P-selectin is a nanotherapeutic delivery target in the tumor microenvironment

Abstract

Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.

One-pot synthesis of nanochain particles for targeting brain tumors

“…11, 16 Notably, the remodeled endothelium associated with brain tumors and its surrounding microenvironment offers a diverse set of targetable biomarkers. For example, vascular targets overexpressed in gliomas include α v β 3 integrin, 17–20 platelet-selectin (P-selectin), 21 vascular endothelial growth factor receptors (VEGFR) and fibronectin. 22–25 In particular, we were interested in fibronectin due to its role in migration of glioma cells.…”

Advances in the clinical translation of nanotechnology

“…Possible toxicities and immune responses (54) engendered by the distinct properties of the nanoparticles are neither well-understood nor predictable yet. In practice, nanomaterials range from extraordinarily inert polymers, such as carbon nanotubes (1, 37) to nucleic acids (55), to biodegradable carbohydrate-based materials (56). The size, shape, changes hydrophobicity, stiffness, and biodegradability will all have important consequences for the use of these drugs in vivo (57).…”

Mechanism of Collaborative Enhancement of Binding of Paired Antibodies to Distinct Epitopes of Platelet Endothelial Cell Adhesion Molecule-1

“…Targeting drugs to endothelial cells has the potential to improve treatment for diseases involving inflammation[1,2], thrombosis[3], ischemia[4], and tumor growth[5,6]. Endothelial delivery is typically achieved by conjugation of drugs or carriers to affinity ligands, such as monoclonal antibodies (mAbs) or their fragments, which bind to endothelial surface determinants.…”