Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery

Abstract

Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases.Methods: Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes. For imaging applications, phospholipids modified with rhodamine and gadolinium were used. Leukosomes incubated with antibodies blocking lymphocyte function-associated antigen 1 (LFA-1) and CD45 were administered to explore their roles in targeting inflammation. In addition, relaxometric assessment of NPs was evaluated.Results: Liposomes and leukosomes were both spherical in shape with sizes ranging from 140-170 nm. Both NPs successfully integrated 8 and 13 µg of rhodamine and gadolinium, respectively, and demonstrated less than 4% variation in physicochemical features. Leukosomes demonstrated a 16-fold increase in breast tumor accumulation relative to liposomes. Furthermore, quantification of leukosomes in tumor vessels demonstrated a 4.5-fold increase in vessel lumens and a 14-fold increase in vessel walls. Investigating the targeting mechanism of action revealed that blockage of LFA-1 on leukosomes resulted in a 95% decrease in tumor accumulation. Whereas blockage of CD45 yielded a 60% decrease in targeting and significant increases in liver and spleen accumulation. In addition, when administered in mice with atherosclerotic plaques, leukosomes exhibited a 4-fold increase in the targeting of inflammatory vascular lesions. Lastly, relaxometric assessment of NPs demonstrated that the incorporation of membrane proteins into leukosomes did not impact the r1 and r2 relaxivities of the NPs, demonstrating 6 and 30 mM-1s-1, respectively.Conclusion: Our study demonstrates the ability of leukosomes to target activated vasculature and exhibit superior accumulation in tumors and vascular lesions. The versatility of the phospholipid backbone within leukosomes permits the incorporation of various contrast agents. Furthermore, leukosomes can potentially be loaded with therapeutics possessing diverse physical properties and thus warrant further investigation toward the development of powerful theranostic agents.

Ultra-sensitive Nanoprobe Modified with Tumor Cell Membrane for UCL/MRI/PET Multimodality Precise Imaging of Triple-Negative Breast Cancer

“…It may also be a potential method to achieve integration of diagnosis and treatment [35], as well as to monitor and evaluate therapeutic effects. In addition, apart from cancer cell membranes, various membrane functions, including chemotaxis of platelets to atherosclerotic plaque [25][26][27]36], chemotaxis of leukocytes to inflammation [37], phagocytosis of macrophages [38], and cancer-targeting capabilities of stem cells [39], have the potential to be used for targeting different lesions. We believe this field has promising application prospects.…”

Recent Advances in Understanding the Protein Corona of Nanoparticles and in the Formulation of “Stealthy” Nanomaterials

“…Leukocytes represent an almost ideal source since they are circulating cells, have still "self " proteins, but they also normally adhere to inflamed blood vessels, extravasate in the surrounding tissue, and interact with foreign bodies. Thus, the use of leukocytes can provide active targeting for inflammation, making the use of such coating highly valuable for a wide array of applications that range from tumors to chronic inflammatory states such as sepsis IBDs (Molinaro et al, 2016(Molinaro et al, , 2019Corbo et al, 2017a;Martinez et al, 2018).…”

Macrophage-Based Therapies for Atherosclerosis Management

“…Development of the macrophage targeting can enhance the targeted cargo (diagnostic imaging and antiinflammatory drugs) delivery to atherosclerotic lesions for diagnosis and therapy [101,102]. Martinez et al demonstrated the ability of rhodamine-labeled lipid films rehydrated with macrophage proteins targeting activated endothelia through CD11a and CD18, which both bind to ICAM-1 [103]. Due to the increased circulation time and homing capabilities, the platform may be loaded with therapeutics with diverse physical properties and hence show promise for use in magnetic resonance imaging applications.…”