Photodynamic Therapy (PDT) has recently gain attention as alternative treatment of Central Nervous System (CNS) cancer diseases, due to the demonstration of successfully elimination of gliomas in patients. The implementation of PDT for brain tumors, and especially glioblastoma (GBM), has already been approved in some countries. Due to their superb light absorption and photostability conjugated polymer nanoparticles (CPNs) are promising photosensitizers (PS) for use in PDT. Recently, we developed metallated porphyrin-doped CPNs for PDT and demonstrated that they were effective eliminating glioma cells trough ROS-mediated photoinduced damage. A problem of many therapies used to eradicate brain gliomas is the difficulty of arrival and preferential accumulation of the active drug into the tumor upon systemic administration due to the selective permeability of the blood-brain barrier (BBB). To solve this problem our approach employs mononuclear cells, which can cross BBB and infiltrate tumors, as stealth carriers for drug delivery into brain tumors. In this study loading of CPNs into monocytes/macrophages was demonstrated and the cellular functionality, chemotaxis and penetration of these loaded monocytes/macrophages into GBM spheroids (3D tumor models) was tested. CPNs loading was successfully achieved using human monocytes THP-1 and mouse bone marrow-derived monocytes (BMdM) without disturbing cell viability and differentiation potential towards macrophage state. CPNs-loaded monocytes were found to better infiltrate spheroids as compared to CPNs. Furthermore, PDT efficacy on GBM spheroids was improved when using our monocyte-mediated delivery strategy
During the past decades, a growing body of evidence clearly indicates that type I IFNs (IFN-1) play a pivotal role in naturally occurring and therapy induced immune responses to cancer. In this context, we describe here a novel effect of photodynamic therapy (PDT): besides its potential to induce apoptosis, PDT elicited an autocrine/paracrine activation of IFN-1 pathway. In the current work, B16-OVA cells were sensitized with Me-ALA-induced protoporphyrin IX (PpIX) which preferentially localized in the endoplasmic reticulum prior to irradiation. Subsequent photoactivation of PpIX with red-light irradiation ignificantly stimulated tumor cells to induce autocrine IFN-1 transcription, concurrently with IRF-3 phosphorylation, at levels that were capable of activating STAT1 and enhancing ligand receptor (cGAS) and ISGs (CXCL10, MX1, ISG15) expression. Among the cellular and molecular pathways identified so far, type I IFNs are critical components for the host immune response against tumor, more specifically for the dendritic cell (DC) compartment. In this sense, PDT-treated melanoma cells induced paracrine IFN-1-dependent phenotypic maturation of monocyte-derived dendritic cells (DCs) by enhancing co-stimulatory signals (CD80, MHC-II) and tumor-directed chemotaxis (transwell migration assay). Collectively, our findings strongly demonstrate the effects of a novel danger signal released by cancer cells undergoing PDT on the maturation and activation of DCs, highlighting the potential added value of PDT in adoptive immunotherapy protocols.
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