Biomedical aspects of targeted delivery of drugs to pulmonary endothelium

Abstract

Drug targeting to selected subcellular compartments of the pulmonary endothelium may optimise treatment of many diseases. This paper describes endothelial determinants that are potentially useful for such targeting, including endothelial ectopeptidases, cell adhesion molecules and novel candidates identified by high-throughput methods, as well as the means to achieve optimal subcellular targeting of drugs in the endothelium that have been explored in cell culture and animal studies. Criteria for determining the applicability for targeting include accessibility, specificity, safety and subcellular precision. The effects of endothelial delivery of therapeutic agents, including the effects mediated by the intervention in the function of the target determinants, must be characterised in the context of given pathological conditions.

Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium

“…We chose the pulmonary vasculature since the lungs contain ~30% of total endothelial surface in the body and, unlike other organs, receive the entire cardiac output of venous blood; hence DDSs targeted to endothelial cells accumulate in lungs [1,3,19,22,39]. In addition, pulmonary endothelium is enriched in some determinant, including thrombomodulin [1,23,[40][41][42][43][44][45].…”

“…Targeted drug delivery to the endothelium may help to improve treatment of diseases affecting the vasculature [1][2][3][4][5][6][7]. Targeted drug delivery systems (DDSs) designed to achieve this goal consist of affinity vectors (e.g., antibodies directed to endothelial surface determinants) coupled either directly to pharmacological cargoes (e.g., therapeutic enzymes) or to drugloaded vehicles or carriers (e.g., liposomes or polymer nanocarriers) [8][9][10][11][12][13][14].…”

“…Targeted drug delivery systems (DDSs) designed to achieve this goal consist of affinity vectors (e.g., antibodies directed to endothelial surface determinants) coupled either directly to pharmacological cargoes (e.g., therapeutic enzymes) or to drugloaded vehicles or carriers (e.g., liposomes or polymer nanocarriers) [8][9][10][11][12][13][14]. Endothelial targeting of DDSs carrying reporter probes, enzymes, other drugs, genes and/or drug nanocarriers has been achieved in a number of animal species and even in a few "proof of principal" human studies (reviewed in [1,8]). However, before this approach can move into the clinical domain, a more thorough understanding of the factors that regulate the effects of drugs targeted to endothelium is needed.…”

“…This study will present experiments that begin to define some of the biological factors and elements of DDS design that regulate the targeting and effects of an enzymatic cargo in the pulmonary vasculature, an important target for pharmacological interventions [1,3,15,16]. To achieve this goal, we utilized an enzyme (glucose oxidase, GOX, that generates H 2 O 2 from O 2 and glucose) as a model cargo coupled with well-characterized antibodies to an endothelial determinant enriched in the lungs, thrombomodulin (TM) [17].…”

Nanoparticle Brownian motion and hydrodynamic interactions in the presence of flow fields

“…39,40 In TDD, the drug carrying nanocarriers are intravascularly introduced into the vasculature. [41][42][43] The drug-laden nanocarriers are functionalized with ligands (e.g., antibodies) and recognize specific determinants (receptors) expressed by endothelial cells. 38,44 The receptor-ligand binding interactions at the involved sites define the efficacy of nanocarrier arrest by the targeted cell.…”