Biology subjects

Omo-Lamai, S.

Publications and source records attributed to Omo-Lamai, S..

3 recordsLinked to original sources

bioRxiv2023

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical targeting, in which LNPs lipid compositions are adjusted to find mixtures with the desired tropism. In a popular approach, physicochemical targeting is accomplished by formulating with charged lipids. Negatively charged lipids localize LNPs to the spleen, and positively charged lipids to the lungs. Here we found that lung-tropic LNPs employing cationic lipids induce massive thrombosis. We demonstrate that thrombosis is induced in the lungs and other organs, and greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles. The mechanism depends on the LNPs binding to fibrinogen and inducing platelet and thrombin activation. Based on these mechanisms, we engineered multiple solutions which enable positively charged LNPs to target the lungs while not inducing thrombosis. Our findings implicate thrombosis as a major barrier that blood erects against LNPs with cationic components and illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.

bioengineering↗

bioRxiv2023

Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke

After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons for the failure has been that drugs achieve very low concentrations in the at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance drug concentration in the penumbras blood-brain barrier (BBB), whose increased permeability in AIS has long been hypothesized to kill neurons by exposing them to toxic plasma proteins. To devise drug-loaded nanocarriers targeted to the BBB, we conjugated them with antibodies that bind to various cell adhesion molecules on the BBB endothelium. In the transient middle cerebral artery occlusion (tMCAO) mouse model, nanocarriers targeted with VCAM antibodies achieved the highest level of brain delivery, nearly 2 orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles loaded with either a small molecule drug (dexamethasone) or mRNA (encoding IL-10) reduced cerebral infarct volume by 35% or 73%, respectively, and both significantly lowered mortality rates. In contrast, the drugs delivered without the nanocarriers had no effect on AIS outcomes. Thus, VCAM-targeted lipid nanoparticles represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/544645v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@86762dorg.highwire.dtl.DTLVardef@1b89a2aorg.highwire.dtl.DTLVardef@916d85org.highwire.dtl.DTLVardef@1ad4670_HPS_FORMAT_FIGEXP M_FIG C_FIG Acute ischemic stroke induces upregulation of VCAM. We specifically targeted upregulated VCAM in the injured region of the brain with drug- or mRNA-loaded targeted nanocarriers. Nanocarriers targeted with VCAM antibodies achieved the highest brain delivery, nearly orders of magnitude higher than untargeted ones. VCAM-targeted nanocarriers loaded with dexamethasone and mRNA encoding IL-10 reduced infarct volume by 35% and 73%, respectively, and improved survival rates.

pharmacology and toxicology↗

bioRxiv2022

Targeted nanocarriers coopting pulmonary leukocytes for drug delivery to the injured brain

Selective drug delivery to injured regions of the brain is an elusive, but biomedically important, goal. It is tempting to co-opt migrating white blood cells (WBC) to carry drugs to the injured brain, using natural WBC tropism. Current approaches to load cargoes to WBC have limited utility, particularly in acute conditions, due to the need for time consuming ex vivo manipulation and loading of cells. Physiological, in vivo loading of WBC may be advantageous in this scenario. Here we devised such a strategy, capitalizing on the unique features of the direct blood exchange between brain and lungs. Mediators emanating from the injured brain directly travel to the pulmonary vasculature via venous flow. In response to these mediators, WBCs, transiently residing in the pulmonary microvascular lumen, disembark and flow with arterial blood to the brain microvasculature, where they adhere and transmigrate to the brain parenchyma via the local chemoattractant gradient. We posited that direct in vivo targeting of cargoes to the pulmonary WBC pool may provide drug transfer to brain via this natural mechanism. To test this, we intravenously injected agents targeted to intercellular adhesion molecule 1 (ICAM) in mice with acute brain inflammation caused by direct injection of tumor necrosis factor alpha (TNF-). We found that: A) At 2 hours, >20% of ICAM/NP accumulated in lungs, predominantly in WBCs; B) At 6 and 22 hours, ICAM/NP pulmonary uptake markedly decreased; C) In contrast, ICAM/NP uptake in brain increased ~5-fold in this time interval, concomitantly with migration of WBCs to the brain. Cranial window fluorescent microscopy confirmed WBC transport of ICAM/NP to the brain in TNF--challenged mice beyond the BBB. Importantly, demonstrating the pharmacologic relevance of this strategy, dexamethasone-loaded ICAM/liposomes abrogated brain edema in this model. In sum, coopting the natural homing of WBC from the lungs via ICAM-targeting to injured brain is an attractive strategy for precise interventions for treatment of acute brain injuries. VISUAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗