carmustine successfully decreased lesion area by reducing SMC proliferation, secretion of inflammatory factors, and macrophage burden in rabbits ( Daminelli et al, 2016 ). Shiozaki et al (2016) recently published a pilot clinical study where cholesterol-rich non-protein nano-emulsion (LDE) particles, which resemble low-density lipoproteins, were loaded with paclitaxel oleate. When delivered systemically via intravenous injection, the nanoparticles were able to reduce total plaque in patients, though the difference was not significant ( Shiozaki et al, 2016 ).…”

“… Shiozaki et al (2016) recently published a pilot clinical study where cholesterol-rich non-protein nano-emulsion (LDE) particles, which resemble low-density lipoproteins, were loaded with paclitaxel oleate. When delivered systemically via intravenous injection, the nanoparticles were able to reduce total plaque in patients, though the difference was not significant ( Shiozaki et al, 2016 ).…”

Efeito do tratamento crônico do metotrexato associado à nanoemulsão de LDE no remodelamento cardíaco por infarto do miocárdio em ratos Wistar

“…Em trabalhos subsequentes, foi demonstrado que outro quimioterápico associado à LDE, o etoposídeo, também reduziu as lesões ateroscleróticas em coelhos em 85% (Tavares et al, 2011). Em pacientes com doença arterial coronária e aterosclerose, também foi observado que a LDE é captada por segmentos arteriais e reduziu as lesões ateroscleróticas (Couto et al, 2003;Shiozaki et al, 2016).…”

Uso de nanopartícula lipídica como veículo do quimioterápico docetaxel no tratamento da aterosclerose induzida em coelhos

“…A associação do paclitaxel à LDE praticamente elimina a toxicidade clínica e laboratorial desta droga, como demonstrado em animais experimentais e em estudos com pacientes com cânceres avançados. A viabilidade e segurança do tratamento com esta formulação também foi comprovada em um estudo piloto envolvendo pacientes com ateromas aórticos (Maranhão et al, 2008;Shiozaki et al, 2016;Graziani et al, 2017).…”