Dataset Information

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice.

ABSTRACT: Drug delivery to the gastrointestinal (GI) tract is key for improving treatment of GI maladies, developing oral vaccines, and facilitating drug transport into circulation. However, delivery of formulations to the GI tract is hindered by pH changes, degradative enzymes, mucus, and peristalsis, leading to poor GI retention. Targeting may prolong residence of therapeutics in the GI tract and enhance their interaction with this tissue, improving such aspects. We evaluated nanocarrier (NC) and ligand-mediated targeting in the GI tract following gastric gavage in mice. We compared GI biodistribution, degradation, and endocytosis between control antibodies and antibodies targeting the cell surface determinant intercellular adhesion molecule 1 (ICAM-1), expressed on GI epithelium and other cell types. These antibodies were administered either as free entities or coated onto polymer NCs. Fluorescence and radioisotope tracing showed proximal accumulation, with preferential retention in the stomach, jejunum, and ileum; and minimal presence in the duodenum, cecum, and colon by 1 hour after administration. Upstream (gastric) retention was enhanced in NC formulations, with decreased downstream (jejunal) accumulation. Of the total dose delivered to the GI tract, ?60% was susceptible to enzymatic (but not pH-mediated) degradation, verified both in vitro and in vivo. Attenuation of peristalsis by sedation increased upstream retention (stomach, duodenum, and jejunum). Conversely, alkaline NaHCO(3), which enhances GI transit by decreasing mucosal viscosity, favored downstream (ileal) passage. This suggests passive transit through the GI tract, governed by mucoadhesion and peristalsis. In contrast, both free anti-ICAM and anti-ICAM NCs demonstrated significantly enhanced upstream (stomach and duodenum) retention when compared to control IgG counterparts, suggesting GI targeting. This was validated by transmission electron microscopy and energy dispersive X-ray spectroscopy, which revealed anti-ICAM NCs in vesicular compartments within duodenal epithelial cells. These results will guide future work aimed at improving intraoral delivery of targeted therapeutics for the treatment of GI pathologies.

SUBMITTER: Mane V

PROVIDER: S-EPMC3418107 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice.

Mane Viraj V Muro Silvia S

International journal of nanomedicine 20120801

Drug delivery to the gastrointestinal (GI) tract is key for improving treatment of GI maladies, developing oral vaccines, and facilitating drug transport into circulation. However, delivery of formulations to the GI tract is hindered by pH changes, degradative enzymes, mucus, and peristalsis, leading to poor GI retention. Targeting may prolong residence of therapeutics in the GI tract and enhance their interaction with this tissue, improving such aspects. We evaluated nanocarrier (NC) and ligand ...[more]

PMID: 22915850

Similar Datasets

Project description:Delivery of drugs into the endothelium by nanocarriers targeted to endothelial determinants may improve treatment of vascular maladies. This is the case for intercellular adhesion molecule 1 (ICAM-1), a glycoprotein overexpressed on endothelial cells (ECs) in many pathologies. ICAM-1-targeted nanocarriers bind to and are internalized by ECs via a non-classical pathway, CAM-mediated endocytosis. In this work we studied the effects of endothelial adaptation to physiological flow on the endocytosis of model polymer nanocarriers targeted to ICAM-1 (anti-ICAM/NCs, ~180 nm diameter). Culturing established endothelial-like cells (EAhy926 cells) and primary human umbilical vein ECs (HUVECs) under 4 dyn/cm(2) laminar shear stress for 24 h resulted in flow adaptation: cell elongation and formation of actin stress fibers aligned to the flow direction. Fluorescence microscopy showed that flow-adapted cells internalized anti-ICAM/NCs under flow, although at slower rate versus non flow-adapted cells under static incubation (~35% reduction). Uptake was inhibited by amiloride, whereas marginally affected by filipin and cadaverine, implicating that CAM-endocytosis accounts for anti-ICAM/NC uptake under flow. Internalization under flow was more modestly affected by inhibiting protein kinase C, which regulates actin remodeling during CAM-endocytosis. Actin recruitment to stress fibers that maintain the cell shape under flow may delay uptake of anti-ICAM/NCs under this condition by interfering with actin reorganization needed for CAM-endocytosis. Electron microscopy revealed somewhat slow, yet effective endocytosis of anti-ICAM/NCs by pulmonary endothelium after i.v. injection in mice, similar to that of flow-adapted cell cultures: ~40% (30 min) and 80% (3 h) internalization. Similar to cell culture data, uptake was slightly faster in capillaries with lower shear stress. Further, LPS treatment accelerated internalization of anti-ICAM/NCs in mice. Therefore, regulation of endocytosis of ICAM-1-targeted nanocarriers by flow and endothelial status may modulate drug delivery into ECs exposed to different physiological (capillaries vs. arterioles/venules) or pathological (ischemia, inflammation) levels and patterns of blood flow.

Project description:Designing of drug nanocarriers to aid delivery of therapeutics is an expanding field that can improve medical treatments. Nanocarriers are often functionalized with elements that recognize cell-surface molecules involved in subcellular transport to improve targeting and endocytosis of therapeutics. Combination-targeting using several affinity elements further modulates this outcome. The most studied example is endothelial targeting via multiple cell adhesion molecules (CAMs), which mimics the strategy of leukocytes to adhere and traverse the vascular endothelium. Yet, the implications of this strategy on intracellular transport and in vivo biodistribution remain uncharacterized. We examined this using nanocarriers functionalized for dual- or triple-targeting to intercellular, platelet-endothelial, and/or vascular CAMs (ICAM-1, PECAM-1, VCAM-1). These molecules differ in expression level, location, pathological stimulation, and/or endocytic pathway. In endothelial cells, binding of PECAM-1/VCAM-1-targeted nanocarriers was intermediate to single-targeted counterparts and enhanced in disease-like conditions. ICAM-1/PECAM-1-targeted nanocarriers surpassed PECAM-1/VCAM-1 in control, but showed lower selectivity toward disease-like conditions. Triple-targeting resulted in binding similar to ICAM-1/PECAM-1 combination and displayed the highest selectivity in disease-like conditions. All combinations were effectively internalized by the cells, with slightly better performance when targeting receptors of different endocytic pathways. In vivo, ICAM-1/PECAM-1-targeted nanocarriers outperformed PECAM-1/VCAM-1 in control and disease-like conditions, and triple-targeted counterparts slightly enhanced this outcome in some organs. As a result, delivery of a model therapeutic cargo (acid sphingomyelinase, deficient in Niemann-Pick disease A-B) was enhanced to all affected organs by triple-targeted nanocarriers, particularly in disease-like conditions. Therefore, multi-CAM targeting may aid the optimization of some therapeutic nanocarriers, where the combination and multiplicity of the affinity moieties utilized allow modulation of targeting performance.

Dataset Information

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice.

Publications

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets