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.

RETRACTED ARTICLE: Nanoscale drug delivery strategies for therapy of ovarian cancer: conventional vs targeted

“…Antibody-functionalised lyophilisomes specifically targeted the ovarian cancer stroma through highly sulphated chondroitin sulphate, CS-E. In a CS-E rich microenvironment in vitro lyophilisomes induced cell death by extracellular release of doxorubicin which localised to the nucleus [127].…”

Engineering Targeting Materials for Therapeutic Cancer Vaccines

“…As an example, Salanti et al targeted a specific sulfated form of CS, called CSA, in melanoma and prostate tumors by using a peptide derived from the Plasmodium falciparum VAR2CSA protein (Salanti et al, 2015). Other approaches to target CS have used antibody fragments (van der Steen et al, 2017) or liposomes containing a cationic lipid TRX-20 (Lee et al, 2002). Lastly, other GAGs can be used as tumoral ECM targets, notably heparan sulfates and aggrecans (Raavé et al, 2018).…”

Nanotechnology and Glycosaminoglycans: Paving the Way Forward for Ovarian Cancer Intervention

“…Most of these studies overlook the cancer ECM as a promising alternative for drug targeting. The largely neglected ECM provides several potential molecular targets for precision therapy of chemotherapeutics [ 126 ]. Recent studies demonstrate that the delivery of anti-cancer drugs to the tumour stroma significantly eliminate cells and their micro-environment in vivo [ 127 , 128 ].…”

“…Recent studies demonstrate that the delivery of anti-cancer drugs to the tumour stroma significantly eliminate cells and their micro-environment in vivo [ 127 , 128 ]. Furthermore, cellular target expressions may change over time resulting in resistance, posing additional challenges [ 126 ]. Therefore, more focus on targeting the ECM may be an important breakthrough for OC [ 126 ].…”

“…Furthermore, cellular target expressions may change over time resulting in resistance, posing additional challenges [ 126 ]. Therefore, more focus on targeting the ECM may be an important breakthrough for OC [ 126 ]. Recently, CS-E was established to be overexpressed in OC ECM and made novel molecular target for anti-cancer therapy [ 115 , 129 ].…”