Theranostics最新文献

Rationale: Acute liver failure (ALF) is characterized by rapid hepatic dysfunction, primarily caused by drug-induced hepatotoxicity. Due to the lack of satisfactory treatment options, ALF remains a fatal clinical disease, representing a grand challenge in global health. Methods: For the drug repositioning to ALF of mesalamine, which is clinically approved for the treatment of inflammatory bowel disease (IBD), we propose a supramolecular prodrug nanoassembly (SPNs). Mesalamine is modified with a functional peptide of the FRRG sequence. The resulting mesalamine prodrugs form nanoassemblies solely through intermolecular interactions, ensuring high drug loading capacity and reducing the potential toxicity associated with the carrier materials of conventional nanoparticle systems. Results: In acetaminophen (APAP)-induced ALF mouse models, the SPNs predominantly accumulate in injured target tissues owing to the nanoparticles' propensity to target the liver. Subsequently, cathepsin B overexpressed in hepatocytes by drug-induced inflammation triggers the release of mesalamine from the nanoassemblies via enzymatic cleavage, resulting in remarkable therapeutic efficacy. Meanwhile, nonspecific drug release in healthy cells is inhibited due to their relatively lower cathepsin B expression, which helps prevent the exacerbation of the ALF by minimizing adverse events related to drug exposure. Conclusions: This study provides valuable insights into designing rational nanomedicine for repurposing mesalamine in ALF treatment, potentially inspiring further research to discover effective and safe therapeutic options for patients.

Alzheimer's Disease (AD) is the most common form of dementia and one of the leading causes of death. AD is known to be correlated to tortuosity in the microvasculature as well as decreases in blood flow throughout the brain. However, the mechanisms behind these changes and their causal relation to AD are poorly understood. Methods: Here, we use volumetric ultrasound localization microscopy (ULM) to non-invasively and quantitatively compare the microvascular morphology and flow dynamics of five wildtype (WT) and five APP^NL-G-F Knock-in mice, a mouse model of AD, across a 1cmx1cmx1cm brain volume and in four specific brain regions: the hippocampal formation, thalamus, hypothalamus, and cerebral cortex. Results: Comparisons between groups showed a significant increase in tortuosity, as measured by the Sum of Angles Metric (SOAM), throughout the brain (p < 0.01) and the hypothalamus (p = 0.01), in mice with AD. While differences in mean velocity (p < 0.01) and blood flow (p=0.04) were detected across the whole brain, their effect size was small and no differences were detected in the four selected regions. There was a significant decrease in the linear log relationship between vessel diameter and blood flow, with AD mice experiencing a lower slope than WT mice across the whole brain volume (p = 0.02) and in the hippocampal formation (p = 0.05), a region affected by Amyloid Beta plaques in this mouse model. The AD mice had higher blood flows in smaller vessels and smaller blood flows in larger vessels than the WT mice. Conclusions: This preliminary demonstrates that the imaging technique can be used for non-invasive, longitudinal, volumetric assessment of AD, which may allow for investigation into the poorly understood microvascular degeneration associated with AD through time as well as the development of early diagnostic techniques.

[This corrects the article DOI: 10.7150/thno.63763.].

[This corrects the article DOI: 10.7150/thno.22252.].

Atherosclerosis remains a significant global health challenge, with its related conditions as the leading cause of death, underscoring the urgent need for enhanced diagnostic and therapeutic approaches. Recently, self-assembled nanoparticles (SANPs) have shown remarkable promise in treating atherosclerosis, attributed to their superior bioavailability, biodegradability, biocompatibility, and ease of functional modification. Numerous SANP variants, such as DNA origami, metal-organic frameworks (MOFs), nanozymes, peptide-based nanoparticles, and self-assembled prodrug nanoparticles, have been engineered, extending their utility in targeted drug delivery and imaging. Advances in fabrication technologies, including microfluidic techniques, allow for precise and scalable SANP production, while innovative nanoparticle designs-such as stimuli-responsive and carrier-free variants-enhance pharmacokinetic properties. The deployment of SANPs in atherosclerosis has introduced a range of diagnostic and therapeutic solutions, from non-invasive imaging and stimuli-responsive drug delivery to vaccination, theranostics, and biosensing. This review consolidates the recent progress in SANP applications for atherosclerosis, emphasizing their transformative potential in disease management.

Rationale: Arterial remodeling serves as a pivotal mechanism underlying the development of diseases such as hypertension. Fibulin-7 (FBLN7), an adhesion protein, remains enigmatic regarding its role in these pathological processes. This study aims to explore whether FBLN7 influences vascular remodeling and its underlying mechanisms. Methods: We generated FBLN7 knockout mice and smooth muscle-specific FBLN7 overexpression mice. Vascular remodeling models were established by administering angiotensin II (Ang II) for 28 days. RNA sequencing, western blot, and immunofluorescence assays were employed to investigate the biological function of FBLN7 in vascular smooth muscle cells (VSMCs). The interaction mechanism between FBLN7 and cell membrane receptors was explored through mass spectrometry analysis, co-immunoprecipitation techniques and molecular dynamics simulations. Results: Bioinformatics analysis revealed an upregulation of FBLN7 expression in the vascular remodeling model, with FBLN7 predominantly localized in VSMCs. Subsequent in vivo validation demonstrated that FBLN7 knockout attenuated Ang II-induced vascular remodeling, reducing aortic wall thickness and collagen formation. Conversely, VSMC-specific overexpression of FBLN7 via AAV vectors exacerbating the remodeling phenotype. Functionally speaking, FBLN7 potentiates Ang II-mediated phenotypic transformation. Mechanistically, FBLN7 interacts with the extracellular and transmembrane domains of syndecan-4 (SDC4) via its C-terminal region, affecting SDC4 signaling and dimer formation. This interaction inhibits SDC4-mediated activation of the Rho-associated protein kinase pathway, subsequently reducing nuclear translocation of myocardin-related transcription factor A, leading to decreased transcription of genes associated with the contractile VSMCs phenotype. Conclusions: These findings reveal FBLN7 promotes the transition of VSMCs from a contractile to a synthetic phenotype, thereby aggravating vascular remodeling. This provides further insights into the pathogenesis of vascular remodeling and potential therapeutic strategies.

Rationale: Ischemia-reperfusion-induced acute kidney injury (IR-AKI), characterized by the abrupt decline in renal function, is distinguished by the intricate interplay between oxidative stress and inflammation. In this study, a reactive oxygen species (ROS) scavenger-CF@PDA was developed to effectively target antioxidant and anti-inflammatory pathways to disrupt the oxidative stress-inflammation cycle in IR-AKI. Methods: UV-vis absorption spectra, FTIR spectra, and TEM were employed to determine the successful construction of CF@P. ABTS, TMB, and NBT analyses were performed to detect the antioxidant ability and enzyme-mimicking ability of CF@P. In vitro and in vitro, the antioxidant/anti-inflammatory effect of CF@P was detected by MTT, qPCR, fluorescence, and flow cytometry. Multi-omics revealed the mechanism of CF@P in IR-AKI therapy, and molecular docking was further used to determine the mechanism. MRI and photoacoustic imaging were employed to explore the dual-mode imaging capacity of CF@P in IR-AKI management. Results: CF@P could disrupt the oxidative stress-inflammatory cascade by scavenging ROS, reducing pro-inflammatory cytokines, and modulation of macrophage polarization. Subsequent multi-omics indicated that the renal protective effects may be attributed to the inhibition of pyruvate dehydrogenase kinase 4 (PDK4). Metabolomics demonstrated that CF@P could improve the production of antioxidant compounds and reduce nephrotoxicity. Additionally, CF@P exhibited promising capabilities in T1-MRI and photoacoustic imaging for AKI management. Conclusions: Collectively, CF@P, possessing antioxidant/anti-inflammatory properties by inhibiting PDK4, as well as imaging capabilities and superior biocompatibility, holds promise as a therapeutic strategy for IR-AKI.

Rationale: Cerebral ischemia-reperfusion injury is a severe neurovascular disease that urgently requires effective therapeutic interventions. Recently, hydrogen sulfide (H₂S) has garnered significant attention as a potential treatment for stroke; however, the precise and targeted delivery of H₂S remains a considerable challenge for its clinical application. Methods: We have developed HSDF-NH₂, a novel H₂S donor characterized by high selectivity, self-reporting capabilities, and the ability to penetrate the blood-brain barrier (BBB). Results: HSDF-NH₂ effectively scavenges reactive oxygen species (ROS) while generating H₂S, with emitted fluorescence facilitating the visualization and quantification of H₂S release. This compound has demonstrated protective effects against cerebral ischemia-reperfusion (I/R) injury and contributes to the reconstruction of brain structure and function in a rat stroke model (tMCAO/R). Conclusion: As a ROS-responsive, self-reporting, and fluorescent H₂S donor, HSDF-NH₂ holds considerable promise for the treatment of ischemic diseases beyond stroke.

Rationale: Melanoma, the deadliest form of skin cancer characterized by high therapy resistance, has undergone extensive investigation through the utilization of BRAF^V600E-driven melanoma animal models. However, there exists a paucity of animal models for the rare hereditary melanoma resulting from germline CDKN2A mutations. Methods: Here, employing CRISPR/Cas9 technology, we generated cdkn2b^-/-/tp53^-/- Xenopus tropicalis on a tp53 knockout background to model human CDKN2A germline mutation-induced hereditary melanoma. Results: The findings unveiled that cdkn2b^-/-/tp53^-/- frogs spontaneously developed melanoma, pancreatic cancer, and other tumors. Specifically, these frogs exhibited a high penetrance of spontaneous melanoma, sharing characteristics with melanomas in human hereditary melanoma caused by germline CDKN2A mutations. During melanoma development in cdkn2b^-/-/tp53^-/- frogs, the occurrences of epithelial-to-mesenchymal transition, the reactivation of pigment cell progenitor cell transcriptional states, and the activation in the MAPK, NF-kB, PI3K-Akt, and TGF-β signaling pathways were noted. Conclusions: Overall, cdkn2b^-/-/tp53^-/- Xenopus tropicalis provides a vertebrate model for investigating the development of CDKN2A germline mutation-induced hereditary melanoma, contributing to the exploration of the pathogenesis of hereditary melanoma in humans.

Rationale: High-grade serous ovarian cancer (HGSOC), the most lethal epithelial ovarian cancer subtype, faces persistent challenges despite advances in the therapeutic use of PARP inhibitors. Thus, innovative strategies are urgently needed to improve survival rates for this deadly disease. Checkpoint kinase 1 (CHK1) is pivotal in regulating cell survival during oncogene-induced replication stress (RS). While CHK1 inhibitors (CHK1i's) show promise as monotherapy for ovarian cancer, a crucial biomarker for effective stratification in clinical trials is lacking, hindering efficacy improvement and toxicity reduction. PP2A B55α, encoded by PPP2R2A, is a regulatory subunit of the serine/threonine protein phosphatase 2 (PP2A) that influences CHK1 sensitivity in non-small cell lung cancer (NSCLC). Given the complexity of PP2A B55α function in different types of cancer, here we sought to identify whether PPP2R2A deficiency enhances the sensitivity of HGSOC to CHK1 inhibition. Methods: To determine whether PPP2R2A deficiency affects the sensitivity of HGSOC to CHK1 inhibition, we treated PPP2R2A knockdown (KD) HGSOC cells or HGSOC cells with naturally low PPP2R2A expression with a CHK1 inhibitor, then assessed cell growth in in vitro and in vivo assays. Additionally, we investigated the mechanisms contributing to the increased RS and the enhanced sensitivity to the CHK1 inhibitor in PPP2R2A-KD or deficient cells using various molecular biology assays, including western blotting, immunofluorescence, and DNA fiber assays. Results: Our study suggests that PPP2R2A-KD elevates c-Myc-induced RS via upregulation of replication initiation, rendering HGSOC cells reliant on CHK1 for survival, including those resistant to PARP inhibitors. Conclusion: Combined, these results identify PPP2R2A/PP2A B55α as a potential predictive biomarker for CHK1i sensitivity in HGSOC, as well as suggesting it as a therapeutic target to overcome PARP resistance.