title: Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates.
abstract: There is currently no effective means to prevent or control metastatic dissemination of cancer cells. E-selectin, an adhesion molecule expressed exclusively on inflamed and angiogenic blood vessels, plays an important role in several rate-limiting steps of cancer metastasis. In this study, we assessed the in vivo antitumor efficacy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to an E-selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped with the chemotherapeutic drug doxorubicin (P-(Esbp)-DOX) or with the proapoptotic peptide D(KLAKLAK)2 (P-(Esbp)-KLAK). Following a single intravenous injection, P-(Esbp)-DOX reduced tumor growth rate and prolonged the survival of mice bearing primary Lewis lung carcinoma (3LL) tumors significantly more than treatment with a non-targeted copolymer (P-DOX) or with free DOX. In an experimental B16-F10 lung metastasis model, a single intravenous dose of P-(Esbp)-DOX or P-(Esbp)-KLAK prolonged mice survival time significantly more than the non-targeted copolymers or the free drugs, and the percentage of complete tumor regression increased with increasing doses and with dosing frequency. In addition, mice pretreated with an E-selectin-targeted "drug-free" copolymer (P-(Esbp)-FITC) exhibited significantly fewer B16-F10 tumor foci in the lungs as compared with non-treated mice, demonstrating the anti-metastatic properties of the copolymer and its ability to control cancer spread through E-selectin-mediated interactions. Biodistribution analysis further confirmed the preferential accumulation of the E-selectin-targeted near-infrared fluorescently-labeled copolymer P-(Esbp)-IR783 in B16-F10 lung metastases. Taken together, this study demonstrates, for the first time, that the E-selectin targeted copolymer-drug conjugates can inhibit primary tumor growth and prevent metastases in vivo.
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Yosi
authors: Y
authors: Shamay
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Lior
authors: L
authors: Raviv
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Moran
authors: M
authors: Golan
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Elena
authors: E
authors: Voronov
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Ron N
authors: RN
authors: Apte
authors: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: ayeletda@bgu.ac.il.
authors: Ayelet
authors: A
authors: David
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019040:E-Selectin / Q000378:metabolism*; D005260:Female; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D019040:E-Selectin; D010455:Peptides; D011108:Polymers; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Cancer metastasis; Doxorubicin; E-selectin; Nanomedicine; Polymer–drug conjugates; Proapoptotic peptide