Targeting Specific Vascular Areas

Injecting of anti-CAM conjugates via catheters inserted in a conduit artery facilitates local delivery in the downstream vascular area. Local delivery may also be enhanced by surface endothelial determinants enriched in particular vascular areas or in focal pathological processes.

For example, endothelium contains surface determinants localized to cholesterol-enriched plasma membrane microdomains, including caveoli. Ligands of these determinants accumulate in the pulmonary vasculature after intravenous injection in rats, then enter and traverse endothelial cells [4]. The functions and human counterparts of these caveoli-localized determinants, interesting candidates for drug delivery, are not known.

Cerebral endothelium is an especially important and difficult target. Carrier antibodies and peptides directed to surface determinants relatively enriched in cerebral endothelium, including receptors for transferrin, insulin, and some growth factors, permit delivery of reporter compounds and genes into the brain in animals. Some of these receptors apparently permit transendothelial delivery into the brain tissue and neurons [10].

Endothelial cells exposed to inflammatory mediators and abnormal shear stress show cell surface expression of P-selectin, normally stored intracellularly and mobilized rapidly to the surface, and E-selectin, which is newly synthesized by activated endothelium. Thus, selectins are transiently exposed on the surface of stressed endothelial cells. Experiments in cell cultures and limited animal studies show that selectins may permit targeting of drugs to cytokine-activated endothelium [2]. However, kinetics and persistence of selectin exposure upon endothelial activation are difficult to follow even in animal studies, where exact initiation of cytokine activation could be easily controlled; thus the transient character of surface exposure hinders targeting of selectins. Further, even at the activation peak, selectins are exposed at relatively low surface densities; hence, robustness of the targeting may be suboptimal for therapeutic interventions requiring delivery of large doses. However, it may suffice for diagnostic visualization of inflammation foci [11] and, perhaps, for gene delivery [12].

Endothelial cells in solid tumors also represent an especially important and challenging target for delivery of agents designed to visualize tumors, inhibit angiogenesis, or eradicate malignant cells. Tumor vasculature is characterized by numerous morphological abnormalities. Endothelial cells in tumor vessels expose abnormal determinants including VCAM, selectins, integrins, apoptosis markers, and receptors for growth factors [13]. Targeting these determinants in tumors might be useful to accomplish two goals: (i) delivery of antitumor agents to the proper malignant cells using, for example, PEG-immunoliposomes or polymers loaded with taxol or doxorubicin; and, (ii) inflicting damage in the tumor vasculature leading to thrombosis, infarction and starvation of malignant cells [14].

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment