Search Results (1,418)

Cancer remains a major global health challenge, and the limitations of conventional therapies have intensified interest in treatment strategies that combine improved selectivity with reduced systemic toxicity. Photothermal therapy and photodynamic therapy have emerged as minimally invasive approaches capable of achieving spatiotemporally controlled tumour ablation. In this context, molybdenum disulfide (MoS₂), a transition metal dichalcogenide with strong near-infrared absorption, high photothermal conversion efficiency, and versatile surface chemistry, has gained increasing attention as a multifunctional platform for drug delivery and light-triggered cancer therapy. This review examines recent advances in engineered MoS₂ nanoplatforms for drug-enhanced cancer phototherapy, with emphasis on how surface design and therapeutic cargoes mechanistically amplify light-triggered tumour killing. Approaches such as polymer coatings, biomimetic membranes, targeting ligands, chemotherapeutic agents, nucleic acids, and photosensitisers have been explored to improve colloidal stability, tumour targeting, immune evasion, and stimulus-responsive drug release, while also adding complementary cytotoxic pathways such as chemotherapy, ROS generation, or gene silencing. Available in vitro and in vivo studies indicate that these systems generally exhibit favourable short-term biocompatibility under the tested conditions and can produce significant antitumour effects following irradiation. The review also discusses key biological barriers and translational challenges, including biodistribution, long-term safety, reproducibility, and regulatory considerations, highlighting opportunities for the development of clinically viable MoS₂-based phototherapeutic platforms. Full article

Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 10¹² or 3 × 10¹³ vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy. Full article

CRISPR–Cas9 has progressed from an experimental tool to a therapeutic modality, marked by the first regulatory approvals of an ex vivo-edited autologous CD34+ hematopoietic stem cell product that induces fetal hemoglobin (CASGEVY/exa-cel). In this narrative review, we synthesize modality-specific molecular diagnostic strategies used across early CRISPR clinical translation. In parallel, early clinical experience has begun to demonstrate the feasibility of in vivo editing, including subretinal delivery for CEP290-associated inherited retinal degeneration (EDIT-101 programme) and hepatocyte-targeted lipid nanoparticles (LNPs) for liver-derived targets such as transthyretin and plasma prekallikrein (KLKB1). As translation expands across hematologic, metabolic, ocular and oncology indications, development is increasingly constrained by the predictability and safety of editing outcomes, delivery-determined biodistribution and exposure time, and immune recognition of bacterial Cas9 orthologs and delivery components. We summarize diagnostic readouts for confirming patient genotype, quantifying on-target editing and expression changes, assessing off-target and structural outcomes using orthogonal assays, and monitoring clonal dynamics and immune responses during long-term follow-up. We also discuss how these readouts interface with CMC controls and regulatory expectations for advanced therapy medicinal products (ATMPs), highlighting the need for fit-for-purpose, standardized testing frameworks in early trials. Full article

Purpose: Prostate-specific membrane antigen (PSMA) is a well-established molecular target in prostate cancer (PCa). Both radionuclide imaging and near-infrared fluorescence (NIRF) imaging offer high sensitivity for in vivo tumor detection. PSMA-targeted dual-modality probes integrating these two imaging techniques provide complementary preoperative and intraoperative tumor visualization, thereby improving surgical guidance in PCa. In this study, we aimed to develop a novel dual-labeled PSMA probe combining radioactive and fluorescent properties to achieve precise tumor delineation during radical prostatectomy (RP). Methods: A high-affinity PSMA-targeted fluorescent probe (PSMA-DF) was synthesized using solid-phase synthesis. Subsequent radiolabeling with the radionuclide [⁶⁸Ga]Ga yielded the successful generation of a dual-modal PSMA-targeted molecular probe, namely [⁶⁸Ga]Ga-PSMA-DF. The probe was systematically evaluated both in vitro and in vivo, and its safety profile was assessed through acute toxicity testing. Tumor-bearing nude mouse models were established using PSMA-positive 22Rv1 and PSMA-negative PC-3 PCa cell lines. Imaging performance, tumor-targeting specificity, and biodistribution of the probe were comprehensively evaluated using micro-PET imaging, in vivo fluorescence imaging, and biodistribution studies. Results: High-quality and high-purity PSMA-DF was successfully prepared, which exhibited excellent optical properties. Following radiolabeling with [⁶⁸Ga]Ga, a dual-modality radionuclide-fluorescence probe ([⁶⁸Ga]Ga-PSMA-DF) was successfully constructed. In vitro cellular uptake studies demonstrated that 22Rv1 cells had relatively high uptake of the probe, reaching 7.34 ± 0.55 IA%/10⁶ cells at 120 min. In contrast, PC-3 cells and blocked 22Rv1 cells displayed minimal uptake, confirming the specific targeting ability of the probe. In vivo evaluations were conducted on tumor-bearing mice using micro-PET/CT and NIRF imaging. The results revealed that [⁶⁸Ga]Ga-PSMA-DF achieved high specific tumor accumulation in 22Rv1 xenografts, with the peak tumor uptake (SUVmax = 1.748 ± 0.132) and tumor-to-muscle ratio (11.542 ± 1.511) observed at 120 min. Notably, high-contrast fluorescence imaging was also achieved at later time points, yielding a tumor-to-background ratio (TBR) of 6.559 ± 1.415 at 48 h. Notably, ex vivo biodistribution data were consistent with in vivo imaging findings. Conclusions: This preclinical study demonstrates that [⁶⁸Ga]Ga-PSMA-DF exhibits high and specific uptake in PCa models, supporting its potential as a dual-modality tracer for both PET/CT imaging and real-time intraoperative fluorescence guidance during PCa surgery. Full article

Kaurenoic acid (KA) is an ent-kaurane diterpenoid present in several medicinal plant species and has been reported to exhibit anti-inflammatory, cytotoxic, and analgesic activity in experimental models. Despite its pharmacological profile, the development of KA as a therapeutic agent has been hindered by its unfavorable physicochemical and biopharmaceutical properties. KA is highly lipophilic and poorly soluble in water, which limits its dissolution, systemic exposure, and oral bioavailability. These limitations are common among plant-derived bioactive compounds and pose significant challenges for clinical development. Lipid-based nanocarrier systems, particularly liposomal formulations, have therefore been investigated as potential delivery strategies for improving the biopharmaceutical performance of KA. Encapsulating KA within phospholipid bilayers can improve its apparent solubility, protect it from degradation, and modify its biodistribution compared to the free compound. In this review, we discuss the pharmacological mechanisms of KA, its physicochemical properties, and the biopharmaceutical barriers to its therapeutic development. We also critically evaluate published studies on nanocarrier-based formulations, focusing on encapsulation efficiency, particle size, release properties, and pharmacokinetics (PK). Additionally, regulatory and pharmaceutical considerations relevant to lipid-based delivery of KA are addressed. Available evidence supports lipid-based nanocarriers as a promising strategy to improve preclinical development and formulation performance of poorly soluble plant bioactives such as kaurenoic acid. Although KA-loaded nanocarriers demonstrate encouraging activity in preclinical models, comprehensive pharmacokinetic and safety evaluations remain necessary before clinical development can be realistically considered. Full article

Nanomaterials are emerging versatile platforms for therapeutic delivery, as they offer precise control over drug, antioxidant, and genetic payload transport across biological barriers. Inorganic, organic, hybrid, and biomimetic systems are the major classes of nanomaterials, which all have different physicochemical properties such as size, surface charge, and surface functionalization. These properties collectively influence stability, biodistribution, cellular uptake, and release kinetics. Engineering strategies are increasingly using stimuli-responsive designs that are triggered by pH, reactive oxygen species (ROS), and intracellular redox gradients to perform spatially and temporally controlled delivery. Antioxidant and redox-modulating nanocarriers are of great importance as they overcome the limited bioavailability and nonspecific activity of conventional antioxidants by improving stability, targeting oxidative microenvironments, and allowing for regulated release. Improvements in lipid, polymeric, and inorganic nanoplatforms have also developed gene delivery applications, including siRNA, mRNA, and CRISPR/Cas systems, to provide better cytosolic release and precise therapeutics. When diagnostic imaging is integrated with therapy through theranostic nanoparticles, real-time monitoring and personalized intervention are possible. Safety, scalable manufacturing, and regulatory alignment are some challenges that show the need for standardization and translational procedures to utilize the potential of theranostic nanomedicine. Full article

Polymer–drug conjugates (PDCs) represent an advanced drug delivery strategy designed to address critical limitations of conventional therapeutics, including poor water solubility, rapid systemic clearance, and off-target toxicity. By covalently linking therapeutic agents to polymeric carriers through rationally designed linkers, PDCs enable improved pharmacokinetic profiles, enhanced stability, and controlled drug release. This review provides a comprehensive overview of the key design principles governing PDC systems, with a particular focus on the role of biofunctional polymers. Essential parameters for polymer selection, including biocompatibility, biodegradability, molecular weight, and functional group availability, are discussed in relation to their influence on drug loading, release kinetics, and biological performance. In addition, both natural and synthetic polymers are evaluated for their ability to improve solubility, modulate biodistribution, and reduce systemic toxicity. An overview of stimuli-responsive PDCs is provided, including pH-, redox-, and temperature-sensitive systems, which enable site-specific and spatiotemporally controlled drug release in response to pathological microenvironments. We emphasize the special role of bioactive polymers such as poly-lysine, hyaluronic acid, chitosan, and gelatin for their intrinsic biological activity, including receptor-mediated targeting, antimicrobial activity, and synergistic therapeutic effects. These properties support the development of dual-active conjugates with enhanced specificity and efficacy. Overall, this review underscores the transition of polymers from passive carriers to active therapeutic components and outlines current challenges and future perspectives for the clinical translation of next-generation PDCs. Full article

[¹¹¹In]In-diethylenetriaminepentaacetic acid-5,10,15,20-tetraphenylporphyrin ([¹¹¹In]In-DTPA-TPP) nanodroplets were developed for cancer theranostics, featuring ultrasound-sensitive properties. The designed nanodroplets that encapsulate the low-boiling-point liquid perfluorocarbon and IR-780 iodide, a near-infrared fluorescent dye, with surface conjugation of ¹¹¹In-labeled porphyrin derivative, were synthesized and evaluated by in vitro and in vivo experiments. The cellular uptake of [¹¹¹In]In-DTPA-TPP nanodroplets was significantly higher than that of control nanodroplets without TPP. Biodistribution experiments revealed greater tumor accumulation in mice injected with [¹¹¹In]In-DTPA-TPP nanodroplets than in those injected with control nanodroplets lacking TPP. Additionally, the accumulation of [¹¹¹In]In-DTPA-TPP nanodroplets in the tumor was visualized by single-photon emission computed tomography. Sonodynamic therapeutic experiments revealed that DTPA-TPP nanodroplets at 10 µmol total lipids/kg weight with a single ultrasound irradiation onto the tumor area significantly inhibited tumor growth. These results indicate that [¹¹¹In]In-DTPA-TPP nanodroplets would be promising cancer theranostic agents. Full article

Nanomaterials (NMs) are increasingly utilized in drug delivery, diagnostic imaging, and therapeutic applications. However, their widespread use raises concerns regarding potential neurotoxicity, particularly for metal and metal oxide nanoparticles. Accumulating evidence indicates that these nanoparticles induce neurotoxicity through interconnected mechanisms, including excessive reactive oxygen species generation, activation of neuroinflammatory pathways, mitochondrial dysfunction, and disruption of blood–brain barrier integrity. These molecular events collectively lead to synaptic impairment, neuronal apoptosis, and progressive cognitive and behavioral deficits, with toxicity severity influenced by dose, exposure duration, and age. Given that in vitro models often fail to capture complex systemic interactions such as nanoparticle biodistribution, blood–brain barrier dynamics, and neuroimmune responses, this review places particular emphasis on in vivo studies to provide a more physiologically relevant understanding of nanoparticle-induced neurotoxicity. Importantly, a growing body of in vivo evidence demonstrates that natural bioactive compounds can mitigate these effects by targeting key pathogenic pathways, including oxidative stress, inflammation, and mitochondrial dysfunction, while preserving neuronal integrity. These findings highlight the therapeutic potential of natural bioactives as protective agents against nanoparticle-induced neurotoxicity and as candidates for broader neuroprotective strategies. This review summarizes the mechanistic basis of metal and metal oxide nanoparticle neurotoxicity and critically evaluates the protective role of natural bioactive compounds, with a focus on evidence derived from animal models. Full article

Background/Objectives: The continuous emergence of immune-evasive SARS-CoV-2 variants underscores the need for adaptable and accessible therapeutics that complement vaccination. Single-domain antibodies (sdAbs) offer advantages in size, stability, and production costs compared to conventional monoclonal antibodies, but their clinical utility is limited by rapid clearance. This study aimed to develop a rabbit-derived sdAb with broad SARS-CoV-2 neutralization capacity and improved pharmacokinetic properties. Methods: A rabbit-derived variable light-chain (VL) sdAb library was constructed and subjected to phage display selection to identify high-affinity binders. Candidate sdAbs were characterized for cross-variant binding and neutralization. The lead sdAb, B3, was fused to the albumin-binding domain (ABD) of the Streptococcus zooepidemicus Zag protein to enhance in vivo half-life. Expression, albumin-binding capacity, and in vitro neutralization were assessed, followed by biodistribution studies in mice. Results: The selected sdAb, B3, showed strong binding and cross-variant neutralization against multiple SARS-CoV-2 lineages, including Delta and Omicron. Fusion to ABD(Zag) preserved neutralization potency, increased expression yields ~5-fold, and enabled cross-species albumin binding. In vivo, B3-ABD(Zag) exhibited markedly extended blood retention, showing a 21.2-fold increase at 24 h post-injection (5.30 vs. 0.25% I.A./g), and reduced renal uptake by 40% compared with unmodified B3. Conclusions: Rabbit-derived VL sdAbs fused to ABD(Zag) provide a promising platform for next-generation SARS-CoV-2 biologics. The enhanced pharmacokinetic profile of B3-ABD(Zag) supports its potential as a scalable therapeutic modality and highlights the broader utility of this approach for future emerging infectious threats. Full article

Background/Objectives: The neonatal Fc receptor (FcRn) plays a crucial role in extending the systemic half-life of monoclonal antibodies (mAbs), but its influence on ocular distribution remains incompletely understood. This study investigated the impact of FcRn on the ocular disposition of mAbs following systemic administration in rabbits. Methods: New Zealand White rabbits received a single intravenous dose (1 mg/kg) of either wild-type trastuzumab (TS-WT) or its FcRn non-binding variant (IHH). Plasma and ocular tissues (retina, iris–ciliary body, vitreous humor, aqueous humor, cornea, conjunctiva, and tears) were collected at terminal time points up to 336 h for TS-WT and 168 h for IHH. Antibody concentrations were quantified using a validated sandwich ELISA. Pharmacokinetic parameters and antibody biodistribution coefficients (ABC) were calculated to assess the FcRn-mediated effects on ocular distribution. Results: TS-WT demonstrated 2-fold higher systemic exposure compared to IHH. The iris–ciliary body exhibited the highest absolute exposure for both antibodies, with TS-WT showing significantly higher accumulation (ABC_0–168h: 14.95% vs. 8.89%). Retinal distribution remained comparable between antibodies (5.96% vs. 5.51%). Both antibodies were detectable in tears, with ABC value of ~4% reported for TS-WT. TS-WT also demonstrated markedly increased distribution in vitreous humor and tear fluid (3.5- and 5.5-fold higher ABC values, respectively) compared to IHH. The cornea (5.76% vs. 5.57%) and conjunctiva (7.71% vs. 7.21%) showed comparable relative distribution between TS-WT and IHH, while aqueous humor showed minimal differences (0.44% vs. 0.52%). Conclusions: This investigation reveals distinct tissue-specific patterns of FcRn-mediated mAb distribution within the eye. FcRn binding significantly enhanced antibody distribution in ocular tissues, such as the iris–ciliary body, and tears, with less pronounced effects on the retina, cornea, conjunctiva and aqueous humor. These findings provide mechanistic insights for optimizing mAb-based therapeutics for ocular disease and understanding the ocular toxicity of mAb-based therapeutics, such as antibody–drug conjugates. Full article

In search of a non-surgical alternative for male animal sterilization, this study investigated the use of gold-coated maghemite nanoparticles (γ-Fe₂O₃@Au) functionalized with citrate to produce testicular photohyperthermia (PHT). Wistar rats received an intratesticular injection of the fluid containing the nanoparticles (150 µL/testicle) followed by testicular irradiation with an LED light (808 nm). Testicular temperature was maintained at ~45 °C for 15 min. The results demonstrated a significant reduction in testicular volume and weight and sperm motility and normal morphology in PHT-treated animals, together with histopathological degeneration of seminiferous tubules. No treatment-related side effects or signs of systemic toxicity were observed. The biodistribution of the gold (Au) and iron (Fe) from the nanoparticles showed that the testes were the primary site of nanoparticle accumulation until day 56 post-treatment with possible renal excretion of Au. These findings support the prospect of testicular PHT mediated by γ-Fe₂O₃@Au nanoparticles as a neutering method for male animals. Full article

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [⁵²Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain desirable. The recently developed BPPA chelator exhibits exceptionally high Mn(II) complex stability and favorable radiolabeling characteristics. This study aimed to characterize the in vivo biodistribution of [⁵²Mn]Mn-BPPA-bevacizumab, and to compare the tumor-to-background ratios of [⁵²Mn]Mn-BPPA-bevacizumab with the previously published values of [⁵²Mn]Mn-DOTAGA-bevacizumab in VEGF-A-expressing cervix carcinoma. Methods: Female KB-3-1 tumor-bearing CB17 SCID mice underwent PET/MRI imaging following intravenous administration of [⁵²Mn]Mn-BPPA-bevacizumab. SUV_mean values were measured in various organs and in the subcutaneously injected tumor, and tumor-to-organ ratios were calculated at various time points up to 10 days post-injection. Results: [⁵²Mn]Mn-BPPA-bevacizumab demonstrated sustained tumor uptake, with tumor SUVmean values increasing from approximately 1.0 at 4 h to peak values of approximately 2.4–2.5 at 72 h post-injection. Tumor-to-background ratios increased progressively over time and were significantly higher for [⁵²Mn]Mn-BPPA-bevacizumab compared with previously reported [52Mn]Mn-DOTAGA-bevacizumab, particularly for tumor-to-blood, tumor-to-liver and tumor-to-lung ratios at later imaging time points (p < 0.0001). Conclusions: The novel [⁵²Mn]Mn-BPPA-bevacizumab tracer exhibits satisfactory in vitro and in vivo stability for PET imaging, high VEGF-A-specific tumor uptake, and markedly improved tumor-to-background ratios compared to the previously published DOTAGA-based probe. These results position [⁵²Mn]Mn-BPPA-bevacizumab as a highly promising next-generation immuno-PET agent for imaging VEGF-A-expressing gynecologic malignancies and for guiding anti-angiogenic therapies. Full article

Background/Objectives: Malignant mesothelioma has a poor prognosis and limited therapeutic options. C-ERC/mesothelin is highly expressed in mesotheliomas and is a potential target for radioimmunotherapy (RIT). This study evaluated the radiolabeled anti-C-ERC/mesothelin antibody mAb 22A31 as a therapeutic agent. Methods: C-ERC/mesothelin expression in mesothelioma cell lines was assessed by Western blotting, and the specific binding of ¹²⁵I-labeled mAb 22A31 was examined. Biodistribution of ¹¹¹In-labeled mAb 22A31 was evaluated in a mesothelioma cell line, MSTO-211H tumor-bearing mice. The therapeutic efficacy of ⁹⁰Y-labeled mAb 22A31 was evaluated in subcutaneous and pleural dissemination models. Results: mAb 22A31 showed specific binding considering the level of C-ERC/mesothelin expression in each mesothelioma cell line. ¹¹¹In-mAb 22A31 accumulated in tumors with minimal uptake in normal tissues. ⁹⁰Y-mAb 22A31 significantly delayed the growth of subcutaneous tumors and improved survival in a pleural dissemination model. Conclusions: Radiolabeled mAb 22A31 specifically targeted C-ERC/mesothelin and demonstrated therapeutic efficacy in a mesothelioma xerograph model. Therefore, ⁹⁰Y-mAb 22A31 is a promising RIT agent and supports the further development of C-ERC/mesothelin-targeted therapy for mesothelioma. Full article

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC. Full article