Endothelial nanomedicine aims to target drugs to endothelial cells, which line the circulatory system. This targeted approach could help treat diseases by restoring endothelial function, boosting antioxidant defenses in endothelial cells, and delivering drugs specifically to inflamed cerebrovascular endothelial cells. The speaker argues that endothelial nanomedicine may revolutionize emergency medicine in the next 5-10 years by changing outcomes for diseases where endothelial injury is a key driver of pathology, such as ischemia-reperfusion injury and conditions involving hemorrhage, edema, inflammation, and secondary thrombosis.

1. Endothelial Nanomedicine:
A coming revolution for EM
Colin F. Greineder MD PhD
Assistant Professor
Departments of Emergency Medicine
Department of Pharmacology
BioInterfaces Institute
University of Michigan
November 16, 2018
What the heck is it and why Colin might sell me on it over the
next 5-10 years
Disclosures:
None

2. Endothelial cells
• Thin layer of cells which line the entire circulatory system
• The largest organ system in the body (> 1012 cells)
• Approximately the area of a football field!
glycocalyx

3. A “multi-functional vascular interface”
1. Maintain blood fluidity
2. Barrier function
3. Control blood flow
4. Regulate cellular adhesion
(immune response)
Our whole
blood
microvessel
perfusion
model

4. What happens when the multi-functional endothelium
stops functioning…?
Quiescent“Dysfunctional”
Quiescent
Activated

5. That’s great… but why should I care?
Alveolar
”Flooding”
Neutrophil
Transmigration
Interstitial edema
(↓↓ compliance)
In some conditions, endothelial injury/dysfunction
is the key pathophysiology

6. Neurons are injured by ischemia & reperfusion
So are ECs…
We’ve tried (unsuccessfully) for decades to deliver neuroprotective
drugs across the BBB… maybe we don’t need to…?!?
↓ edema
↓ inflammation
↓ 2° thrombosis
Neurons are injured by Hgb, heme,
and oxidative stress…
So are ECs...
Could you change outcomes in your
disease of interest if you could:

7. Endothelial-targeted drug delivery:
3 quick examples
I. Restoring the anticoagulant phenotype of the endothelium
ATIII
Pg Plasmin
tPA
Thr TM
Thr
PC
APC
Thr
EPCR
PC APC
APC
tPA
Pg
Plasmin
EPCR
APC
PECAM-1
Greineder CF et al FASEBJ 2015
Greineder CF* et al Blood Adv 2017
Greineder CF et al Blood 2013
Greineder CF et al PLoS One 2013
Dysfunctional
Dysfunctional + TM-R6.5

8. II. Boosting EC antioxidant defense through artificial peroxisomes
GreinederCFetalJControlRelease2016
GreinederCFetalBioconjChem2017
Peroxisome – a
membrane bound
organelle containing
many of the
antioxidant
enzymes within the
cell
-mVCAM-1
VHH-DBCO
SOD-azide
VHH-SOD
b c
0 10 20 30
0
50000
100000
150000
200000
250000
REN-VCAM
REN-WT
Concentration (nM)
MedianFluorescenceIntensity
0
0
100000
200000
300000
400000
MedianFluorescenceIntensity
Naive Untargeted Control
KD = 2.77  0.27 nM
Endothelial cell
Neo-
peroxisome

9. Targeting is predominantly endothelial, even in diseased animals
III. Delivering liposomal nanocarriers to inflamed
cerebrovascular endothelial cells
Greineder CF* et al Nat Biomed Eng In press
1uL TNF-𝜶
Immunoliposomes

10. Thank you!
Questions?
Muzykantov Lab:
• Vladimir R. Muzykantov
• Ron Carnemolla
• Carlos H. Villa
• Raisa Kiseleva
• Makan Khoshnejad
• Oscar Marcos-Contreras
• Patrick Glassman
Greineder Lab:
• Landis Walsh
• Boya Zhang
Collaborators:
• Mortimer Poncz (CHOP)
• Charles Esmon (OMRF)
• Yuri Persidsky (Temple)
Funding:
• AHA (10FTF4150053)
• NHLBI (K08-HL130430)
• SAEM Foundation
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