Targeting the extracellular matrix of ovarian cancer using functionalized, drug loaded lyophilisomes

• Published in: European journal of pharmaceutics and biopharmaceutics 2017-04, Vol.113, p.229-239
• Main Authors: van der Steen, Sophieke C.H.A., Raavé, René, Langerak, Sjoerd, van Houdt, Laurens, van Duijnhoven, Sander M.J., van Lith, Sanne A.M., Massuger, Leon F.A.G., Daamen, Willeke F., Leenders, William P., van Kuppevelt, Toin H.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Carcinoma, Ovarian Epithelial; Chondroitin sulfate; Drug Delivery Systems; Drug-delivery system; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Female; Glycosaminoglycans; Humans; Lyophilisomes; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Targeted therapy
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2016.12.010

[Display omitted] 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.