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

Jonathan O. Martinez, Roberto Molinaro, Kelly A. Hartman, Christian Boada, Roman Sukhovershin, Enrica De Rosa, Dickson Kirui, Shanrong Zhang, Michael Evangelopoulos, Angela M. Carter, James A. Bibb, John P. Cooke, Ennio Tasciotti

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1131-1145
Number of pages15
JournalTheranostics
Volume8
Issue number4
DOIs
StatePublished - Jan 1 2018

Fingerprint

Biomimetics
Nanoparticles
Endothelium
Leukocytes
Blood Vessels
Lymphocyte Function-Associated Antigen-1
Phospholipids
Rhodamines
Gadolinium
Liposomes
Pharmaceutical Preparations
Membrane Proteins
Neoplasms
Tropism
Blocking Antibodies
Vascular Endothelium
Atherosclerotic Plaques
Chemokines
Contrast Media
Disease Progression

Keywords

  • Biomimetic
  • Endothelium
  • Inflammation
  • Leukocyte
  • Magnetic resonance imaging
  • Nanoparticles

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Martinez, J. O., Molinaro, R., Hartman, K. A., Boada, C., Sukhovershin, R., De Rosa, E., ... Tasciotti, E. (2018). Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery. Theranostics, 8(4), 1131-1145. https://doi.org/10.7150/thno.22078

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.

In: Theranostics, Vol. 8, No. 4, 01.01.2018, p. 1131-1145.

Research output: Contribution to journalArticle

Martinez, JO, Molinaro, R, Hartman, KA, Boada, C, Sukhovershin, R, De Rosa, E, Kirui, D, Zhang, S, Evangelopoulos, M, Carter, AM, Bibb, JA, Cooke, JP & Tasciotti, E 2018, 'Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery', Theranostics, vol. 8, no. 4, pp. 1131-1145. https://doi.org/10.7150/thno.22078
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. / Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery. In: Theranostics. 2018 ; Vol. 8, No. 4. pp. 1131-1145.
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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.",
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AU - Sukhovershin, Roman

AU - De Rosa, Enrica

AU - Kirui, Dickson

AU - Zhang, Shanrong

AU - Evangelopoulos, Michael

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