Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage

Reyes-Esteves, Sahily; Nong, Jia; Glassman, Patrick M.; Omo-Lamai, Serena; Ohashi, Sarah N; Myerson, Jacob W.; Zamora, Marco; Ma, Xiaonan; Kasner, Scott E.; Sansing, Lauren H; Muzykantov, Vladimir R.; Marcos‐Contreras, Oscar A.; Brenner, J.

doi:10.1016/j.jconrel.2023.02.037

Cited by 19 publications

(13 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In general, direct targeting of the blood–brain barrier via transferrin receptor results in low levels of tissue uptake (≤1%ID/g) and no specificity for sites of injury. , In the present work and in our recent publications, we describe the use of CAM targeting to provide specific delivery to the injured brain. We achieved high levels (∼4%ID/g) of delivery to the brain by targeting to PECAM in the brain; however, similar to targets such as transferrin receptor, PECAM does not provide specificity for injured regions . We have recently reported studies of targeting to the brain in the same injury model described here (TNF-α), but with injection of targeting ligands occurring the day after injury (rather than 2 h postinjury in this study).…”

Section: Discussionmentioning

confidence: 76%

“…Targeted drug delivery to the brain promises breakthroughs in treatment of debilitating and lethal pathologies, including stroke, traumatic brain injury, glioblastoma and other brain tumors, meningitis, and neurodegenerative diseases. , Various carriers with distinct chemistry, geometry, mechanical flexibility, and affinity have been devised to achieve this elusive goal. − One approach to enhancing delivery employs targeting to and across the cerebral vasculature using antibodies, peptides, and other ligands of molecules that are stably expressed on the luminal surface of brain vessels. However, targeting these molecules, including receptors for transferrin, insulin, and growth factors, does not provide selectivity for sites of injury and inflammation. , In order to achieve enhanced specificity for injured regions of the brain, targeting inducible cell adhesion molecules (CAMs) expressed on endothelial cells, such as vascular CAM (VCAM), − has been tested and has shown improved delivery and pharmacologic effects. Despite these inroads, direct, specific delivery to the parenchyma of the injured region of the brain remains an elusive goal.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain

et al. 2023

Self Cite

View full text Add to dashboard Cite

Ex vivo-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven in vivo loading of WBC in order to bypass the need for ex vivo WBC manipulation. We used a mouse model of acute brain inflammation caused by local injection of tumor necrosis factor alpha (TNF-α). We intravenously injected nanoparticles targeted to intercellular adhesion molecule 1 (anti-ICAM/NP). We found that (A) at 2 h, >20% of anti-ICAM/NP were localized to the lungs; (B) of the anti-ICAM/NP in the lungs >90% were associated with leukocytes; (C) at 6 and 22 h, anti-ICAM/NP pulmonary uptake decreased; (D) anti-ICAM/NP uptake in brain increased up to 5-fold in this time interval, concomitantly with migration of WBCs into the injured brain. Intravital microscopy confirmed transport of anti-ICAM/NP beyond the blood–brain barrier and flow cytometry demonstrated complete association of NP with WBC in the brain (98%). Dexamethasone-loaded anti-ICAM/liposomes abrogated brain edema in this model and promoted anti-inflammatory M2 polarization of macrophages in the brain. In vivo targeted loading of WBC in the intravascular pool may provide advantages of coopting WBC predisposed to natural rapid mobilization from the lungs to the brain, connected directly via conduit vessels.

show abstract

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, nanocarriers are easily recognized by phagocytes once entering the blood stream and accumulate in the liver and spleen. Our lab has extensively studied the comparison of antibody vs. nanocarriers in various animal models of acute injuries, and have previously found other pathologies (e.g., acute lung injury) that dramatically change the pharmacokinetics profiles of antibodies and nanocarriers [ 21 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…We first showed VCAM-1-based targeting to the brain is greatly augmented in a mouse model of acute neurovascular inflammation [ 21 ]. More recently, we showed VCAM-1-targeting significantly outperforms untargeted IgG-conjugated nanocarriers in a mouse model of intracerebral hemorrhage (ICH) and ischemic stroke [ 30 , 31 ]. Compliance with the finding of previous studies, this TBI study showed augmented VCAM-1-targeting.…”

Section: Discussionmentioning

confidence: 99%

Targeting of nanoparticles to the cerebral vasculature after traumatic brain injury

Omo-Lamai,

Nong,

Savalia

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins. Consequently, an appealing approach for TBI treatment involves using drug delivery systems that utilize targeting antibodies and nanocarriers to help restore BBB integrity. In our investigation of this strategy, we examined the efficacy of free antibodies and nanocarriers targeting a specific endothelial surface marker called vascular cell adhesion molecule-1 (VCAM-1), which is known to be upregulated during inflammation. In a mouse model of TBI utilizing central fluid percussion injury, free VCAM-1 antibody did not demonstrate superior targeting when comparing sham vs. TBI brain. However, the administration of VCAM-1-targeted nanocarriers (liposomes) exhibited a 10-fold higher targeting specificity in TBI brain than in sham control. Flow cytometry and confocal microscopy analysis confirmed that VCAM-1 liposomes were primarily taken up by brain endothelial cells post-TBI. Consequently, VCAM-1 liposomes represent a promising platform for the targeted delivery of therapeutics to the brain following traumatic brain injury.

show abstract

“…Much has been written comparing affinity moiety targeting and physicochemical tropism. − ,− Advantages cited for affinity moieties include a known mechanism of action, enabling rational engineering. Physicochemical targeting usually does not have a known mechanism of action (ApoE binding is a rare exception), and therefore, rational engineering is difficult.…”

mentioning

confidence: 99%

Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting

Zamora,

Omo-Lamai,

Patel

et al. 2024

Nano Lett.

Self Cite

View full text Add to dashboard Cite

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

show abstract

Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage

Cited by 19 publications

References 67 publications

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain

Targeting of nanoparticles to the cerebral vasculature after traumatic brain injury

Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting

Contact Info

Product

Resources

About