부산대학교 도서관

Over the last decades, the occurrence of patients with brain metastases, originating mostly from melanoma, lung and breast cancer, has increased. Despite some progress, there are still no effective therapies that target brain metastases. Due to the blood-brain barrier, which restricts the access of conventional therapies to the central nervous system, therapeutic strategies need to include novel means of drug delivery. Furthermore, these therapies have to target multiple lesions simultaneously, as brain lesions often present multifocally. This study aimed to develop a Haematopoietic stem cell (HSC)-based therapy that has the potential to overcome these limitations. In doing so, the suitability of HSCs and their myeloid progeny as cellular delivery vehicles for the delivery of genetically encoded therapeutic molecules into brain metastases was investigated. A strong infiltration of murine and human brain metastases tissue by the myeloid progeny of HSCs, which mostly consisted of macrophages, was demonstrated. Moreover, following ex vivo modification, the progeny of HSCs were able to deliver an expressed transgene to the proximity of brain metastases in preclinical models. To reduce the toxic effect of the delivered therapeutic molecules, an enzyme prodrug approach was developed and tested in the context of HSC therapy for targeting of brain metastases. In addition to homing to brain metastases, the progeny of HSCs also infiltrates organs. In the context of the cell therapy this could lead to the accumulation of therapeutic molecules at those sites, resulting in possible side effects of the therapy. To address this issue, three promoters with high specificity and activity in murine and human brain metastases-infiltrating myeloid cells were identified, which could be used to restrict the delivery of genetically encoded therapeutic agents to brain metastases.