Adoptive Transfer of Photosensitizer-Loaded Cytotoxic T Cells for Combinational Photodynamic Therapy and Cancer Immuno-Therapy.

Adoptive cell transfer (ACT) has shown remarkable therapeutic efficacy against blood cancers such as leukemia and lymphomas, but its effect is still limited due to the lack of well-defined antigens expressed by aberrant cells within tumors, the insufficient trafficking of administered T cells to the tumor sites, as well as immunosuppression induced by the tumor microenvironment (TME). In this study, we propose the adoptive transfer of photosensitizer (PS)-loaded cytotoxic T cells for a combinational photodynamic and cancer immunotherapy. Temoporfin (Foscan®), a clinically applicable porphyrin derivative, was loaded into OT-1 cells (PS-OT-1 cells). The PS-OT-1 cells efficiently produced a large amount of reactive oxygen species (ROS) under visible light irradiation in a culture; importantly, the combinational photodynamic therapy (PDT) and ACT with PS-OT-1 cells induced significant cytotoxicity compared to ACT alone with unloaded OT-1 cells. In murine lymphoma models, intravenously injected PS-OT-1 cells significantly inhibited tumor growth compared to unloaded OT-1 cells when the tumor tissues were locally irradiated with visible light. Collectively, this study suggests that combinational PDT and ACT mediated by PS-OT-1 cells provides a new approach for effective cancer immunotherapy.

Liposome-mediated PD-L1 multivalent binding promotes the lysosomal degradation of PD-L1 for T cell-mediated antitumor immunity.

Immune checkpoint blockade (ICB) has shown remarkable therapeutic efficacy in a variety of cancers. However, patients exhibit unexpectedly low response rates to ICB therapy owing to the unwanted recycling and cellular abundance of PD-L1. Herein, rational design of PD-L1 multivalent binding liposome is investigated through PEGylated liposomes incorporating different ratios of PD-L1 binding peptide. Liposomes incorporating 10 mol% PD-L1 binding peptides (10-PD-L1-Lipo) promote the multivalent binding with PD-L1 on tumor cell surface, which is endocytosed for its trafficking toward the lysosomes instead of the recycling endosomes. Thereby, 10-PD-L1-Lipo leads to a significant PD-L1 degradation that prevents its recycling and cellular abundance compared to anti-PD-L1 antibody, disrupting immune escape mechanism of tumor cells and enhancing T cell-mediated antitumor immunity. Moreover, a clinically applicable doxorubicin (DOX) liposomal formulation is established via drug encapsulation into 10-PD-L1-Lipo. The resulting DOX-PD-L1-Lipo primes tumors via immunogenic chemotherapy by preferential DOX accumulation by the EPR effect and overcomes PD-L1 abundance induced following chemotherapy through multivalent binding-mediated PD-L1 degradation. As a result, the synergistic immunogenic chemotherapy and multivalent binding-mediated PD-L1 degradation by DOX-PD-L1-Lipo show significantly enhanced antitumor efficacy and immune responses in colon tumor models. Collectively, this study suggests the rationally designed PEGylated liposomes to promote PD-L1 multivalent binding providing a new route for safe and more effective ICB therapy.

Capacitive coupling leading to electrical skin burn injury during laparoscopic surgery.

Purpose: Trocar-site burns occurring during laparoscopic surgery have been reported in various cases, and several efforts to reduce them are underway. This study aimed to analyze the effect of capacitive coupling on trocar site by observing electrical and histological changes for electrical skin burn injury. Methods: To measure the electrical changes relating to capacitive coupling, the temperature, current, voltage, and impedance around the trocar were measured when an open circuit and a closed circuit were formed using insulation intact instruments and repeated after insulation failure. After the experiment, the tissue around the trocar was collected, and microscopic examination was performed. Results: When open circuits were formed with the intact insulation, the impedance was significantly reduced compared to the cases of closed circuits (142.0 Ω vs. 109.3 Ω, p = 0.040). When the power was 30 W and there was insulation failure, no significant difference was measured between the open circuit and the closed circuit (147.7 Ω vs. 130.7 Ω, p = 0.103). Collagen hyalinization, nuclear fragmentation, and coagulation necrosis suggesting burns were observed in the skin biopsy at the trocar insertion site. Conclusion: This study demonstrated that even with a plastic trocar and electrosurgical instruments that have intact insulation, if an open circuit is formed, capacitive coupling increases, and trocar-site burn can occur. When using electrocautery, careful manipulation must be taken to avoid creating an open circuit to prevent capacitive coupling related to electrical skin burn.

Cancer-activated doxorubicin prodrug nanoparticles induce preferential immune response with minimal doxorubicin-related toxicity.

The effective chemotherapeutic drug, doxorubicin (DOX), elicits immunogenic cell death (ICD) and additional anticancer immune responses during chemotherapy. However, it also induces severe side effects and systemic immunosuppression, hampering its wide clinical application. Herein, we constructed cancer-activated DOX prodrug by conjugating the cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in FRRG-DOX that self-assembled into cancer-activated DOX prodrug nanoparticles (CAP-NPs). The resulting CAP-NPs were further stabilized with the FDA-approved compound, Pluronic F68. CAP-NPs formed stable prodrug nanoparticles and they were specifically cleaved to cytotoxic DOX molecules only in cathepsin B-overexpressing cancer cells, inducing a cancer cell-specific cytotoxicity. In particular, the CAP-NPs induced ICD through cathepsin B-cleavage mechanism only in targeted cancer cells in vitro. In colon tumor-bearing mice, selectively accumulated CAP-NPs at tumors enhanced antitumor immunity without DOX-related severe toxicity, inflammatory response and systemic immunosuppression. Moreover, cytotoxicity against immune cells infiltrated into tumor microenvironment was significantly reduced compared to free DOX, leading to increased response to checkpoint inhibitor immunotherapy. The combinatorial treatment of CAP-NPs with anti-PD-L1 exhibited high rate of complete tumor regression (50%) compared to free DOX with anti-PD-L1. Concurrently, DOX-related side effects were greatly reduced during chemoimmunotherapy. Collectively, our results suggest that cancer-activated DOX prodrug nanoparticles provide a promising approach to increase clinical benefit by inducing an immune response preferentially only to targeted cancer cells, not to normal cells and immune cells, and potentiates checkpoint inhibitor immunotherapy.

Advances in the strategies for designing receptor-targeted molecular imaging probes for cancer research.

Receptor targeted imaging has emerged as a promising tools for imaging tumor tissues. Receptor targeted molecular imaging confers critical information on clinicians including tumor location, expression level of certain receptors, and biological process, which enables early diagnosis and treatment of tumor to control cancer mortality. Receptor targeted probe design is a key to successfully deliver accurate information through many imaging modalities. When designing receptor targeted imaging probes, a variety of targeting receptors and imaging modalities are selected depending on type of cancer because overexpression of receptors are variant among tumors and each imaging modality has advantages and disadvantages. Subsequently selecting appropriate tumor targeting strategies is critical to efficiently visualize tumor of interest. In this review, we presented the strategies commonly used for designing receptor targeted probes and summarized the recent studies that implemented each strategies.

The three dimensional cues-integrated-biomaterial potentiates differentiation of human mesenchymal stem cells.

Alginate (Alg) hydrogels, the most popular natural biomaterials, mimic the extracellular matrix (ECM) microenvironment and offer potential biomedical applications. Despite their excellent properties such as biocompatibility, hydrophilicity and ionic crosslinking, the absence of an intrinsic cell adhesion domain lessens their cell-carrier applications in tissue engineering. Herein, we suggest a three-dimensional (3D) cell culture system by integrating Alg hydrogel and fibroblast-derived matrix (FDM). FDM including cell-adhesion motifs, signaling, and physico-mechanical cues is prepared by the decellularization process by avoiding unfavorable chemical reactions. This cues-integrated-biomaterials (CiB) 3D platform shows increased cell viability, proliferation, chondrogenic and osteogenic differentiation of human bone-marrow-derived mesenchymal stem cells (hMSCs) in situ. The results show that the Alg/FDM hydrogel (CiB) matrix provides an excellent microenvironment for cell adhesion and can control the differentiation of hMSCs into specific lineages. Thus, these results suggest the potential applications of the Alg/FDM hydrogel matrix as a viable 3D culture system for tissue regeneration.