Degradable poly(apigenin) polymer inhibits tumor cell adhesion to vascular endothelial cells.

Cancer and the inflammatory system share a complex intertwined relationship. For instance, in response to an injury or stress, vascular endothelial cells will express cell adhesion molecules as a means of recruiting leukocytes. However, circulating tumor cells (CTCs) have been shown to highjack this expression for the adhesion and invasion during the metastatic cascade. As such, the initiation of endothelial cell inflammation, either by surgical procedures (cancer resection) or chemotherapy can inadvertently increase the metastatic potential of CTCs. Yet, systemic delivery of anti-inflammatories, which weaken the entire immune system, may not be preferred in some treatment settings. In this work, we demonstrate that a long-term releasing flavone-based polymer and subsequent nanoparticle delivery system can inhibit tumor cell adhesion, through the suppression of endothelial cell adhesion molecule expression. The degradation of a this anti-inflammatory polymer provides longer term, localized release profile of active therapeutic drug in nanoparticle form as compared with that of the free drug, permitting more targeted anti-metastatic therapies. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1438-1447, 2016.

Binding, transcytosis and biodistribution of anti-PECAM-1 iron oxide nanoparticles for brain-targeted delivery.

OBJECTIVE: Characterize the flux of platelet-endothelial cell adhesion molecule (PECAM-1) antibody-coated superparamagnetic iron oxide nanoparticles (IONPs) across the blood-brain barrier (BBB) and its biodistribution in vitro and in vivo. METHODS: Anti-PECAM-1 IONPs and IgG IONPs were prepared and characterized in house. The binding affinity of these nanoparticles was investigated using human cortical microvascular endothelial cells (hCMEC/D3). Flux assays were performed using a hCMEC/D3 BBB model. To test their immunospecificity index and biodistribution, nanoparticles were given to Sprague Dawley rats by intra-carotid infusion. The capillary depletion method was used to elucidate their distribution between the BBB and brain parenchyma. RESULTS: Anti-PECAM-1 IONPs were ~130 nm. The extent of nanoparticle antibody surface coverage was 63.6 ± 8.4%. Only 6.39 ± 1.22% of labeled antibody dissociated from IONPs in heparin-treated whole blood over 4 h. The binding affinity of PECAM-1 antibody (KD) was 32 nM with a maximal binding (Bmax) of 17 × 10(5) antibody molecules/cell. Anti-PECAM-1 IONP flux across a hCMEC/D3 monolayer was significantly higher than IgG IONP's with 31% of anti-PECAM-1 IONPs in the receiving chamber after 6 h. Anti-PECAM-1 IONPs showed higher concentrations in lung and brain, but not liver or spleen, than IgG IONPs after infusion. The capillary depletion method showed that 17±12% of the anti-PECAM-1 IONPs crossed the BBB into the brain ten minutes after infusion. CONCLUSIONS: PECAM-1 antibody coating significantly increased IONP flux across the hCMEC/D3 monolayer. In vivo results showed that the PECAM-1 antibody enhanced BBB association and brain parenchymal accumulation of IONPs compared to IgG. This research demonstrates the benefit of anti-PECAM-1 IONPs for association and flux across the BBB into the brain in relation to its biodistribution in peripheral organs. The results provide insight into potential application and toxicity concerns of anti-PECAM-1 IONPs in the central nervous system.

Suppressing iron oxide nanoparticle toxicity by vascular targeted antioxidant polymer nanoparticles.

The biomedical use of superparamagnetic iron oxide nanoparticles has been of continued interest in the literature and clinic. Their ability to be used as contrast agents for imaging and/or responsive agents for remote actuation makes them exciting materials for a wide range of clinical applications. Recently, however, concern has arisen regarding the potential health effects of these particles. Iron oxide toxicity has been demonstrated in in vivo and in vitro models, with oxidative stress being implicated as playing a key role in this pathology. One of the key cell types implicated in this injury is the vascular endothelial cells. Here, we report on the development of a targeted polymeric antioxidant, poly(trolox ester), nanoparticle that can suppress oxidative damage. As the polymer undergoes enzymatic hydrolysis, active trolox is locally released, providing a long term protection against pro-oxidant agents. In this work, poly(trolox) nanoparticles are targeted to platelet endothelial cell adhesion molecules (PECAM-1), which are able to bind to and internalize in endothelial cells and provide localized protection against the cytotoxicity caused by iron oxide nanoparticles. These results indicate the potential of using poly(trolox ester) as a means of mitigating iron oxide toxicity, potentially expanding the clinical use and relevance of these exciting systems.

Synthesis and characterization of poly(antioxidant ß-amino esters) for controlled release of polyphenolic antioxidants.

Attenuation of cellular oxidative stress, which plays a central role in biomaterial-induced inflammation, provides an exciting opportunity to control the host tissue response to biomaterials. In the case of biodegradable polymers, biomaterial-induced inflammation is often a result of local accumulation of polymer degradation products, hence there is a need for new biomaterials that can inhibit this response. Antioxidant polymers, which have antioxidants incorporated into the polymer backbone, are a class of biomaterials that, upon degradation, release active antioxidants, which can scavenge free radicals and attenuate oxidative stress, resulting in improved material biocompatibility. In this work, we have synthesized poly(antioxidant ß-amino ester) (PAßAE) biodegradable hydrogels of two polyphenolic antioxidants, quercetin and curcumin. The degradation characteristics of PAßAE hydrogels and the antioxidant activity of PAßAE degradation products were studied. Treatment of endothelial cells with PAßAE degradation products protected cells from hydrogen-peroxide-induced oxidative stress.