Targeting Nanoparticles to tumor vasculature

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Targeting Nanoparticles to tumor vasculature

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Title: Targeting Nanoparticles to tumor vasculature
Author: Marconescu, Andrei
Abstract: Targeting tumor vessels represents an indirect therapeutic approach in oncology by shifting the treatment away from the tumor cells themselves. Endothelial cells are generally considered genetically stable and do not use escape mechanisms against chemotherapeutic agents as frequently as tumor cells do. Also, a very large number of tumor cells can be killed by ischemia if a single vessel is occluded. Tumor vascular markers have been identified and monoclonal antibodies targeting them have been constructed in my laboratory. There are numerous approaches to make antibodies more effective in cancer treatment. One option we have investigated is to use them for liposomal targeting to tumor vessels. Nanoparticles, and liposomes in particular, are extremely versatile because they can be adapted to carry drugs, imaging agents, or energy capture agents. In my project, I have constructed liposomes targeted to three molecules identified as tumor vascular markers: VEGFR-2, phosphatidylserine (PS), and phosphatidylethanolamine (PE). To target VEGFR-2, I have used Fab' fragments derived from a series of rat monoclonal antibodies (RAFL) that bind to the extracellular domain of the receptor. For PS targeting, I used Fab' fragments derived from an anionic phospholipid binding antibody (bavituximab) and also a serum protein, beta-2-glycoprotein 1 (beta 2GP1). PE was targeted using a small antibiotic peptide, duramycin. All the liposome constructs bound to the purified target, as tested by solid phase assays. VEGFR-2 targeted liposomes bound to and were internalized by mouse endothelial cells expressing VEGFR-2. PS and PE targeted liposomes bound to endothelial cells that were subjected to stress factors that mimic the conditions encountered in the tumor environment. All the liposomes were also detected on the surface of endothelial cells inside tumors. The tumor treatment potential was assessed by loading the liposomes with doxorubicin and treating mice in an orthotopic breast cancer model. The therapeutic benefit was also assessed for its ability to prolong survival in a lung pseudometastatic model. The tumor growth in the orthotopic model was not inhibited by any of the constructs compared with control liposomes, but VEGFR-2 targeted liposomes extended the survival in the pseudometastatic model. These data suggest that VEGFR-2 targeted liposomes could potentially be used as an antimetastatic agent in combination with treatments that would target the tumor of origin. PS and PE binding liposomes were also used as probes for describing the membrane localization and exposure dynamics of PS and PE on the surface of irradiated cells. I have shown that PS and PE follow a similar exposure time course and they colocalize on the cell surface. PS and PE positive membrane patches appear to detach from the cytoskeleton and bud out from the cell surface. These findings suggest that PE and PS share common regulatory mechanisms of membrane translocation. PS and PE binding liposomes were also used as probes for describing the membrane localization and exposure dynamics of PS and PE on the surface of irradiated cells. I have shown that PS and PE follow a similar exposure time course and they colocalize on the cell surface. PS and PE positive membrane patches appear to detach from the cytoskeleton and bud out from the cell surface. These findings suggest that PE and PS share common regulatory mechanisms of membrane translocation. Long circulating liposomes provide benefit through passive targeting to the tumor environment. My findings imply that active targeting by adding a ligand should be done with care, so as not to impede the passive targeting effect. Compared to other vascular targeting agents, liposomes require
URI: http://hdl.handle.net/2152.5/288
Date: 2008-09-18

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