Biodegradable polymeric nanoparticles increase risk of cardiovascular diseases by inducing endothelium dysfunction and inflammation.

Biodegradable polymers are expected to be an alternative to plastics. Because of its high biocompatibility, poly (lactic-co-glycolic acid) (PLGA) is widely used in medicine. It has been reported that micro-nano plastics can be accumulated in the circulatory system and cause tissue injury. With the increasing environmental exposure of degradable polymer nanoparticles (NPs), the impact of this risk factor on cardiovascular disease deserves attention. Thus, we aim to study the harmful effect of PLGA NPs on the process of vascular stenosis which is a typical pathological feature of cardiovascular diseases. We establish a mouse vascular stenosis model with intravenously injecting of PLGA NPs for 2 weeks. This model leads to a significant narrowing of the left common carotid artery which is characterized by the increasing intima area and focal stenosis. We observe that PLGA NPs accelerate stenosis progression by inducing inflammation and impairing vascular function. It promotes the proliferation of smooth muscle cells and causes abnormal collagen distribution. The combination of wall shear stress and PLGA NPs uptake speed up endothelial cell damage, decrease endothelial permeability and cell migration capacity. Our results suggest that PLGA NPs may pose a risk in cardiovascular stenosis which inspire us to concern the biodegradable polymeric materials in our living especially the clinic applications.

Phagocytosis of polymeric nanoparticles aided activation of macrophages to increase atherosclerotic plaques in ApoE-/- mice.

The unique physiochemical properties of nanomaterials have been widely used in drug delivery systems and diagnostic contrast agents. The safety issues of biomaterials with exceptional biocompatibility and hemo-compatibility have also received extensive attention at the nanoscale, especially in cardiovascular disease. Therefore, we conducted a study of the effects of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) on the development of aortic atherosclerotic plaques in ApoE-/- mice. The particle size of PLGA NPs was 92.69 ± 3.1 nm and the zeta potential were - 31.6 ± 2.8 mV, with good blood compatibility. ApoE-/- mice were continuously injected with PLGA NPs intravenously for 4 and 12 weeks. Examination of oil red O stained aortic sinuses confirmed that the accumulation of PLGA NPs caused a significantly higher extension of atherosclerotic plaques and increasing the expression of associated inflammatory factors, such as TNF-α and IL-6. The combined exposure of ox-LDL and PLGA NPs accelerated the conversion of macrophages to foam cells. Our results highlight further understanding the interaction between PLGA NPs and the atherosclerotic plaques, which we should consider in future nanomaterial design and pay more attention to the process of using nano-medicines on cardiovascular diseases.

Crosstalk between arterial components and bioresorbable, 3-D printed poly-L-lactic acid scaffolds.

Bioresorbable scaffolds (BRSs) are designed to provide a temporary support that subsequently leaves behind native vessels after its complete degradation. The accumulation of mechanical changes influences the vascular histological characteristics and vice versa, leading to crosstalk and various behaviors in BRSs in different arterial components, which is different from that observed in traditional metal stents. Hence, we analyzed typical elastic and muscular arteries, the abdominal aorta of Sprague-Dawley rats and carotid arteries of New Zealand rabbits, after both received 3-D printed poly-L-lactic acid BRSs. We observed a lower level of scaffold degradation and severe intimal hyperplasia in the carotid arteries of rabbits because of the synthetic phenotypic transformation of vascular smooth muscle cells (SMCs) and endothelial-to-mesenchymal transition of endothelial cells (ECs). Extracellular matrix remodeling and endothelial repair occurred in a less rapid manner in the abdominal aorta of rats. These results suggest that muscular arterial components such as SMCs and ECs are more sensitive to BRS degradation-induced mechanical changes compared to those of elastic arteries. Therefore, the rat abdominal aorta might be more suitable for assessing BRS degradation and safety, while the carotid artery of rabbits could be used to evaluate drug coatings on BRSs, as it closely reflects the recovery of ECs and proliferation of SMCs. Our study also confirmed that the histological characteristics of vasculature should be considered while choosing an animal model for BRS evaluation.

Penetration of the blood-brain barrier and the anti-tumour effect of a novel PLGA-lysoGM1/DOX micelle drug delivery system.

Effective treatment of glioma and other central nervous system (CNS) diseases is hindered by the presence of the blood-brain barrier (BBB). A novel nano-delivery vehicle system composed of PLGA-lysoGM1/DOX micelles was developed to cross the BBB for CNS treatment. We have shown that doxorubicin (DOX) as a model drug encapsulated in PLGA-lysoGM1 micelles can achieve up to 3.8% loading efficiency and 61.6% encapsulation efficiency by the orthogonal test design. Our in vitro experiments demonstrated that PLGA-lysoGM1/DOX micelles had a slow and sustainable drug release under physiological conditions and exhibited a high cellular uptake through the macropinocytosis and the autophagy/lysosomal pathways. In vivo experimental studies in zebrafish and mice confirmed that PLGA-lysoGM1/DOX micelles could cross the BBB and be specifically accumulated in the brain. Moreover, an excellent anti-glioma effect was observed in intracranial glioma-bearing rats. Therefore, PLGA-lysoGM1/DOX micelles not only effectively can cross the BBB, but our results also suggest that they have great potential for anti-glioma therapy and other central nervous system diseases.

An asymmetrical dual coating on the stent prepared by ultrasonic atomization.

This study aims to design an asymmetric dual coating (ADC) on the stent by ultrasonic atomization to solve the problem of delayed endothelialization and late or very late stent thrombosis which caused by drug eluting stent (DES) with symmetric coating. Chitosan-loaded monoclonal platelet glycoprotein IIIa receptor antibody SZ-21 coating (CSC) was sprayed on inner surface of stents, and outer surface was sprayed CSC and poly(lactic-co-glycolic acid) (PLGA) loaded with docetaxel (DTX) coating (PDC). The coated surface was uniform without aggregation and no shedding phenomenon either before or after stent expanded. Fluorescence labeling has confirmed that the coating has an asymmetric structure. The cumulative release for SZ-21 and DTX was 40.11% and 27.22% within first 24 h, then DTX became the major released drug from 24 h to 7 d, after released for 28 d about 40% of the SZ-21 and 50% DTX still remained on the coated stent. It achieved that ADC can inhibit thrombosis at earlier period and inhibit vascular smooth muscle cells (VSMCs) proliferation at later period. And that ADC has good hemocompatibility and can significantly inhibit VSMCs proliferation. Finally, 4 and 12 weeks after the stent with ADC implanted into rabbit carotid arteries, it showed that the stent with ADC was safe and could effectively prevent thrombosis and in-stent restenosis. © 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 825-837, 2019.

Design, preparation and performance of a novel drug-eluting stent with multiple layer coatings.

Drug-eluting stents (DESs) can effectively control the harmful effects of coronary artery disease, because of their excellent ability to reduce in-stent restenosis. However, delayed re-endothelialization and late stent thrombosis have caused concern over the safety of DESs. In this study, according to time-ordered pathological responses after stent implantation, a hierarchical multiple drug-eluting stent was designed and prepared to overcome the existing DES limitations. A platelet membrane glycoprotein IIIa monoclonal antibody (SZ-21) and a vascular endothelial growth factor (VEGF121) were loaded into the inner coating of 316L stainless steel (316L SS) stents to inhibit thrombosis and promote re-endothelialization; rapamycin (RAPA) was loaded into the third layer to inhibit intima hyperplasia; a drug-free poly-l-lactic acid coating was located on the second and fourth layers and used as sustained release layers. The results showed that the three drugs exhibited sequential release kinetics without significant burst release. RAPA released quickly at the early stage, while SZ-21 and VEGF121 achieved a slow and prolonged release. In vitro experiments showed that the stents had excellent hemocompatibility and anti-inflammatory properties, and promoted the proliferation and migration of endothelial cells while inhibiting the proliferation and migration of smooth muscle cells. Finally the stents were implanted in the carotid arteries of New Zealand white rabbits. In vivo results showed that compared to 316L SS stents, the multiple drug-eluting stents could accelerate re-endothelialization and inhibit thrombosis, inflammation and in-stent restenosis after 4 weeks (12.79 ± 2.45% vs. 25.27 ± 4.81%) and 12 weeks (15.87 ± 3.62% vs. 58.84 ± 6.87%). These results indicate that the novel drug-eluting stent with multiple layer coatings will have a highly potential clinical application.