دورية أكاديمية
Assessing the therapeutic efficacy of VEGFR-1-targeted polymer drug conjugates in mouse tumor models.
| العنوان: | Assessing the therapeutic efficacy of VEGFR-1-targeted polymer drug conjugates in mouse tumor models. |
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| المؤلفون: | Shamay Y; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel., Golan M; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel., Tyomkin D; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel., David A; Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; The Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: ayeletda@bgu.ac.il. |
| المصدر: | Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2016 May 10; Vol. 229, pp. 192-199. Date of Electronic Publication: 2016 Mar 19. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 8607908 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4995 (Electronic) Linking ISSN: 01683659 NLM ISO Abbreviation: J Control Release Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam : Elsevier Science Publishers, 1984- |
| مواضيع طبية MeSH: | Acrylamides/*administration & dosage , Antibiotics, Antineoplastic/*administration & dosage , Doxorubicin/*administration & dosage , Drug Carriers/*administration & dosage , Vascular Endothelial Growth Factor Receptor-1/*metabolism, Acrylamides/chemistry ; Animals ; Antibiotics, Antineoplastic/chemistry ; Carcinoma, Lewis Lung/drug therapy ; Carcinoma, Lewis Lung/metabolism ; Carcinoma, Lewis Lung/pathology ; Cell Line ; Cell Survival/drug effects ; Disease Models, Animal ; Doxorubicin/chemistry ; Drug Carriers/chemistry ; E-Selectin/metabolism ; HT29 Cells ; Humans ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/metabolism ; Mice, Inbred C57BL ; Skin Neoplasms/drug therapy ; Skin Neoplasms/metabolism ; Treatment Outcome ; Tumor Burden/drug effects |
| مستخلص: | Polymer-drug conjugates that can actively target the tumor vasculature have emerged as an attractive technology for improving the therapeutic efficacy of cytotoxic drugs. We have recently provided, for the first time, in vivo evidence showing the significant advantage of the E-selectin-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate, P-(Esbp)-DOX, in inhibiting primary tumor growth and preventing the formation and development of cancer metastases. Here, we describe the design of a vascular endothelial growth factor receptor (VEGFR)-1-targeted HPMA copolymer-DOX conjugate (P-(F56)-DOX) that can actively and simultaneously target different cell types in the tumor microenvironment, such as endothelial cells (ECs), bone marrow-derived cells and many human cancer cells of diverse tumor origin. The VEGFR-1-targeted copolymer was tested for its binding, internalization and in vitro cytotoxicity in ECs (bEnd.3 and cEND cells) and cancer cells (B16-F10, 3LL and HT29). The in vivo anti-cancer activity of P-(F56)-DOX was then tested in two tumor-bearing mice (TBM) models (i.e., primary Lewis lung carcinoma (3LL) tumors and B16-F10 melanoma pulmonary metastases), relative to that of the E-selectin-targeted system (P-(Esbp)-DOX) that solely targets ECs. Our results indicate that the binding and internalization profiles of the VEGFR-1-targeted copolymer were superior towards ECs as compared to cancer cells and correlated well to the level of VEGFR-1 expression in cells. Accordingly, the VEGFR-1-targeted copolymer (P-(F56)-DOX) was more toxic towards bEnd.3 cells than to cancer cells, and exhibited significantly higher cytotoxicity than did the non-targeted control copolymer. P-(F56)-DOX inhibited 3LL tumor growth and significantly prolonged the survival of mice with B16-F10 pulmonary metastases. When compared to a system that actively targets only tumor vascular ECs, P-(F56)-DOX and P-(Esbp)-DOX exhibited comparable efficacy in slowing the growth of primary 3LL tumors and prolonging the survival of these mice. Still, P-(Esbp)-DOX had more pronounced anti-tumor activity in mice bearing B16-F10 lung metastases after a single intravenous injection, at an equivalent DOX dose. Overall, our results indicate that the VEGFR-1- and E-selectin-targeted drug delivery systems evaluated here show enhanced anti-cancer activity, and prolonged the survival of mice after a single intravenous injection. This is thus the first study comparing the anti-tumor activity of VEGFR-1- and E-selectin-targeted polymer drug conjugates in the same TBM models at an equivalent drug dose. (Copyright © 2016 Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Anti-cancer therapy; E-selectin; Polymer–drug conjugates; Tumor microenvironment; VEGFR-1 |
| المشرفين على المادة: | 0 (Acrylamides) 0 (Antibiotics, Antineoplastic) 0 (Drug Carriers) 0 (E-Selectin) 80168379AG (Doxorubicin) EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1) R3F262Z4E0 (N-(2-hydroxypropyl)methacrylamide) |
| تواريخ الأحداث: | Date Created: 20160323 Date Completed: 20171030 Latest Revision: 20180316 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.jconrel.2016.03.024 |
| PMID: | 27001892 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-4995 |
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| DOI: | 10.1016/j.jconrel.2016.03.024 |