Cancer Biotherapy and Radiopharmaceuticals最新文献

Objectives: Nectin-4 has been successfully used as a target for tumor therapy. Although several bicyclic peptides and antibodies, Nectin-4 positron emission tomography (PET) probes, have been reported for tumor imaging and expression detection, their production costs or pharmacokinetics still need further improvement. This study developed a novel linear peptide PET probe for rapid examination of Nectin-4-related tumors.

Methods: [⁶⁸Ga]Ga-NOTA-SP was prepared by a one-step chelation reaction, and its quality control was carried out by using radio-high-performance liquid chromatography and thin-layer chromatography. Molecular docking was used to predict the predominant binding of NOTA-SP to Nectin-4. Cell experiments using SW780 cells and PET/computed tomography (CT) imaging, using the SW780 tumor model, were performed to assess the specific binding and targeting ability of [⁶⁸Ga]Ga-NOTA-SP to Nectin-4. Normal BALB/c mice were used to investigate the plasma concentration-time curves.

Results: Under optimal labeling conditions, the labeling efficiency of [⁶⁸Ga]Ga-NOTA-SP can reach above 95%, with a molar-specific activity of 2.45 MBq/nmol and high in vitro stability. The high specificity of [⁶⁸Ga]Ga-NOTA-SP to Nectin-4 is demonstrated by molecular docking and cell uptake experiment, showing a binding energy of -5.4 kcal/mol and K_d value of 2.483 nM, which was further confirmed by PET-CT imaging.

Conclusions: [⁶⁸Ga]Ga-NOTA-SP using a linear peptide as a vector shows favorable pharmacokinetics and specific targeting ability to Nectin-4, enabling rapid tumor mouse model imaging. It would be a promising PET/CT imaging probe for optimizing Nectin-4-related tumor diagnoses and therapy.

Background: Response to neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer varies. This study compares tumor response to NACT across anatomical locations, considering clinicopathological differences.

Materials and methods: This retrospective study included 212 patients with gastric adenocarcinoma who received NACT followed by surgery. Tumors were classified by location (antrum-pylorus, corpus-fundus, cardia). Treatment response was assessed using the Modified Ryan Scoring System (0 = complete, 1 = near complete, 2 = partial, 3 = minimal/none).

Results: Tumor locations were antrum-pylorus (30.2%), corpus-fundus (28.3%), and cardia (41.5%). Localization showed no statistically significant differences in response (p = 0.337). However, cardia tumors were more frequent in Groups 3 (40.9%) and 4 (48.1%), which showed poorer pathological responses, whereas antrum (34.6%) and corpus (38.5%) tumors were more common in Group 1, representing patients with a pathological complete response. These findings suggest that cardia tumors may have a lower response to NACT, although definitive conclusions cannot be drawn. In multivariate analysis, only advanced T stage (T3-4) was independently associated with poor tumor regression grade response (odds ratio 14.3, 95% confidence interval 5.4-37.5, p < 0.001).

Conclusions: Tumor response to NACT varied by anatomical location, although differences were not statistically significant. Cardia tumors showed a trend toward lower response rates. To the authors' knowledge, this is the first study evaluating gastric anatomical subgroups in this context. While not conclusive, the findings suggest that tumor location may influence treatment strategies, warranting validation in larger studies.

This review assesses the promise of nanoparticles containing melatonin and lactoferrin (ML-Lf-NPs) in treating cancer, concentrating on their capacity to improve drug delivery, pinpoint tumors, and optimize therapeutic efficacy. A thorough examination of recent progress in nanoparticle-oriented drug delivery systems was performed, highlighting the physicochemical characteristics, mechanisms of action, and biological interactions of ML-Lf-NPs. Melatonin nanoparticles demonstrate antioxidant and anti-inflammatory characteristics that enhance tumor targeting and therapeutic results. Lactoferrin nanoparticles show potential anticancer effects by improving cellular absorption and enabling targeted drug release at tumors. Both systems demonstrate considerable promise for enhancing drug bioavailability and minimizing side effects. ML-Lf-NPs signify creative strategies for cancer treatment. Their distinct characteristics allow for precise delivery and improved therapeutic effectiveness, opening doors for future clinical uses in cancer treatment.

β-glucans are structurally diverse polysaccharides from fungi, yeasts, bacteria, and cereals, exhibiting variable branching and molecular weights that shape their biological activity. Emerging preclinical and clinical evidence highlights their ability to modulate innate and adaptive immunity, exerting direct and adjunct antitumor effects via dectin-1, toll-like receptors, and complement receptor 3. Although well known as nutraceuticals, their integration into advanced cancer biotherapeutics, such as monoclonal antibody regimens, cytokine modulation, and nanoparticle delivery, remains in early translation. This review examines the molecular basis of β-glucan-induced immunostimulation, emphasizing how linkage type, branching frequency, triple-helical structure, and source influence receptor engagement and downstream immune responses. Emerging evidence is presented on β-glucan formulation engineering, including β-glucan-coated polymeric nanoparticles and micelles, β-glucan-complexed lipid nanoparticles for nucleic acid delivery, polymersomes with splenic/myeloid avidity, and β-glucan-stabilized nanosuspensions, several of which show enhanced lymphatic targeting, improved drug bioavailability, or reduced tumor growth in preclinical cancer models. Clinical translation is analyzed with attention to dosing protocols, administration routes (oral, intravenous, topical), and the impact of β-glucan adjuvancy in therapeutic antibodies, immunotoxins, and vascular disrupting agents. The review further addresses essential safety and toxicology data, regulatory compliance challenges, and the imperative for rigorous physicochemical standardization to ensure clinical reproducibility and patient safety. β-glucans have emerged as multifunctional immunomodulators and drug delivery enhancers, driving progress toward personalized cancer immunotherapy and innovative combinatorial regimens. Continued interdisciplinary research and harmonization of extraction, characterization, and delivery protocols are paramount for success in precision oncology.

Introduction: Epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide range of epithelial malignancies, and thus is a potential target for antibody-based radiotherapy. This work describes the synthesis, labeling, and biological evaluation of an alpha-emitting radioconjugate, [²²⁵Ac]Ac-Macropa-PEG₄-HEA125, as a targeted alpha therapy candidate for EpCAM-positive tumors.

Materials and methods: The murine anti-EpCAM monoclonal antibody HEA125 was site-specifically conjugated to the chelator Macropa using a PEG₄-maleimide linker. The structural integrity and chelator-to-antibody (C/A) ratio of the conjugate were confirmed by SDS-PAGE and LC-MS. Radiolabeling with ²²⁵Ac was performed under mild conditions, and radiochemical purity was assessed using iTLC and radio-HPLC. In vitro studies included stability testing, immunoreactivity, and cytotoxicity assays using MCF-7 (EpCAM⁺) and CHO-K1 (EpCAM^-) cell lines. In vivo biodistribution and therapeutic efficacy were evaluated in MCF-7 xenograft-bearing female athymic nude mice (BALB/c nu/nu).

Results: Conjugation with HEA125 resulted in a C/A ratio of 4.2 ± 0.3, and SDS-PAGE proved integrity of antibodies to be preserved. Purity of radiolabeling was >98%, and >94% stability was retained for more than 120 h both in PBS and serum. Immunoreactive fraction was 86.2 ± 2.4%, and cytotoxicity assays showed, dose-dependent MCF-7 cell killing with minimal impact on EpCAM-negative controls. In vivo, [²²⁵Ac]Ac-Macropa-PEG₄-HEA125, exhibited significant tumor uptake (15.7 ± 2.3 %ID/g at 24 h), maintained retention (12.1 ± 1.9 %ID/g at 72 h), and minimal off-target accumulation. Therapeutic injection resulted in extensive tumor growth inhibition and long-term survival, with 60% of the mice surviving past day 30 with little overt toxicity.

Conclusions: [²²⁵Ac]Ac-Macropa-PEG₄-HEA125, establishes high radiochemical purity, in vitro stability, EpCAM specificity, and strong antitumor activity in preclinical models. These results warrant its advancement as a promising targeted alpha therapy candidate for EpCAM-expressing carcinomas.

Background: Dynamic characteristics such as cancer stemness and the epithelial-to-mesenchymal transition (EMT) cause the spread of colorectal cancer (CRC). Although there are now few pharmaceutical approaches, therapeutically correcting these conditions may improve prognosis. Acoustic radiation force and other mechanical ultrasonic forces have become new, noninvasive methods for modifying tumor biology. Nevertheless, little is known about their molecular influence on CRC EMT-stemness pathways.

Materials and methods: The authors created a simulation pipeline to predict the effects of ultrasound-induced mechanical stress on CRC samples enriched for tumor-infiltrating T cells using transcriptome datasets (GSE108989). Heatmap visualizations, differential expression, pathway enrichment, principal component analysis (PCA), and EMT and stemness scores were computed using bulk RNA-seq. To evaluate mechanistic suppression, signaling axes such as TGF-β, Wnt/β-catenin, Notch, and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) were investigated. The potential ultrasonic sensitivity of key gene modules was assessed.

Results: Mesenchymal and stemness-associated transcriptional pathways were found to be downregulated in response to simulated acoustic modulation. Coherent clustering of decreased EMT/stemness genes was shown via heatmaps. Modified tumor groupings were identified by PCA. In the simulated postultrasound condition, canonical pathways associated with invasion, immunological evasion, and stemness maintenance were diminished. These results lend credence to the theory that CRC cellular plasticity may be reprogrammed by mechanical ultrasonic force.

Conclusions: Early mechanistic understanding of how acoustic force-based ultrasound may inhibit EMT and stemness in CRC is provided by this transcriptome simulation. This data-driven approach presents ultrasound as a promising supplement to immune-oncology and antimetastatic methods and encourages more in vitro validation.

Background: Focused ultrasound, low-intensity focused ultrasound, and microbubble-enhanced sonoporation are examples of ultrasound-based cancer therapies that have shown promise as biophysical modalities for enhancing drug penetration, immunogenic cell death, and targeted delivery of radiopharmaceuticals in solid tumors. The molecular factors controlling ultrasonic therapy receptivity, however, are still not well understood. Because of the significant variability of the tumor microenvironment (TME), colorectal cancer (CRC) necessitates biomarker-guided techniques to enhance ultrasound-based therapy regimens.

Methods: To investigate serotonylation-related and hallmark-pathway-related genes that might influence ultrasound-responsive cellular pathways, such as extracellular matrix (ECM) remodeling, mechanotransduction, and immune activation, the authors combined bulk RNA-sequencing (RNS-seq) (TCGA-COAD), single-cell RNA-seq (GSE132465), and spatial transcriptomics (GSE280313) datasets. Nine prognostic genes were found using survival analysis and differential expression screening. To create a prognostic classifier with translational relevance for ultrasonic therapies, the authors used non-negative matrix factorization clustering, single-cell functional scoring, spatial deconvolution, and 101 machine-learning models.

Results: Of the 2475 serotonylation-hallmark genes found, 784 exhibited differential expression in tumor and normal tissues. CRC was divided into six molecular subgroups with different TME symptoms and survival patterns by nine important prognostic genes (PCOLCE2, TIMP1, FJX1, FABP4, CALB2, NAT1, CDKN2A, FSTL3, and INHBB). Elevated stromal activation, epithelial-mesenchymal transition signals, macrophage infiltration, and ECM stiffness were seen in high-risk clusters; these variables are known to affect cavitation thresholds, ultrasonic energy absorption, and treatment response. Strong prognostic accuracy was demonstrated by the final RSF-SuperPC model (concordance index 0.72-0.85 across validation cohorts). Strong enrichment in mechanotransduction, oxygen metabolism, and immune chemotaxis pathways-pathways previously demonstrated to regulate ultrasound-triggered drug delivery and immune activation-was revealed by functional studies.

Conclusions: This multiomics integration reveals a serotonylation-hallmark gene signature that represents microenvironmental characteristics, such as matrix stiffness, stromal density, and immune infiltration, that are pertinent to ultrasound-based CRC therapy. These biomarkers could direct patient classification for radiopharmaceutical, immunotherapy, and ultrasound-enhanced medication delivery. This work supports future clinical trial stratification frameworks and offers a mechanistic basis for precision ultrasound oncology.

Malignant brain tumors remain a major therapeutic challenge due to poor intracellular delivery of therapeutics. Radiopharmaceuticals such as Technetium-99m (^^99mTc) are valuable for imaging and therapy but suffer from limited tumor uptake caused by cellular and membrane barriers. Focused ultrasound (FUS) offers a noninvasive strategy to transiently enhance membrane permeability through sonoporation. Unlike prior studies largely focused on blood-brain barrier disruption, this work specifically investigates direct tumor cell sonoporation as an independent uptake mechanism. This study evaluates FUS-mediated enhancement of ^^99mTc radiopharmaceutical uptake in brain tumor cells and determines optimal acoustic parameters balancing efficacy and safety. Human glioblastoma (U87-MG) and astrocytoma (A172) cells were cultured and exposed to FUS at intensities of 0.3, 0.5, and 0.7 W/cm² for 30-120 s. Radiopharmaceutical uptake was quantified using γ-scintillation counting. Membrane integrity was assessed by live/dead fluorescence microscopy and lactate dehydrogenase release, while cell viability was evaluated via medical training therapy (MTT) assays. U87-MG cells exhibited up to a 3.1-fold increase at 0.7 W/cm² for 120 s, with a 2.3-fold enhancement at the clinically relevant 0.5 W/cm² for 60 s while maintaining >92% viability. A172 cells showed similar trends with slightly lower magnitudes. Safety assays confirmed reversible membrane permeabilization at ≤0.5 W/cm². The temporal uptake kinetics aligned with established membrane pore resealing dynamics, supporting reversible sonoporation as the uptake mechanism. Importantly, while ^^99mTc complexes are primarily diagnostic, enhanced intracellular delivery achieved by optimized FUS may also support future theranostic strategies, including radionuclide therapy. These findings underscore the translational potential of FUS in neuro-oncology, where tumor heterogeneity necessitates parameter optimization to maximize radiopharmaceutical delivery, improve imaging contrast, and overcome therapeutic resistance.