Theranostics最新文献

Rationale: The role of oxidative stress metabolism during hepatocellular carcinoma (HCC) formation potentially allows for positron emission tomography (PET) imaging of oxidative stress activity for early and precise HCC detection. However, there is currently limited data available on oxidative-stress-related PET imaging for longitudinal monitoring of the pathophysiological changes during HCC formation. This work aimed to explore PET-based longitudinal monitoring of oxidative stress metabolism and determine the sensitivity of [18F]-5-fluoroaminosuberic acid ([18F]FASu) for assessing pathophysiological processes in diethylnitrosamine (DEN) induced rat HCC. Methods: Genomic and clinical data were obtained from the HCC dataset (n = 383) in The Cancer Genome Atlas (TCGA-LIHC) and Gene Expression Omnibus (GEO) datasets. Wistar rats were administered DEN weekly, either by gavage (i.g.) at doses of 10 mg/kg or 80 mg/kg or by intraperitoneal injection (i.p.) at 80 mg/kg, with continuous modeling over a 12-week period followed by 24 weeks of consecutive feeding. PET/CT imaging was conducted at weeks 8, 15, and 21 by tail vein injections of [18F]FASu and [18F]FDG (~3.7 MBq). Finally, contrast-enhanced CT imaging of the nodules was performed at the designed time point. The rats in each group were sacrificed at multiple time points to perform a correlation analysis between PET imaging findings and histological examinations. Results: Bioinformatics analysis revealed that upregulation expression of SLC7A11 in HCC indicates oxidative stress-altered cellular metabolism and allows early detection of HCC formation. By simulating different levels of oxidative stress in DEN-induced rat HCC, the SUVmax of [18F]FASu PET imaging positively correlated with the expression of CD44 and SLC7A11 (r = 0.7913, P < 0.0001; r = 0.7173, P < 0.0001, respectively), which maintain redox homeostasis in the cells. Compared with 18F-fluorodeoxyglucose ([18F]FDG), [18F]FASu PET imaging demonstrated higher sensitivity for HCC diagnosis and enabled the characterization of pathological changes in DEN-induced rat HCC at an early stage. Conclusions: Our findings regarding the oxidative stress characterization of HCC formation in DEN-induced rat models using [18F]FASu PET imaging demonstrated the exciting potential of oxidative-stress-related PET imaging for monitoring the pathophysiological changes during HCC formation.

Background: Activatable multifunctional nanoparticles present considerable advantages in cancer treatment by integrating both diagnostic and therapeutic functionalities into a single platform. These nanoparticles can be precisely engineered to selectively target cancer cells, thereby reducing the risk of damage to healthy tissues. Once localized at the target site, they can be activated by external stimuli such as light, pH changes, or specific enzymes, enabling precise control over the release of therapeutic agents or the initiation of therapeutic effects. Furthermore, these nanoparticles can be designed to incorporate multiple therapeutic modalities, including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT). This comprehensive approach facilitates real-time monitoring of treatment efficacy and allows for dynamic adjustments to therapy, resulting in more personalized and effective cancer treatments. Methods: This study reports the synthesis of perfluorocarbon (PFC)-encapsulated fluorescent polyepinephrine (PEPP) nanoshells chelated with Fe²⁺ (PFC@PEPP-Fe) and explores their potential for bimodal imaging and synergistic combination therapy in cancer treatment. The cellular uptake, cytotoxicity, and in vitro therapeutic efficacy of PFC@PEPP-Fe were assessed using 4T1 breast cancer cells. In vivo bimodal imaging using fluorescence (FL) and ultrasound (US) was conducted after injection into 4T1 tumor-bearing balb/c nude mice. The synergistic anticancer effects of PFC@PEPP-Fe, combining CDT and PTT, were evaluated following 808 nm laser irradiation (1 W/cm²) for 5 min, with treatment outcomes monitored over a 14 days period. Results: Both in vitro and in vivo studies demonstrated that PFC@PEPP-Fe enables effective bimodal imaging and exhibits substantial anticancer efficacy through the synergistic effects of PTT and CDT. Near-infrared (NIR) laser irradiation increased the temperature, enhancing the release of O₂ and the production of H₂O₂, which in turn amplified the CDT effect. The combination of PFC@PEPP-Fe administration and NIR laser significantly reduced tumor volume, slowed tumor growth, and improved survival in 4T1 tumor-bearing mice, confirming the strong anticancer activity due to the PTT/CDT synergy. Conclusions: As a multifunctional theranostic nanoparticle, PFC@PEPP-Fe not only enables cancer cell-specific US/FL bimodal imaging through the generation of microbubbles from its PFC core and fluorescent PEPP shells but also facilitates synergistic chemodynamic and photothermal therapeutic actions under NIR laser irradiation, which induces the self-supply of H₂O₂ and O₂ within cancer cells.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.

Background: Cathepsin D (Ctsd) has emerged as a promising therapeutic target for Alzheimer's disease (AD) due to its role in degrading intracellular amyloid beta (Aβ). Enhancing Ctsd activity could reduce Aβ42 accumulation and restore the Aβ42/40 ratio, offering a potential AD treatment strategy. Methods: This study explored Ctsd demethylation in AD mouse models using dCas9-Tet1-mediated epigenome editing. We identified dCas9-Tet1 as an effective tool for demethylating the endogenous Ctsd gene in primary neurons and in vivo brains. Results: Treatment with Ctsd-targeted dCas9-Tet1 in primary neurons overexpressing mutant APP (mutAPP) reduced Aβ peptide levels and the Aβ42/40 ratio. Additionally, in vivo demethylation of Ctsd via dCas9-Tet1 in 5xFAD mice significantly altered Aβ levels and alleviated cognitive and behavioral deficits. Conclusion: These findings offer valuable insights into developing epigenome editing-based gene therapy strategies for AD.

Rational: White matter has emerged as a key therapeutic target in ischemic stroke due to its role in sensorimotor and cognitive outcomes. Our recent findings have preliminarily revealed a potential link between microglial HDAC3 and white matter injury following stroke. However, the mechanisms by which microglial HDAC3 mediates these effects remain unclear. Methods : We generated microglia-specific HDAC3 knockout mice (HDAC3-miKO). DTI, electrophysiological technique and transmission electron microscopy were used to assess HDAC3-miKO's effects on white matter. RNA sequencing, flow cytometry, immunofluorescence staining and ex vivo phagocytosis assay were conducted to investigate the mechanism by which HDAC3-miKO ameliorated white matter injury. Macrophage depletion and reconstitution experiments further confirmed the involvement of macrophage CCR2 in the enhanced white matter repair and sensorimotor function in HDAC3-miKO mice. Results : HDAC3-miKO promoted post-stroke oligodendrogenesis and long-term histological and functional integrity of white matter without affecting early-stage white matter integrity. In the acute phase, HDAC3-deficient microglia showed enhanced chemotaxis, recruiting macrophages to the infarct core probably by CCL2/CCL7, where dMBP-labelled myelin debris surged and coincided with their infiltration. Infiltrated macrophages outperformed resident microglia in myelin phagocytosis, potentially serving as true pioneers in myelin debris clearance. Although macrophage phagocytosis potential was similar between HDAC3-miKO and WT mice, increased macrophage numbers in HDAC3-miKO accelerated myelin debris clearance. Reconstitution with CCR2-KO macrophages in HDAC3-miKO mice slowed this clearance, reversing HDAC3-miKO's beneficial effects. Conclusions : Our study demonstrates that HDAC3-deficient microglia promote post-stroke remyelination by recruiting macrophages to accelerate myelin debris clearance, underscoring the essential role of infiltrated macrophages in HDAC3-miKO-induced beneficial outcomes. These findings advance our understanding of microglial HDAC3's role and suggest therapeutic potential for targeting microglial HDAC3 in ischemic stroke.

Background: Intracerebral hemorrhage (ICH) is a devastating form of stroke with a lack of effective treatments. Following disease onset, ICH activates microglia and recruits peripheral leukocytes into the perihematomal region to amplify neural injury. Bruton's tyrosine kinase (BTK) controls the proliferation and survival of various myeloid cells and lymphocytes. However, the role of BTK in neuroinflammation and ICH injury remains poorly understood. Methods: Peripheral blood samples were collected from ICH patients and healthy controls to measure BTK expression profile in immune cell subsets. C57BL/6 mice were used to measure BTK expression and the activity of immune cell subsets following ICH induction. Neurological tests, brain water content, Evans blue leakage, MRI were used to assess the therapeutic effects of ibrutinib on ICH injury. Flow cytometry was used to investigate immune cell infiltration and microglial activity. Microglia were depleted using a CSF1R inhibitor PLX5622. Gr-1⁺ myeloid cells and B cells were depleted using monoclonal antibodies. Microglia-like BV2 cells were cultured to test the effects of BTK inhibition on these cells. Results: In humans and mice, we found that BTK was remarkably upregulated in myeloid cells after ICH. Inhibition of BTK using ibrutinib led to reduced neurological deficits, perihematomal edema, brain water content and blood-brain barrier disruption. BTK inhibition suppressed the inflammatory activity of microglia and brain infiltration of leukocytes. In contrast, BTK inhibition did not alter the counts of peripheral immune cells other than B cells. Further, the depletion of microglia or Gr-1⁺ myeloid cells ablated the protective effects of BTK inhibition against ICH injury. Notably, the depletion of B cells did not alter the protective effects of BTK inhibition against ICH injury. This suggests that the benefit of BTK inhibition in ICH mainly involves its impact on microglia and Gr-1⁺ myeloid cells. Conclusion: Our findings demonstrate that BTK inhibition attenuates neuroinflammation and ICH injury, which warrants further investigation as a potential therapy for ICH.

Rationale: Aortic aneurysms and dissections (AAD) cause more than 10,000 deaths in the United States each year. However, there are no medications that can effectively prevent the pathogenesis of AAD. MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. Here, we mainly focused on ascending aortic aneurysms and dissections (AAAD) and investigated the role of endothelial MerTK in AAAD progression. Methods: Single-cell RNA sequencing (scRNA-seq) analysis in human AAAD samples and RNA-seq big data analytics, combined with our unique MerTK^flox/flox/Tie2^Cre mouse model with MerTK deficiency in endothelial cells (ECs), were applied to define the role of endothelial MerTK in AAAD. Results: Through comparative analyses of scRNA-seq in human AAAD (communications of ECs with other cells) and comprehensive big data analytics including about 600,000 cross analyses, we found that the expression of endothelial MerTK is significantly inhibited in human AAAD, resulting in decreased ability of ECs to engulf antigen presenting cells, phagocytes, leukocytes, blood cells and myeloid cells. Our in vivo data showed a significantly higher incidence of AAAD in MerTK ^flox/flox/Tie2^Cre mice compared to that of their littermate controls of MerTK ^flox/flox mice (100% vs. 11.1%). MerTK deficiency in ECs induces both endothelial dysfunction and SMC phenotypic alterations, subsequently promoting AAAD development. Conclusions: Our findings indicate that endothelial MerTK impairment and subsequent endothelial dysfunction and SMC phenotypic alterations represent novel mechanisms promoting AAAD.

Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration. It can cause severe pain, deformity and even amputation risk. However, existing clinical treatment methods for cartilage repair present certain deficiencies. Meanwhile, the repair effect of cartilage tissue engineering is also unsatisfactory. Cartilage organoids are multicellular aggregates with cartilage-like three-dimensional structure and function. On the one hand, cartilage organoids can be used to explore the pathogenesis of OA by constructing disease models. On the other hand, it can be used as filler for rapid cartilage repair. Extracellular matrix (ECM)-like three-dimensional environment is the key to construct cartilage organoids. Silk fibroin (SF)-based hydrogels not only have ECM-like structure, but also have unique mechanical properties and remarkable biocompatibility. Therefore, SF-based hydrogels are considered as ideal biomaterials for constructing cartilage organoids. In this review, we reviewed the studies of cartilage organoids and SF-based hydrogels. The advantages of SF-based hydrogels in constructing cartilage organoids and the iterative optimization of cartilage organoids through designing hydrogels by using artificial intelligence (AI) calculation are also discussed. This review aims to provide a theoretical basis for the treatment of OA using SF-based biomaterials and cartilage organoids.

Depression is a prevalent public health issue, characterized by persistent low mood, impaired concentration, and diminished motivation. Photobiomodulation (PBM), which involves the application of red or near-infrared light, modulates physiological processes by enhancing cerebral blood flow, reducing inflammation, inhibiting apoptosis, and promoting neurogenesis. PBM can be administered transcranially or through systemic approaches, offering a potentially effective intervention for depression. This review discusses the characteristics of PBM, its underlying neurobiological mechanisms, and relevant physical parameters. Recent progress in both animal and clinical research underscores PBM's therapeutic potential for depression and emphasizes the need for further studies to establish a robust theoretical basis for standardized treatment protocols.

The cascade of events leading to tumor formation includes induction of a tumor supporting neovasculature, as a primary hallmark of cancer. Developing vasculature is difficult to evaluate in vivo but can be captured using microfluidic chip technology and patient derived cells. Herein, we established an on chip approach to investigate the mechanisms promoting tumor vascularization and vascular targeted therapies via co-culture of cancer spheroids and endothelial cells in a three dimensional environment. Methods: We investigated both, tumor neovascularization and therapy, via co-culture of human derived endothelial cells and adjacently localized metastatic renal cell carcinoma spheroids on a commercially available microfluidic chip system. Metastatic renal cell carcinoma spheroids adjacent to primary vessels model tumor, and induce vessels to sprout neovasculature towards the tumor. We monitored real time changes in vessel formation, probed the interactions of tumor and endothelial cells, and evaluated the role of important effectors in tumor vasculature. In addition to wild type endothelial cells, we evaluated endothelial cells that overexpress Prostate Specific Membrane Antigen (PSMA), that has emerged as a marker of tumor associated neovasculature. We characterized the process of neovascularization on the microfluidic chip stimulated by enhanced culture medium and the investigated metastatic renal cell carcinomas, and assessed endothelial cells responses to vascular targeted therapy with bevacizumab via confocal microscopy imaging. To emphasize the potential clinical relevance of metastatic renal cell carcinomas on chip, we compared therapy with bevacizumab on chip with an in vivo model of the same tumor. Results: Our model permitted real-time, high-resolution observation and assessment of tumor-induced angiogenesis, where endothelial cells sprouted towards the tumor and mimicked a vascular network. Bevacizumab, an antiangiogenic agent, disrupted interactions between vessels and tumors, destroying the vascular network. The on chip approach enabled assessment of endothelial cell biology, vessel's functionality, drug delivery, and molecular expression of PSMA. Conclusion: Observations in the vascularized tumor on chip permitted direct and conclusive quantification of vascular targeted therapies in weeks as opposed to months in a comparable animal model, and bridged the gap between in vitro and in vivo models.