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: Yosi Shamay, Lior Raviv, Moran Golan, Elena Voronov, Ron N Apte, Ayelet David
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 217 Pg. 102-12 (Nov 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26297207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Acrylamides
• Antineoplastic Agents
• E-Selectin
• Peptides
• Polymers
• Doxorubicin
• N-(2-hydroxypropyl)methacrylamide

Topics

• Acrylamides (chemistry)
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, therapeutic use)
• Cell Line
• Cell Line, Tumor
• Doxorubicin (chemistry, pharmacokinetics, therapeutic use)
• E-Selectin (metabolism)
• Female
• Melanoma, Experimental
• Mice
• Mice, Inbred C57BL
• Neoplasms (drug therapy, metabolism, pathology)
• Peptides (chemistry, pharmacokinetics, therapeutic use)
• Polymers (chemistry, pharmacokinetics, therapeutic use)
• Tumor Burden (drug effects)