Anti-nucleolin agent-conjugated nanoparticles as radio-sensitizers and mri and/or x-ray contrast agents

Abstract

A composition comprises an anti-nucleolin agent conjugated to nanoparticles, and optionally containing gadolinium. Furthermore, a pharmaceutical composition for treating cancer comprises a composition including an anti-nucleolin agent conjugated to nanoparticles, and a pharmaceutically acceptable carrier. The composition enhances the effectiveness of radiation therapy, enhancing contrast in X-ray imaging techniques, and when gadolinium is present, provide cancer selective MRI contrast agents.

1 . A composition, comprising an anti-nucleolin agent and gadolinium conjugated to nanoparticles. 
     
     
         2 . The composition of  claim 1 , wherein the nanoparticles comprise at least one member selected from the group consisting of metals, elements and oxides. 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the anti-nucleolin agent is selected from the group consisting of an anti-nucleolin oligonucleotide, an antibody, a nucleolin targeting protein and a guanosine-rich oligonucleotide (GRO). 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The composition of  claim 1  further comprising a cyanine dye. 
     
     
         10 . The composition of  claim 1 , wherein the nanoparticles have an average diameter of 1 to 50 nm. 
     
     
         11 . The composition of  claim 1 , wherein the nanoparticles have an average diameter of 1 to 20 nm. 
     
     
         12 . The composition of  claim 1 , wherein the nanoparticles comprise at least one member selected from the group consisting of gold, platinum, iridium and palladium. 
     
     
         13 . The composition of  claim 1 , wherein the gadolinium is present as a complex of gadolinium (III). 
     
     
         14 . The composition of  claim 1 , wherein the gadolinium is present as 10-(2-sulfanylethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H3-DO3A-SH) coordinated to the gadolinium ion (Gd-DO3A-SH). 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method of treating cancer, comprising administering an effective amount of a pharmaceutical composition comprising an anti-nucleolin agent conjugated to nanoparticles, to a patient in need thereof, followed by radiation therapy. 
     
     
         19 . The method of treating cancer of  claim 18 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, plasmocytoma, sarcoma, glioma, thymoma, leukemia, breast cancer, prostate cancer, colon cancer, liver cancer, esophageal cancer, brain cancer, lung cancer, ovary cancer, cervical cancer and hepatoma. 
     
     
         20 . (canceled) 
     
     
         21 . The method of treating cancer of  claim 18 , further comprising administering a second cancer treatment selected from the group consisting of vinorelbine, mitomycin, camptothecin, cyclophosphamide, methotrexate, tamoxifen citrate, 5-fluorouracil, irinotecan, doxorubicin, flutamide, paclitaxel, docetaxel, vinblastine, imatinib mesylate, anthracycline, letrozole, arsenic trioxide, anastrozole, triptorelin pamoate, ozogamicin, irinotecan hydrochloride, BCG live, leuprolide acetate implant (VIADUR®), bexarotene, exemestane, topotecan hydrochloride, gemcitabine HCL, daunorubicin hydrochloride, toremifene citrate (FARESTON®), carboplatin, cisplatin, oxaliplatin, trastuzumab, lapatinib, getitinib, cetuximab, panitumumab, temsirolimus, everolimus, vandetanib, vemurafenib, crizotinib, vorinostat, bevacizumab, hyperthermia, gene therapy and photodynamic therapy. 
     
     
         22 - 25 . (canceled) 
     
     
         26 . A method of imaging cancer by MRI and/or X-ray imaging techniques in vivo, comprising:
 administering a composition comprising an anti-nucleolin agent and gadolinium conjugated to nanoparticles to a subject; and   forming an image of the imaging agent present in the subject by MRI and/or an X-ray imaging technique.   
     
     
         27 . The method of imaging cancer of  claim 26 , wherein the administering occurs more than 24 hours before the forming. 
     
     
         28 . The method of imaging cancer of  claim 26 , wherein the administering occurs more than 48 hours before the forming. 
     
     
         29 . The method of imaging cancer of  claim 26 , wherein the cancer is lung cancer. 
     
     
         30 . The method of imaging cancer of  claim 26 , wherein the method is capable of identifying malignant lesions in the lung that are less than 4 mm. 
     
     
         31 . The composition of  claim 1 , wherein the anti-nucleolin agent comprises AS1411. 
     
     
         32 . The method of treating cancer of  claim 18 , wherein the anti-nucleolin agent comprises AS1411. 
     
     
         33 . The method of imaging cancer of  claim 26 , wherein the anti-nucleolin agent comprises AS1411.