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

Citation

Targeting Nanoparticles to tumor vasculature. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /288 .

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