title: Targeting the extracellular matrix of ovarian cancer using functionalized, drug loaded lyophilisomes.
abstract: Epithelial ovarian cancer is characterized by a high mortality rate and is in need for novel therapeutic avenues to improve patient outcome. The tumor's extracellular matrix ("stroma") offers new possibilities for targeted drug-delivery. Recently we identified highly sulfated chondroitin sulfate (CS-E) as a component abundantly present in the ovarian cancer extracellular matrix, and as a novel target for anti-cancer therapy. Here, we report on the functionalization of drug-loaded lyophilisomes (albumin-based biocapsules) to specifically target the stroma of ovarian carcinomas with the potential to eliminate cancer cells. To achieve specific targeting, we conjugated single chain antibodies reactive with CS-E to lyophilisomes using a two-step approach comprising sortase-mediated ligation and bioorthogonal click chemistry. Antibody-functionalized lyophilisomes specifically targeted the ovarian cancer stroma through CS-E. In a CS-E rich micro-environment in vitro lyophilisomes induced cell death by extracellular release of doxorubicin which localized to the nucleus. Immunohistochemistry identified CS-E rich stroma in a variety of solid tumors other than ovarian cancer, including breast, lung and colon cancer indicating the potential versatility of matrix therapy and the use of highly sulfated chondroitin sulfates in cancer stroma as a micro-environmental hook for targeted drug delivery.
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Obstetrics and Gynaecology, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sophieke C H A
authors.initials: SC
authors.lastname: van der Steen
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Raavé
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Langerak
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Laurens
authors.initials: L
authors.lastname: van Houdt
authors.affiliation: Department of Pathology, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sander M J
authors.initials: SM
authors.lastname: van Duijnhoven
authors.affiliation: Department of Pathology, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sanne A M
authors.initials: SA
authors.lastname: van Lith
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Willeke.Daamen@radboudumc.nl.
authors.forename: Willeke F
authors.initials: WF
authors.lastname: Daamen
authors.affiliation: Department of Pathology, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: William P
authors.initials: WP
authors.lastname: Leenders
authors.affiliation: Department of Biochemistry, Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D016503:Drug Delivery Systems; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents
keywords: Chondroitin sulfate; Drug-delivery system; Extracellular matrix; Glycosaminoglycans; Lyophilisomes; Ovarian cancer; Targeted therapy