Search Results (75)

In boron neutron capture therapy (BNCT), the intracellular localization and concentration of boron-10 atoms significantly influence therapeutic efficacy. Although various boronic-acid-targeted fluorescent probes have been developed to evaluate BNCT agents, most of these probes emit at short wavelengths and are, therefore, incompatible with common nuclear-staining reagents such as Hoechst 33342 and 4′,6-diamidino-2-phenylindole (DAPI). While our previously reported probe, BS-631, emitted fluorescence above 500 nm, it exhibited limitations in terms of reaction rate and fluorescence intensity. To address these issues, we developed a boronic-acid-targeted fluorescent probe with a longer emission wavelength, rapid reactivity, and strong fluorescence intensity. Herein, we designed and synthesized BTTQ, a probe based on a 2-(2-hydroxyphenyl)benzothiazole core structure. BTTQ exhibited immediate fluorescence upon reaction with 4-borono-L-phenylalanine (BPA), with an emission wavelength of 567 nm and a sufficiently high fluorescence quantum yield for detection. BTTQ quantitatively detected BPA with high sensitivity (quantification limit of 10.27 µM), suitable for evaluating BNCT agents. In addition, BTTQ exhibited selective fluorescence for BPA over metal cations. Importantly, BTTQ enabled fluorescence microscopic imaging of intracellular BPA distribution in living cells co-stained with Hoechst 33342. These results suggest that BTTQ is a promising fluorescent probe for the evaluation of future BNCT agents. Full article

According to the WHO, in 2022, there were 2.3 million women diagnosed with breast cancer (BC) and 670,000 deaths globally. BC remains the leading cause of cancer-related mortality, with therapeutic resistance representing a significant barrier to effective treatment, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This review article discusses emerging strategies to overcome resistance by integrating precision oncology, nanotechnology-based drug delivery, and immune modulation. Resistance mechanisms—such as metabolic reprogramming, tumor heterogeneity, immune evasion, autophagy, and the role of cancer stem cells—are critically examined. We highlight cutting-edge nanoplatforms that co-deliver chemotherapeutics and immune stimulants with spatiotemporal precision, including sonodynamic and photothermal systems, ADCs, and targeted nanoparticles. Moreover, advances in tumor microenvironment (TME) modulation, photoimmunotherapy, and exosomal miRNA targeting offer promising avenues to enhance immunogenicity and therapeutic durability. The integration of molecular profiling with advanced computational approaches, including artificial intelligence and biomimetic models, holds significant promise for the future development of personalized resistance-mitigating interventions, though a detailed exploration is beyond the current scope. Collectively, these strategies reflect a paradigm shift from conventional monotherapies toward multifaceted, precision-guided treatment approaches. This review aims to provide a comprehensive overview of current innovations and propose future directions for overcoming drug resistance in BC. Full article

Traditional oncological therapies have contributed to reducing the global cancer burden; however, they have not achieved complete eradication, nor have they effectively prevented relapses, minimized toxicity, or preserved immune function. Recent advances, particularly the introduction of immune checkpoint inhibitors (ICIs) and CAR-T cell therapies, have markedly improved clinical outcomes and overall survival in certain cancer subtypes. Nevertheless, response rates remain suboptimal, and adverse immunological events are frequent. This review starts by highlighting the FDA-approved ICIs currently utilized in cancer immunotherapy, emphasizing those that have demonstrated clinical efficacy in recent years. The true focus of our analysis is on the latest clinical applications of near-infrared photoimmunotherapy (NIR-PIT). This emerging modality is evaluated in patients with head and neck cancers (HNC), particularly in cases that are unresectable, locally advanced, or recurrent. Finally, the review explores the current landscape and prospects of NIR-PIT, considering its potential to enhance therapeutic efficacy and extend relapse-free survival. Photoimmunotherapy is a promising, molecularly targeted option for patients with limited prognosis, offering new hope where conventional therapies fail. By synthesizing recent clinical trial data, this work highlights how NIR-PIT could bridge the translational gap between preclinical research and clinical practice. The integration of advanced technologies and interdisciplinary collaboration among researchers, clinicians, and technologists will be critical in optimizing NIR-PIT, improving its accuracy, efficacy, and safety, and ultimately advancing standards of cancer care and patient survival. Full article

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb–IR700 conjugate through the blood–brain barrier (BBB), which is a significant challenge for NIR-PIT in treating brain tumors. Innovative approaches for delivering the mAb–IR700 conjugate across the BBB include exosomes, nanoparticle-based systems, and cell-penetrating peptides. Small-molecule compounds, such as affibodies, are anticipated to rapidly accumulate in tumors within intracranial models, and our preliminary experiments demonstrated rapid uptake. NIR-PIT also induces immunogenic cell death and activates the anti-tumor immune response. Overall, NIR-PIT is a promising approach for treating brain tumors. It has the potential to overcome the limitations of conventional therapies and offers new hope to patients with brain tumors. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC. Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye^®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/nu mice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT. Results: The binding rate of anti-FAP antibody-AlexaFluor^®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p < 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm³, p < 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group. Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC. Full article

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 receptor α chain subunit (IL-15Rα), followed by trans-presentation to the IL-15 receptor β/γ chain subunit on the effector cells for pharmacologic activation. Therefore, the delivery of IL-15 remains a major challenge owing to its short half-life, its lack of targeting activity, and the limited availability of IL-15Rα. Methods: A co-hitchhiking delivery approach using recombinant IL-15 (rIL-15) and a photosensitizer, pheophorbide A (PhA), is developed for enhanced combinatorial cancer immunotherapy with PDT. A recombinant IL-15Rα-sushi-Fc fusion protein (rILR-Fc) is designed to load rIL-15 through the IL-15Rα sushi domain, which mimics its trans-presentation. Moreover, the Fc moiety of rILR-Fc can load PhA based on its high binding affinity. Results: Through self-assembly, rILR-Fc/PhA/rIL-15 nanoparticles (NPs) are formulated to co-hitchhike PhA and rIL-15, which improves the tumor accumulation of PhA and rIL-15 through receptor-mediated transcytosis. Moreover, the nanoparticles prolong the blood half-life of rIL-15 but do not alter the elimination rate of PhA from the blood. The rILR-Fc/PhA/rIL-15 NPs effectively elicit potent systemic antitumor immunity and long-lasting immune memory against tumor rechallenge in model mice bearing orthotopic colon tumors. Conclusions: The enhanced antitumor therapeutic effect demonstrates that the co-hitchhiking delivery strategy, optimizing the pharmacokinetics of both the photosensitizer and IL-15, provides a promising strategy for combinatorial photodynamic and IL-15 immunotherapy. Full article

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum, while simultaneously upregulating pathogen-associated molecular patterns and damage-associated molecular patterns to potentiate tumor immunotherapy. Methods: The liposomes (PD/GA-LPs) loaded with the perylene diimide complex (PD) and gambogic acid (GA) were fabricated via the extrusion method. Subsequently, comprehensive evaluations including physicochemical characteristics, antibacterial activity, antitumor effect, and immunomodulatory effect evaluation were systematically conducted to validate the feasibility of this delivery system. Results: The resulting PD/GA-LPs exhibited a dynamic size (121.3 nm, zeta potential −44.1 mV) and a high encapsulation efficiency of approximately 78.1% (PD) and 91.8% (GA). In addition, the optimized PD/GA-LPs exhibited excellent photothermal performance and antibacterial efficacy. In vitro cellular experiments revealed that PD/GA-LPs exhibited enhanced internalization by neutrophils, followed by extracellular trap-mediated release, ultimately significantly inhibiting tumor cell proliferation and inducing immunogenic cell death. During in vivo treatment, PD/GA-LPs exhibited targeted tumor accumulation, where F. nucleatum-driven PD reduction activated near-infrared-responsive photothermal ablation. When combined with GA, this delivery system effectively eliminated tumor cells and F. nucleatum, while facilitating the subsequent T-cell infiltration. Conclusions: This strategy amplified the antitumor immune response, thus leading to effective treatment of BC and prevention of metastasis. In summary, this approach, grounded in the distinct microecology of tumor and normal tissues, offers novel insights into the development of precise and potent immunotherapies for BC. Full article

Background/Objectives: The kinase p38α, a member of the mitogen-activated protein kinase (MAPK) family, is activated by external stimuli and plays a crucial role in inflammation, tumor growth, and metabolic disorders. In particular, p38α is involved in thermogenesis and the metabolism of glucose in brown adipose tissue (BAT), and it contributes to the suppression of obesity and diabetes. The noninvasive imaging of activated p38α could help elucidate diverse pathological processes, including metabolic and inflammatory conditions. This study aimed to develop and evaluate a novel fluorine-18-labeled positron emission tomography (PET) probe for imaging activated p38α in vivo. Methods: We designed 6-(4-[¹⁸F]fluoro-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([¹⁸F]R1487) by replacing a fluorine atom in R1487, which is a highly selective p38α inhibitor, with ¹⁸F. A tributylstannyl precursor was reacted with [¹⁸F]KF in the presence of a copper catalyst to synthesize [¹⁸F]R1487. Biodistribution studies and PET/computed tomography (CT) were performed on normal mice to evaluate the in vivo potential of [¹⁸F]R1487. Results: [¹⁸F]R1487 was obtained with a decay-corrected radiochemical conversion of 30.6 ± 5.6% and a decay-corrected radiochemical yield of 6.9 ± 3.6% with a radiochemical purity of >99% after reversed-phase high-performance liquid chromatography purification. The biodistribution study demonstrated high and rapid radioactivity accumulation in BAT (16.3 ± 2.7 %ID/g at 5 min post-injection), with a consistently high BAT-to-blood ratio (>5 over 2 h post-injection). PET/CT imaging successfully visualized BAT with high contrast. Conclusions: These results suggest that [¹⁸F]R1487 is a promising PET probe for imaging activated p38α in vivo, which has potential applications for pathophysiological conditions such as inflammation, cancer, and metabolic disorders. Full article

Background/Objectives: Integrin α_Vβ₃ plays a crucial role in tumor angiogenesis and cancer progression, making it a key target for radiolabeled probes used in imaging and therapy. A previously developed probe, [¹²⁵I]bcRGD, exhibited high selectivity for α_Vβ₃ but limited tumor accumulation due to rapid blood clearance. This study aimed to address this issue through two strategies: (1) conjugating albumin-binding molecules to enhance systemic circulation and (2) dimerizing RGD peptides to improve binding affinity via multivalency effects. Methods: Three [¹²⁵I]bcRGD derivatives were synthesized: [¹²⁵I]bcRGD_pal (with palmitic acid), [¹²⁵I]bcRGD_iba (with 4-(p-iodophenyl)butyric acid), and [¹²⁵I]bcRGD_dimer (a dimeric bicyclic RGD peptide). Their physicochemical properties, α_Vβ₃-selectivity, albumin-binding capacity, and biodistribution were assessed in vitro and in vivo using tumor-bearing mice. Tumor models included α_Vβ₃-high U-87 MG and α_Vβ₃-low A549 xenografts. Results: [¹²⁵I]bcRGD_pal and [¹²⁵I]bcRGD_iba exhibited prolonged blood retention (30-fold and 55-fold vs. [¹²⁵I]bcRGD, respectively) and increased tumor accumulation (3.9% ID/g and 3.6% ID/g at 2 h, respectively). Despite improved systemic circulation, tumor-to-blood ratios remained low (<1), indicating limited tumor retention. [¹²⁵I]bcRGD_dimer achieved significantly greater tumor accumulation (4.2% ID/g at 2 h) and favorable tumor-to-blood (22) and tumor-to-muscle (14) ratios, with a 5.4-fold higher uptake in U-87 MG tumors compared to A549 tumors. Conclusions: Dimerization was more effective than albumin binding in enhancing bcRGD’s tumor-targeting potential. The dimeric probe demonstrated improved tumor accumulation, favorable pharmacokinetics, and preserved integrin selectivity. These findings provide a foundation for further structural optimization of bicyclic RGD peptides for integrin α_Vβ₃-targeted imaging and therapy applications. Full article

Glucagon-like peptide-1 receptor (GLP-1R) is an emerging critical target for the diagnosis and treatment of various diseases. Radiolabeled exendin-4 (Ex-4), a GLP-1R agonist, has been widely used as an imaging probe. However, its potential to induce hypoglycemia, especially in patients with insulinoma, limits its applicability. This study evaluated whether Ex-D3, a Glu3Asp substitution of Ex-4 with a higher internalization rate, could enhance the imaging efficacy of Ex-4 while reducing its hypoglycemic effects. We synthesized derivatives with an additional C-terminal Cys (Ex-D3-C40) for site-specific ¹²⁵I labeling. Surface plasmon resonance analysis revealed that C-terminus modification did not significantly alter the binding affinity of Ex-D3-C40 to GLP-1R. In vivo studies in mice demonstrated that Ex-D3-C40 induced weaker hypoglycemic effects than Ex-4-C40. Biodistribution studies showed that ¹²⁵I-labeled Ex-D3 ([¹²⁵I]I-Ex-D3) achieved significantly higher pancreatic accumulation and higher pancreas-to-blood and pancreas-to-muscle ratios than [¹²⁵I]I-Ex-4. Ex vivo autoradiography confirmed the binding specificity of [¹²⁵I]I-Ex-D3 to GLP-1R-expressing pancreatic β-cells. These findings indicate that Ex-D3 is a promising parent peptide for the development of superior GLP-1R imaging probes with reduced hypoglycemic risk, highlighting the importance of considering pharmacological effects in designing molecular imaging probes. Full article

Background: Seasonal influenza causes significant morbidity and mortality each year. Since viruses can easily acquire drug-resistant mutations, it is necessary to develop new antiviral strategies with different targets. Near-infrared photoimmunotherapy (NIR-PIT) is a type of anti-cancer therapy that has recently attracted considerable attention, with favorable outcomes reported for several cancers. In this study, we investigated whether this approach could be used as a novel anti-influenza therapy to destroy influenza virus and infected cells. Methods: To evaluate the efficacy of near-infrared antiviral photoimmunotherapy (NIR-AVPIT), we prepared an anti-hemagglutinin (HA) monoclonal antibody without neutralizing activity against influenza A virus (FluV) labeled with IR-700 and reacted it with FluV and infected cells, as well as HA-expressing HEK293 cells. Results: NIR-AVPIT strongly inactivated FluV virions, suppressed cytopathic effects, and achieved more than a 4-log reduction in viral RNA amplification. Treatment of FluV-infected cells with the antibody-IR700 complex and NIR in the early stages of infection significantly inhibited viral propagation, and double treatment with time apart exerted a greater inhibitory effect. NIR-AVPIT rapidly induced morphological changes in HA-expressing HEK293 cells and inhibited the proliferation of these cells. Conclusions: These results suggest that NIR-AVPIT targeting HA antigens could inactivate FluV and eliminate infected cells in vitro. This strategy is a promising approach to treat various viral infections, including influenza. Full article

Background/Objectives: Photoimmunotherapy (PIT) is an innovative approach for the targeted therapy of cancer. In PIT, photosensitizer dyes are conjugated to tumor-specific antibodies for targeted delivery into cancer cells. Upon irradiation with visible light, the photosensitizer dye is activated and induces cancer-specific cell death. In the present article, we describe the PIT of prostate cancer (PC) as a therapeutic option for the targeted treatment of localized prostate cancer. Methods: We conjugated the silicon phthalocyanine dye WB692-CB2 to recombinant cysteine-modified anti-CD44 and anti-EpCAM antibodies via a maleimide linker and tested the antibody dye conjugates for PIT on PC cells and prostate cancer stem cell (PCSC)-like cells. Results: The anti-CD44 and anti-EpCAM antibody dye conjugates showed specific binding and high cytotoxicity against PC and PCSC-like cells following irradiation with red light. Combined treatment with both conjugates led to enhanced cytotoxic effects. Conclusions: PIT with our dye WB692-CB2 can serve as an effective focal therapy against prostate cancer, preserving the prostate gland and minimizing side effects. It can be employed during radical prostatectomy (RP) to treat residual tumor cells or lymph node metastases in areas where further surgical intervention is not feasible. Utilizing multiple conjugates against antigens expressed on differentiated PC and PCSC-like cells, such as CD44 and EpCAM, could be an effective method to eradicate residual cancer cells in heterogeneous tumors. This approach could reduce the risk of local recurrence after RP and thus increase the therapeutic outcome of PC patients. Full article

Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X (IR700) fluorescence intensity plateaus during treatment, indicating a particular threshold for the antitumor effects. Therefore, we investigated the NIR laser dose across varying tumor sizes and irradiation methods until the antitumor effects of the fluorescence decay rate plateaued. Methods: Mice were subcutaneously transplanted with A431 xenografts and categorized into control, clinical dose (cylindrical irradiation at 100 J/cm², frontal irradiation at 50 J/cm²), and evaluation groups. The rate of tumor IR700 fluorescence intensity decay to reach predefined rates (−0.05%/s or −0.2%/s) until the cessation of light irradiation was calculated using a real-time fluorescence imaging system. Results: The evaluation group exhibited antitumor effects comparable to those of the clinical dose group at a low irradiation dose. Similar results were observed across tumor sizes and irradiation methods. Conclusions: In conclusion, the optimal antitumor effect of NIR-PIT is achieved when the fluorescence decay rate reaches a plateau, indicating the potential to determine the appropriate dose for PIT using a real-time fluorescence monitoring system. Full article

Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer therapy that uses NIR light and conjugates of a tumor-targeting monoclonal antibody and phthalocyanine dye. In clinical practice, frontal and cylindrical diffusers are the only options for NIR illumination. However, illumination in a narrow space is technically difficult with such diffusers. Therefore, we evaluated a lateral illumination system using a lateral emitting laser (LEL) fiber. The LEL fiber illuminated a certain area in a lateral direction. NIR-PIT with an LEL fiber reduced luciferase activity in a light-dose-dependent manner in A431-GFP-luc cells in vitro and significantly suppressed tumor proliferation in a xenograft mouse model. To evaluate the usefulness of the LEL fiber in the illumination of a narrow space, a tumor was illuminated from the inside of a cylinder, mimicking a narrow space, and the fluorescence intensity in the tumor was monitored. In the frontal diffuser, NIR light was unevenly delivered and little light reached a distal tumor area from the illuminated side. By contrast, the LEL fiber allowed a uniform illumination of the entire tumor, and a loss of fluorescence was observed even in distal areas. These findings suggested that the LEL fiber can be used for NIR-PIT and is suitable for NIR light illumination in a narrow space. Full article

Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients. Full article