Dataset Information

PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer.

ABSTRACT: Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFRβ is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z_PDGFRβ affibody with a 0.9 nM affinity for PDGFRβ was produced. The Z_PDGFRβ affibody showed PDGFRβ-dependent pericyte binding. Intravenously injected Z_PDGFRβ affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z_PDGFRβ affibody and IR700 dye, i.e. Z_IR700, bound to PDGFRβ⁺ pericytes but not to PDGFRβ^- LS174T tumor cells. Accordingly, Z_IR700-mediated PDT in vitro induced the death of pericytes but not of LS174T tumor cells. In mice bearing LS174T tumor grafts, Z_IR700-mediated PDT damaged tumor blood vessels, thus inducing tumor destruction by intensifying tissue hypoxia. The average mass of tumor grafts administered with Z_IR700-mediated PDT was approximately 20-30% of that of the control, indicating that pericyte-targeted PDT is efficient for cancer therapy. In addition, Z_IR700-mediated PDT increased the tumor uptake of TNF-related apoptosis-inducing ligand (TRAIL) injected post-illumination. Consequently, combination therapy of Z_IR700-mediated PDT and TRAIL showed greater tumor suppression than Z_IR700-mediated PDT- or TRAIL-based monotherapy. These results demonstrated that active vascular-targeted PDT could be achieved by using Z_PDGFRβ affibody-directed delivery of PS.

SUBMITTER: Shi Q

PROVIDER: S-EPMC8240977 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Photodynamic therapy (PDT) has been proven to be a minimally invasive and effective therapeutic strategy for cancer treatment. It can be used alone or as a complement to conventional cancer treatments, such as surgical debulking and chemotherapy. The mitochondrion is an attractive target for developing novel PDT agents, as it produces energy for cells and regulates apoptosis. Current strategy of mitochondria targeting is mainly focused on utilizing cationic photosensitizers that bind to the negatively charged mitochondria membrane. However, such an approach is lack of selectivity of tumor cells. To minimize the damage on healthy tissues and improve therapeutic efficacy, an alternative targeting strategy with high tumor specificity is in critical need. Herein, we report a tumor mitochondria-specific PDT agent, IR700DX-6T, which targets the 18kDa mitochondrial translocator protein (TSPO). IR700DX-6T induced apoptotic cell death in TSPO-positive breast cancer cells (MDA-MB-231) but not TSPO-negative breast cancer cells (MCF-7). In vivo PDT study suggested that IR700DX-6T-mediated PDT significantly inhibited the growth of MDA-MB-231 tumors in a target-specific manner. These combined data suggest that this new TSPO-targeted photosensitizer has great potential in cancer treatment.Statement of significancePhotodynamic therapy (PDT) is an effective and minimally invasive therapeutic technique for treating cancers. Mitochondrion is an attractive target for developing novel PDT agents, as it produces energy to cells and regulates apoptosis. Current mitochondria targeted photosensitizers (PSs) are based on cationic molecules, which interact with the negatively charged mitochondria membrane. However, such PSs are not specific for cancerous cells, which may result in unwanted side effects. In this study, we developed a tumor mitochondria-targeted PS, IR700DX-6T, which binds to translocator protein (TSPO). This agent effectively induced apoptosis in TSPO-positive cancer cells and significantly inhibited tumor growth in TSPO-positive tumor-bearing mice. These combined data suggest that IR700DX-6T could become a powerful tool in the treatment of multiple cancers that upregulate TSPO.

Dataset Information

PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets