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Introduction This study aims to investigate and fairly compare the oncological therapeutic efficacy of red photodynamic therapy (Red-PDT) and near-infrared photodynamic therapy (NIR-PDT), to support the selection of suitable photosensitizers (PSs) for optimal PDT. Methods Two different representative PSs, trastuzumab-HiLyte Fluor™ 647 conjugate (Tra-HLF647) and trastuzumab-Indocyanine Green conjugate (Tra-ICG), activated by two laser systems at 635 nm and 808 nm, respectively, were used. To ensure a fair comparison, we used the same A4 cell line/tumor model expressing the same target, human epidermal growth factor receptor 2 (HER-2), and employed the same delivery approach. To comprehensively evaluate and compare the potential effects of Tra-HLF647-mediated Red-PDT and Tra-ICG-mediated NIR-PDT, we conducted cell viability imaging assays, intracellular reactive oxygen species (ROS) generation measurements, longitudinal monitoring of tumor volume changes, histological and immunohistochemical (IHC) analyses of tumor sections, and measurements of tumor necrotic depth. Results Both PDTs exerted similar rapid cell death in cell viability imaging assays. There was no significant difference in ROS generation between cells subjected to Red-PDT and NIR-PDT. Both PDTs caused a statistically significant tumor growth delay compared to the control groups; however, no significant difference was detected between the Red-PDT and NIR-PDT groups. The H&E-stained sections of tumors that received Red-PDT and NIR-PDT showed a similar pattern of necrosis-associated features. No conspicuous tissue damage was observed in the control groups. The depth of necrosis, estimated via the coincided accumulation of a fluorescent necrosis marker (AF546-pHLIP) and utilized as an indirect index to approximate laser light penetration, was also nearly identical between tumors treated with Red-PDT and NIR-PDT. Conclusions Target-specific Red-PDT and NIR-PDT, using their respective PSs, demonstrated equivalent therapeutic efficacy in tumor models. These findings suggest that wavelength differences between Red-PS and NIR-PS may not critically impact treatment outcomes, offering flexibility in fluorophore selection for future PS conjugate design.

To select the most suitable chelate for 225Ac radiolabeling of the anti‐FZD10 antibody OTSA101, we directly compared three chelates: S‐2‐(4‐isothiocyanatobenzyl)‐1,4,7,10‐tetraazacyclododecane tetraacetic acid (p‐SCN‐Bn‐DOTA), 2,2′,2″‐(10‐(1‐carboxy‐4‐((4‐isothiocyanatobenzyl)amino)‐4‐oxobutyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl) triacetic acid (p‐SCN‐Bn‐DOTAGA), and 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid mono‐N‐hydroxysuccinimide ester (DO3A‐NHS‐ester). We evaluated the binding affinity of the chelate‐conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225Ac‐labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate‐conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO‐1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA‐OTSA101 and DO3A‐OTSA101 were 1.8‐fold higher than that of DOTA‐OTSA101 (p < 0.01). The stabilities were similar between 225Ac‐labeled DOTA‐OTSA101, DOTAGA‐OTSA101, and DO3A‐OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor‐absorbed doses by 225Ac‐labeled DOTA‐OTSA101 and DOTAGA‐OTSA101 compared with 225Ac‐DO3A‐OTSA101 (p < 0.05). 225Ac‐DOTAGA‐OTSA101 exhibited the highest tumor‐to‐bone marrow ratio, with bone marrow being the dose‐limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225Ac‐labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow. A direct comparison of three bifunctional chelates, p‐SCN‐Bn‐DOTA, p‐SCN‐Bn‐DOTAGA, and DO3A‐NHS‐ester demonstrated that DOTAGA would be the most promising chelate to produce 225Ac‐labeled OTSA101 with high binding affinity and high labeling efficiency and to provide high absorbed doses to tumors and limited ones to bone marrow.

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the 90Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent 111In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y‐labeled OTSA101. 90Y‐ and 225Ac‐labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with 225Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma. FZD10‐targeted alpha‐radioimmunotherapy with 225Ac‐labeled OTSA101 provided a high radiation dose to tumors and achieved 60% complete response in the synovial sarcoma mouse model SYO‐1. This is the best outcome among FZD10‐targeted therapy to date. Our alpha‐radioimmunotherapy would provide an additional therapeutic option to synovial sarcoma patients that do not show a good response to conventional therapy.

Pancreatic cancer (PC) has a poor prognosis owing to difficulties in the diagnosis of resectable PC at early stages. Several clinical studies have indicated that the detection and surgery of small resectable PC (<1 cm) can significantly improve survival; however, imaging diagnosis and accurate resection of small PC remain challenging. Here, we report the feasibility of “immuno-OpenPET” as a novel approach enabling not only early diagnosis but also image-guided surgery, using a small (<1 cm) resectable PC orthotopic xenograft mouse model. For immuno-OpenPET, we utilized our original OpenPET system, which enables high-resolution positron emission tomography (PET) imaging with depth-of-interaction detectors, as well as real-time image-guided surgery, by arranging the detectors to create an open space for surgery and accelerating the image reconstruction process by graphics processing units. For immuno-OpenPET, 64 Cu-labeled anti-epidermal growth factor receptor antibody cetuximab was intraperitoneally administered into mice. It clearly identified PC tumors ≥3 mm. In contrast, neither OpenPET with intravenous-administered 64 Cu-cetuximab nor intraperitoneal/intravenous-administered 18 F-FDG (a traditional PET probe) could detect PC in this model. Immuno-OpenPET-guided surgery accurately resected small PC in mice and achieved significantly prolonged survival. This technology could provide a novel diagnostic and therapeutic strategy for small resectable PC to improve patient survival.

Auger electrons can cause nanoscale physiochemical damage to specific DNA sites that play a key role in cancer cell survival. Radio-Pt is a promising Auger-electron source for damaging DNA efficiently because of its ability to bind to DNA. Considering that the cancer genome is maintained under abnormal gene amplification and expression, here, we developed a novel 191Pt-labeled agent based on pyrrole–imidazole polyamide (PIP), targeting the oncogene MYCN amplified in human neuroblastoma, and investigated its targeting ability and damaging effects. A conjugate of MYCN-targeting PIP and Cys-(Arg)3-coumarin was labeled with 191Pt via Cys (191Pt-MYCN-PIP) with a radiochemical purity of >99%. The binding potential of 191Pt-MYCN-PIP was evaluated via the gel electrophoretic mobility shift assay, suggesting that the radioagent bound to the DNA including the target sequence of the MYCN gene. In vitro assays using human neuroblastoma cells showed that 191Pt-MYCN-PIP bound to DNA efficiently and caused DNA damage, decreasing MYCN gene expression and MYCN signals in in situ hybridization analysis, as well as cell viability, especially in MYCN-amplified Kelly cells. 191Pt-MYCN-PIP also induced a substantial increase in cytosolic dsDNA granules and generated proinflammatory cytokines, IFN-α/β, in Kelly cells. Tumor uptake of intravenously injected 191Pt-MYCN-PIP was low and its delivery to tumors should be improved for therapeutic application. The present results provided a potential strategy, targeting the key oncogenes for cancer survival for Auger electron therapy.

Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality, the effect of which is improved in combination with chemotherapy. PIT causes a super-enhanced permeability and retention (SUPR) effect. Here, we quantitatively evaluated the SUPR effect using radiolabeled drugs of varying molecular weights (18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808 nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both hindlimbs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were evaluated using positron emission tomography or single-photon emission computed tomography. Imaging studies found increased tumor accumulation of agents after PIT. PIT-treated tumors showed significantly increased uptake of 18F-5FU (p < 0.001) and 99mTc-HSA-D (p < 0.001). A tendency toward increased accumulation of 111In-DTPA and 111In-IgG was observed. These findings suggest that some low- and medium-molecular-weight agents are promising candidates for combined PIT, as are macromolecules; hence, administration after PIT could enhance their efficacy. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs.

Background Several platinum radionuclides, including 191 Pt, are promising candidates for DNA-targeted Auger electron radiotherapy; however, effective compound designs are needed for this application. In this study, we developed six novel 191 Pt-labeled compounds and evaluated their DNA-targeting properties in PSMA-positive tumors. Results Six trithiol-Hoechst-PSMA (THP) conjugates that consist of a trithiol ligand for 191 Pt labeling, Hoechst33258 for DNA binding, and a PSMA-targeted moiety were synthesized and labeled with 191 Pt, achieving radiochemical yields of 60–80%. The six [ 191 Pt]Pt-THP compounds were evaluated for DNA-binding ability and PSMA targeting specificity in vitro, and biodistribution experiments were performed with five of the compounds in mice bearing subcutaneous PSMA-positive and PSMA-negative xenografts. Among them, [ 191 Pt]Pt-THP3–4 and [ 191 Pt]Pt-THP3–8, in which Hoechst33258 is linked on one side of the trithiol ligand via a linear PEG linker and the PSMA-targeting moiety is linked on the other side via a C4 linker, had the best properties. These compounds maintained higher PSMA targeting specificity and DNA-binding ability both in vitro and in vivo than the other [ 191 Pt]Pt-THP compounds, exhibiting similar DNA binding in PSMA-positive PC3 PIP tumors in vivo as in the cultured cells from which the xenograft was derived. Conclusions This study highlighted the importance of the linkers between the three components (trithiol-Hoechst-PSMA) and demonstrated binding of intravenously administered [ 191 Pt]Pt-THP3–4 and [ 191 Pt]Pt-THP3–8 to DNA in PSMA-positive tumors. Our compound designs and findings could be a useful foundation for DNA-targeted Auger electron cancer therapy, especially with Pt radionuclides.

Background: CD73 is an ectonucleotidase regulating extracellular adenosine concentration and plays an important role in adenosine-mediated immunosuppressive pathways. The efficacy of CD73-targeted therapy depends on the expression levels of CD73; therefore, monitoring CD73 status in cancer patients would provide helpful information for selection of patients who would benefit from CD73-targeted therapy. Here, we evaluated the ability of 111In-labeled antibody 067-213, which has high affinity for human CD73, to act as a noninvasive imaging probe. Methods: Cell binding and competitive inhibition assays for 111In-labeled 067-213 were conducted using MIAPaCa-2 (high CD73 expression) and A431 (low CD73 expression) cells. For in vivo assessments, biodistribution and SPECT/CT studies were conducted in MIAPaCa-2 and A431 tumor-bearing mice. To estimate the absorbed dose in humans, biodistribution and SPECT/CT studies were conducted in healthy rats. Results: 111In-labeled 067-213 bound to MIAPaCa-2 and A431 cells in a CD73-dependent manner and the affinity loss after 111In-labeling was limited. Biodistribution and SPECT/CT studies with 111In-labeled 067-213 in mice showed high uptake in MIAPaCa-2 tumors and lower uptake in A431 tumors. In rats, the probe did not show high uptake in normal organs, including endogenously CD73-expressing organs. The estimated absorbed doses in humans were reasonably low. Conclusions: 111In-labeled 067-213 showed CD73-expression-dependent tumor uptake and low uptake in normal organs and tissues. Radiolabeled 067-213 holds promise as an imaging probe for noninvasive evaluation of CD73 expression levels in patients. Our data encourage further clinical studies to clarify a role for CD73 monitoring in patients receiving CD73-targeted immune therapy.

Due to their short-range (2–500 nm), Auger electrons (Auger e−) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Auger e−, it remains challenging to maximize the interaction between Auger e− and DNA. To assess the DNA-damaging effect of Auger e− released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by immunofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incubation), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by the release of Auger e− very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e−.

The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12. Methods: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted. Results: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect. Conclusions: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.