Development of Dextran-Coated Magnetic Nanoparticles Loaded with Protocatechuic Acid for Vascular Inflammation Therapy

Vascular inflammation plays a crucial role in the progression of various pathologies, including atherosclerosis (AS), and thus it has become an attractive therapeutic target. The protocatechuic acid (PCA), one of the main metabolites of complex polyphenols, is endowed with anti-inflammatory activity, but its formulation into nanocarriers may increase its bioavailability. In this study, we developed and characterized dextran shell‒iron oxide core nanoparticles loaded with PCA (MNP-Dex/PCA) and assessed their cytotoxicity and anti-inflammatory potential on cells acting as key players in the onset and progression of AS, namely, endothelial cells (EC) and monocytes/macrophages. The results showed that MNP-Dex/PCA exert an anti-inflammatory activity at non-cytotoxic and therapeutically relevant concentrations of PCA (350 μM) as supported by the reduced levels of inflammatory molecules such as MCP-1, IL-1β, TNF-α, IL-6, and CCR2 in activated EC and M1-type macrophages and functional monocyte adhesion assay. The anti-inflammatory effect of MNP-Dex/PCA was associated with the reduction in the levels of ERK1/2 and p38-α mitogen-activated protein kinases (MAPKs) and NF-kB transcription factor. Our data support the further development of dextran shell-magnetic core nanoparticles as theranostic nanoparticles for guidance, imaging, and therapy of vascular inflammation using PCA or other anti-inflammatory compounds.

Computational modeling of virucidal inhibition mechanism for broad-spectrum antiviral nanoparticles and HPV16 capsid segments

Solid core nanoparticles coated with sulfonated ligands that mimic heparan sulfate proteoglycans (HSPG) can exhibit virucidal activity against many viruses that utilize HSPG interactions with host cells for the initial stages of the infection. How the interactions of these nanoparticles with large capsid segments of HSPG-interacting viruses lead to their virucidal activity has been unclear. Here, we describe the interactions between sulfonated nanoparticles and segments of the human papilloma virus type 16 (HPV16) capsids using atomistic molecular dynamics simulations. The simulations demonstrate that nanoparticles primarily bind at interfaces of two HPV16 capsid proteins. Insertions of nanoparticles at these interfaces leads to increased separation in distances and angles between capsid proteins. As the time progresses, the nanoparticle binding can lead to breaking of contacts between two neighboring proteins. The revealed mechanism of nanoparticles targeting the interfaces between pairs of capsid proteins can be utilized for designing new generations of virucidal materials and contribute to the development of new broad-spectrum non-toxic virucidal materials.Abstract Figure

Little things make big things happen

Iron core nanoparticles can serve as vesicle shuttles and be guided by external magnetic fields to deliver therapeutic exosomes to injured tissue.

Abstract 13025: Methotrexate Carried in Lipid Core Nanoparticles Prevented the Dilation and Dissection of the Aortic Arch in Mice With Marfan Syndrome by Increasing the Bioavailability of Intracellular Adenosine

Introduction: Mutations in the fibrillin-1 gene result in aneurysms and rupture of the aorta, the main cause of mortality in patients with Marfan syndrome (MFS). Inflammation is associated with dissection and rupture of the aorta. We showed that methotrexate (MTX) carried in lipid core nanoparticles (LDE) had powerful anti-inflammatory effects on atherosclerotic lesions and myocardial infarction. Hypothesis: To investigate whether treatment with LDE-MTX can prevent the development of aortic arch lesions in MFS. Methods: mgΔloxPneo MFS murine model and wild-type mice were allocated in 3 groups of treatment: LDE only; MTX in commercial formulation; LDE-MTX. The treatment occurred weekly at a dose of 1mg/kg ip, between the 3rd and 6th month of life, period in which both dilation and dissection of the aortic arch are observed. After 12 weeks, animals were submitted to analysis of the aortic arch. Results: Compared to LDE and MTX groups, LDE-MTX treatment showed smaller lumen area of ascending and descending aorta and aortic arch segments in MFS mice. LDE-MTX also decreased collagen volume fraction and the amount of aortic dissections, but did not affect the thickness of the vessel wall and the number of elastic fiber ruptures. Protein expression of the inflammatory markers CD68 (macrophages), CD3 (lymphocytes) and tumor necrosis factor alpha, of the apoptotic marker caspase 3 and of type 1 collagen were lower in LDE-MTX group when compared to LDE and MTX. Moreover, treatment with LDE-MTX reduced TGF-β, ERK and SMAD3 protein expression. Of note, CD68 and CD3 protein expression were positively correlated with the lumen area of the aortic arch (r2=0.36; p<0.001), indicating the importance of inflammation for the aortic dilation. The increase in bioavailability of intracellular adenosine was suggested by higher expression of A2a adenosine receptor and lower levels of adenosine deaminase in the aortic arch. Conclusions: Possibly by increasing the bioavailability of intracellular adenosine, LDE-MTX treatment had the ability to reduce the processes of inflammation, apoptosis and fibrosis that are consequent to fibrillin-1 mutation. By these means, LDE-MTX may conceivably prevent the development of the dilation and dissection in the aortic arch, the hallmarks of MFS.

Daunorubicin associated to lipid core nanoparticles reduces atherosclerotic lesions, inflammation and cardiotoxicity in atherosclerosis rabbit model

Introduction Antiproliferative agents used in cancer chemotherapy have low toxicity and increased pharmacological action when carried into lipid core nanoparticles (LDE). LDE has similar structure to LDL and binds to LDL receptors through apo E it acquires in contact with plasma. Previously, we showed that treatment of rabbits with atherosclerosis with drugs such as taxanes and etoposide associate to LDE had pronounced reduction of the atherosclerotic lesions. In this study, we hypothesized whether daunorubicin (DNR) that belongs to another class of anti-cancer drugs, with a distinct mechanism of action and that has strong cardiotoxicity could also have effects against atherosclerosis. Methods Sixteen New Zealand male rabbits were fed with a 1% cholesterol diet for 8 weeks to induce atherosclerosis. After 4 weeks, the animals were treated weekly with LDE-DNR (6mg/kg, iv, n=9) or with LDE only (n=7). In addition, 3 animals without any intervention were used as a control group. Chow consumption, lipid and hematological profiles, body weight, and echocardiography were evaluated at baseline, pre-treatment and post-treatment. Morphometry and protein expression were performed to analyze the aortas. Results There was no difference in food intake and body weight for control, LDE and LDE-DNR groups. Total cholesterol, HDL-C, non-HDL-C and triglycerides increased in LDE and LDE-DNR groups when comparing baseline and post-treatment. Red blood cells decreased in LDE group at post-treatment in comparison to baseline, while LDE-DNR presented no such difference. Regarding aortic lesions of LDE-DNR group was 50% lower than LDE group. The protein expression of the inflammatory markers CD68, TNF-α and IL-6 in LDE-DNR was lower than LDE. Pro-apoptotic factors caspase 3, caspase 9 and BAX were also lower in LDE-DNR compared to LDE. Protein expression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule (VCAM) was lower in the LDE-DNR group when compared to the LDE group. To test the cardiotoxicity of LDE-DNR, echocardiography was performed and observed that under LDE-DNR both systolic and diastolic function were preserved with no difference in cardiac mass in LDE-DNR when compared to control and LDE groups. However, LDE showed a significant increase in relative heart weight compared to control while LDE-DNR had no such difference. Treatment with LDE-DNR did not induce observable hematological toxicity. Conclusion The treatment with LDE-DNR reduced aortic lesions, diminished inflammatory and pro-apoptotic factors, diminished VCAM expression in the aorta and promoted cardiac preservation in a rabbit atherosclerosis model. In conclusion, LDE-DNR can be eligible for future developments in the quest for novel effective and safe treatments for atherosclerosis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): FAPESP (Fundaçao de Amparo a Pesquisa do Estado de Sao Paulo)