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

Martinez, Jonathan O

Molinaro, Roberto

Hartman, Kelly A

Boada, Christian

Sukhovershin, Roman

De Rosa, Enrica

Kirui, Dickson

Zhang, Shanrong

Evangelopoulos, Michael

Carter, Angela M

Bibb, James A

Cooke, John P

Tasciotti, Ennio

2019-12-27T21:57:45Z

2019-12-27T21:57:45Z

2018-01-05

2019-12-27T21:57:44Z

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.

thnov08p1131

1838-7640

1838-7640

https://hdl.handle.net/10161/19658

eng

Ivyspring International Publisher

Theranostics

10.7150/thno.22078

Endothelium, Vascular

Leukocytes

Animals

Mice

Neoplasms

Vascular Diseases

Gadolinium

Rhodamines

Phospholipids

Membrane Proteins

Drug Carriers

Fluorescent Dyes

Staining and Labeling

Protein Binding

Biomimetic Materials

Nanoparticles

Theranostic Nanomedicine

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

Journal article

1131

1145

4

Staff

Duke

Medicine, Nephrology

Medicine

Clinical Science Departments

School of Medicine

Published

8