Sheri Peterson

EFFECTS OF NONTARGETED, DOXORUBICIN-CONTAINING NANOPARTICLES ON NEOINTIMAL THICKENING AFTER CAROTID INJURY IN RATS. Sheri Peterson¹, Dana Abendschein², Washington University Department of Biology, St. Louis, MO¹, Washington University School of Medicine Department of Internal Medicine, St. Louis, MO².

A serious problem with the traumatic injury to blood vessels is the vessel’s response, called stenosis, which involves narrowing of the vessel lumen, and can be induced clinically during knee or hip replacement surgery and coronary angioplasty. The process of stenosis consists of proliferation and migration of vascular smooth muscle cells (VSMC) from the media to the vessel’s inner layer, or intima, which becomes thickened. Stenosis (or restenosis in the case of renarrowing after angioplasty of an atherosclerotic plaque) can create problems by restricting blood flow, leading to symptoms of pain and muscle weakness. Neointimal thickening and stenosis have been attenuated using intravascular stents, but it still remains a problem for a significant minority of patients.

Doxorubicin is a cell cycle inhibitor in the anthracycline drug family known for its antiproliferative effects. It has been used as an effective chemotherapeutic agent, especially for breast cancer. Doxorubicin has more recently been utilized to decrease VSMC proliferation in vivo. Previous studies in rats with balloon catheter-induced injury of the carotid artery have shown decreased neointimal thickening after intravenous administration of a core-shell nanoparticle containing doxorubicin, but the efficacy may have been limited by low concentrations of inhibitor achieved at the site of vascular injury.

The present investigation was the first step in testing the hypothesis that a nanoparticle releasing doxorubicin and targeted to α_vβ₃ integrin receptors exposed on the injured vessel wall would significantly attenuate neointimal thickening after vessel injury. Initial studies completed this summer were designed to determine whether treatment with a non-targeted bowtie dendrimer-type nanoparticle designed to release doxorubicin under acidic conditions would be effective in reducing neointimal thickening and stenosis after overstretch injury to rat carotid arteries, compared to treatment with saline vehicle or unbound doxorubicin. To investigate this, the common carotid arteries of rats were injured using three passes of a balloon catheter introduced through the external carotid branch. The lumen of the injured vessel segment was then exposed for 15 minutes to either non-targeted nanoparticles containing doxorubicin, an equivalent amount of unbound doxorubicin, or saline as a control.

Microscopic analysis of the vessels four weeks after injury and treatment indicated no significant difference between the areas of neointima (with respect to the area of the media) in the vessels treated with the nontargeted nanoparticle versus unbound doxorubicin or saline. There are several possibilities for these unexpected results. One possibility is that the nanoparticle never associated with the vessel wall, but escaped into the surrounding tissue. This idea is supported by the preliminary results with unbound doxorubicin, which also had minimal effects on neointimal thickening. A second possibility is that the nanoparticle never released the doxorubicin, possibly because the injured vessel wall does not become acidic enough. To address these possibilities, assays are currently being developed to determine the pH and the concentration of doxorubicin in the injured vessel segment. We are also awaiting the arrival of an α_vβ₃-targeted version of the nanoparticle, which we believe will have increased association with the vessel and achieve efficacy for inhibition of neointimal thickening in this model.