Efficient Intratumoral Delivery of Oncolytic Vaccinia Virus Using Keratin-based Hydrogel into Breast Cancer

Abstract

Basal-like breast cancers have been found to be highly malignant, which cannot be treated with a hormonal therapy, as they lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The introduction of gene therapy has paved the way to combat those basal-like breast cancers or triple-negative breast cancer. Oncolytic vaccinia virus has been genetically engineered for targeted anti-cancer therapy against various types of tumor through gene-mediated mechanisms as cancer cell-selective replication and cell lysis. However, the clinical efficacy of oncolytic virus has been limited for complete remission of cancer due to complex immunological reaction of the human body, high dose-dependency of oncolytic virus, and difficult distribution throughout the dense tumor cells. For these reasons, we developed an oncolytic virus delivery system using keratin-crosslinked hyaluronic acid hydrogels for both sustained release of virus in the tumor tissue and synergetic anti-tumoral effect of human hair-extracted keratin. This injectable hydrogel delivery system would improve subcutaneously localization and protection of virus from antiviral environment in breast tumor tissue. T cells and cytokine levels were also upregulated by viral delivery with injectable hydrogel. Furthermore, histological examination revealed that necrotic tumor lesion was increased by intratumoral virotherapy in mouse 4T1 cell carcinoma syngeneic model. The results suggest that the viral delivery with biocompatible injectable hydrogel provided an improved tumor targeting and antitumor efficiency of virotherapy for treatment of cancer.