- 标题
- 摘要
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- 实验方案
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Smart NIR-Light-Mediated Nanotherapeutic Agents for Enhancing Tumor Accumulation and Overcoming Hypoxia in Synergistic Cancer Therapy
摘要： The efficacy of photodynamic therapy (PDT) still shows limited success in clinical application due to hypoxia in the solid tumor, low tumor accumulation and limited light penetration depth of photosensitizers (PS). The previously reported MnO2-based nanotherapeutic agents always required intratumoral injection or complex targeting modification process to improve the therapeutic efficacy. Herein, new MnO2-based nanotherapeutic agents (honeycomb MnO2/IR780/BSA nanoparticles, HMIB NPs) are designed and prepared to achieve excellent phototherapeutic performance characterized by NIR-light-mediation, deep diffusion via TME response and O2 self-supply. The ex vivo and in vivo NIR fluorescence imaging results demonstrate that the honeycomb nanostructure of HMIB NPs facilitates the high tumor accumulation of hydrophobic IR780 via enhanced permeability and retention (EPR) effect after intravenous injection. The immunofluorescence results demonstrate that the TME response of HMIB NPs not only provides O2 for relieving hypoxia but also reduces size for improving deep intratumoral diffusion. As a result, under the synergy of NIR fluorescence imaging, photothermal effect and PDT of IR780 with TME responsive size-change and O2 self-supply of honeycomb MnO2, the HMIB NPs have achieved all-in-one NIR fluorescence and photothermal dual-model imaging guided synergistic PDT/PTT under a single-wavelength NIR light irradiation.
关键词： nanotherapeutic agents,tumor microenvironment responsive degradation,photodynamic therapy,hypoxia,honeycomb manganese dioxide
更新于2025-09-23 15:22:29
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Oxygen Vacancies-Enhanced CeO2:Gd Nanoparticles for Sensing Tumor Vascular Microenvironment by Magnetic Resonance Imaging
摘要： The specific characteristics of the tumor vascular microenvironment such as microvascular permeability and water diffusion have been demonstrated to play essential roles in the evaluation of infiltration of tumors. However, at present, there are few contrast agents (CAs) for magnetic resonance imaging (MRI) to enhance the sensitivity to acquire this vital information. Herein, we develop Gd doped (CeO2:Gd) nanoparticles as CA to detect the tumor vascular microenvironment with high sensitivity. The lattice oxygen vacancies on the surface of CeO2:Gd nanoparticles could bind considerable water molecules to improve the r1 value, achieving an excellent dynamic contrast-enhanced perfusion weighted imaging (DCE-PWI) performance for the measurement of microvascular permeability. The water molecules’ diffusion limited by oxygen vacancies of CeO2:Gd nanoparticles further enhance the diffusion-weighted magnetic resonance imaging (DWI) signal in vitro and in vivo. Excitingly, the strategy is not only essential for obtaining tumor vascular microenvironment information but also offers a way for further research of how to design magnetic resonance CAs.
关键词： CeO2:Gd nanoparticles,oxygen vacancies,microvascular,tumor microenvironment,DWI/DCE-PWI
更新于2025-09-23 15:21:01
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New tools for pathology: a user's review of a highly multiplexed method for <i>in situ</i> analysis of protein and RNA expression in tissue
摘要： Tumor cell heterogeneity and tumor cell - stromal interactions are being explored as determinants of disease progression and treatment resistance in solid tumor and hematologic malignancies. As such, tools simultaneously capable of highly-multiplexed profiling of tissues’ protein and RNA content, as well as interrogation of rare or single cells, are required to precisely characterize constituent tumor cell populations, infiltrating lymphocytes and stromal elements. Access to spatial relationships will enable more precise characterization of tumors, support patient stratification and may help to identify novel drug targets. Multiple platforms are being developed to address these critical unmet needs. The NanoString Digital Spatial Profiling (DSP) platform enables highly multiplexed, spatial assessment of protein and/or RNA targets in tissues by detecting oligonucleotide barcodes conjugated via a photocleavable linker to primary antibodies or nucleic acid probes. While this platform enables high-dimensional spatial interrogation of tissue protein and RNA expression, a detailed understanding of its composition, function and chemistry is advisable to guide experimental design and data interpretation. The purpose of this review is to provide an independent, comprehensive description of the DSP technology including an overview of NanoString’s capture and antibody barcode conjugation chemistries, experimental workflow, data output and analysis methods. The DSP technology will be discussed in the context of other highly multiplexed immunohistochemistry methods, including imaging mass cytometry (IMC) and multiplexed ion beam imaging (MIBI), to inform potential users of the advantages and limitations of each. Additional issues such as pre-analytical variability, sampling and specimen adequacy will be considered with respect to the platforms to inform potential experimental design.
关键词： tissue biomarkers,in situ hybridization,multiplexed immunohistochemistry,NanoString,tumor microenvironment
更新于2025-09-23 15:19:57
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Combining laser microdissection and microRNA expression profiling to unmask microRNA signatures in complex tissues
摘要： Neglecting tissue heterogeneity during the analysis of microRNA (miRNA) levels results in average signals from an unknown mixture of different cell types that are difficult to interpret. Here we demonstrate the technical requirements needed to obtain high-quality, quantitative miRNA expression information from tumor tissue compartments obtained by laser microdissection (LMD). Furthermore, we show the significance of disentangling tumor tissue heterogeneity by applying the newly developed protocols for combining LMD of tumor tissue compartments with RT-qPCR analysis to reveal compartment-specific miRNA expression signatures. An important advantage of this strategy is that the miRNA signature can be directly linked to histopathology. In summary, combining LMD and RT-qPCR is a powerful approach for spatial miRNA expression analysis in complex tissues, enabling discovery of disease mechanisms, biomarkers and drug candidates.
关键词： laser microdissection (LMD),biomarker discovery,tumor microenvironment,drug discovery,microRNA profiling,tissue complexity
更新于2025-09-19 17:13:59
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Cerenkov Luminescence-Induced NO Release from 32P-Labeled ZnFe(CN)5NO Nanosheets to Enhance Radioisotope-Immunotherapy
摘要： The combination of radiotherapy with immunotherapy has emerged as a promising combinational therapeutic methodology. The efficacies of both types of therapies, however, are hampered by the abnormal tumor microenvironment (TME) with hypoxic and immunosuppressive features. Herein, we discover that by mixing zinc ions with sodium nitroprusside, a clinical anti-hypertensive drug, ZnFe(CN)5NO single-layer nanosheets can be obtained. Interestingly, after being labeled with 32P by simple mixing, the 32P-induced Cerenkov luminescence stimulated persistent release of NO from nanosheets. Owing to the modulation of hypoxic immunosuppressive TME by NO, such 32P-labeled nanosheets are able to completely eliminate local tumors after local administration, and proffer a strong abscopal effect after being combined with immune-checkpoint blockade therapy. Our work presents a unique 2D nanoplatform comprising Zn2+ and a clinical drug to enable chelator-free radiolabeling, Cerenkov luminescence-triggered NO release, effective TME modulation, and enhanced combination radioisotope-immunotherapy are promising for tumor metastasis treatment.
关键词： radioisotope-immunotherapy,ZnFe(CN)5NO nanosheets,Cerenkov luminescence,tumor microenvironment,NO release
更新于2025-09-12 10:27:22
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Smart Plasmonic Nanozyme Enhances Combined Chemo-Photothermal Cancer Therapy and Reveals Tryptophan Metabolic Apoptotic Pathway
摘要： The tumor microenvironment regulation is considered as an intelligent strategy for cancer therapeutics, but the related metabolic pathways of cell apoptosis still remains a great challenge. Herein, by applying multifunctional carbon dot-decorated Ag/Au bimetallic nanoshells (CDs-Ag/Au NSs, CAANSs) nanoprobes as smart plasmonic nanozymes for combined chemo-photothermal cancer therapy, we achieved a high efficiency in cancer cell therapy and revealed a tryptophan metabolic apoptotic pathway. In addition to high photothermal conversion efficiency, the CAANSs can act as a smart nanozyme to catalyze intracellular H2O2 to the cytotoxic reactive oxygen species (ROS) of superoxide anion (·O2-) in response to mild acidic cancerous cell microenvironment to damage cellular DNA. More importantly, the tryptophan metabolic pathway during the combined chemo-photothermal therapy has been revealed that the tryptophan participates in oxidative stress process, which can be decomposed to produce H2O2 and further formed into superoxide anion to kill cells under the catalytic nanomedicine process. The current work provides an effective platform for cancer therapeutics and is promising for cancer-related molecular biology studies.
关键词： Tryptophan Metabolic Apoptotic Pathway,Smart Plasmonic Nanozyme,Tumor Microenvironment,Chemo-Photothermal Cancer Therapy,Reactive Oxygen Species
更新于2025-09-11 14:15:04
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Gene expression profiling of single cells from archival tissue with laser-capture microdissection and Smart-3SEQ
摘要： RNA sequencing (RNA-seq) is a sensitive and accurate method for quantifying gene expression. Small samples or those whose RNA is degraded, such as formalin-fixed paraffin-embedded (FFPE) tissue, remain challenging to study with nonspecialized RNA-seq protocols. Here, we present a new method, Smart-3SEQ, that accurately quantifies transcript abundance even with small amounts of total RNA and effectively characterizes small samples extracted by laser-capture microdissection (LCM) from FFPE tissue. We also obtain distinct biological profiles from FFPE single cells, which have been impossible to study with previous RNA-seq protocols, and we use these data to identify possible new macrophage phenotypes associated with the tumor microenvironment. We propose Smart-3SEQ as a highly cost-effective method to enable large gene expression profiling experiments unconstrained by sample size and tissue availability. In particular, Smart-3SEQ’s compatibility with FFPE tissue unlocks an enormous number of archived clinical samples; combined with LCM it allows unprecedented studies of small cell populations and single cells isolated by their in situ context.
关键词： laser-capture microdissection,single-cell gene expression,RNA-seq,tumor microenvironment,FFPE tissue,Smart-3SEQ
更新于2025-09-11 14:15:04
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Collagenase Encapsulated pH-Responsive Nanoscale Coordination Polymers for Tumor Microenvironment Modulation and Enhanced Photodynamic Nanomedicine
摘要： The abundant tumor extracellular matrix (ECM) could result in the insufficient tumor retention and ineffective intra-tumor penetration of therapeutic agents, as well as acidic & hypoxic tumor microenvironment (TME), further leading to the unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG) encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn2+ and an acid-sensitive benzoic-imine organic linker (BI-linker), and then modified by polyethylene glycol (PEG). Upon intravenous (i.v.) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released due to the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to loosened ECM structure, enhanced tumor perfusion and relieved hypoxia. As the results, the second-wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (Liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of Liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers.
关键词： Nanoscale coordination polymers,Extracellular matrix,Collagenase,Photodynamic therapy,Tumor microenvironment
更新于2025-09-10 09:29:36
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Designing luminescent ruthenium prodrug for precise cancer therapy and rapid clinical diagnosis
摘要： The effective design of a targeted drug delivery system could improve the therapeutic efficacy of anticancer drugs by reducing their undesirable adsorption and toxic side effects. Here, an RGD-peptide functionalized and bioresponsive ruthenium prodrug (Ru-RGD) was designed for both cancer therapy and clinical diagnosis. This prodrug can be selectively delivered to cervical tumor sites to enhance theranostic efficacy. The benzimidazole-based ligand of the complex is susceptible to acidic conditions so, after reaching the tumor microenvironment, ligand substitution occurs and the therapeutic drug is released. The deep-red emissions produced by both one-photon and two-photon excitation increases the potential of Ru-RGD for use in the deep tissue imaging of 3D tumor spheroids. The specific accumulation of the Ru prodrug in tumor sites allows for precise tumor diagnosis and therapy in vivo. Luminescence staining of 38 clinical patient specimens shows that Ru-RGD exhibits differences in binding capability between cervical cancer and normal tissue, with a sensitivity of 95% and a specificity of 100%. This study thus provides an approach for the effective design and application of targeted metal complexes in cancer therapy and clinical diagnosis.
关键词： targeted drug delivery,cancer theranosis,rapid clinical diagnosis,two-photon imaging,tumor microenvironment
更新于2025-09-10 09:29:36
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Versatile polymeric microspheres with tumor-microenvironment bioreducible degradation, pH-activated surface charge-reversal, pH-triggered “off-on” fluorescence and drug release as theranostic nanoplatforms
摘要： Facile approach has been developed for the versatile polymeric microspheres with tumor-microenvironment bioreducible degradation, pH-activated surface charge-reversal, pH-triggered “off-on” fluorescence and drug release via emulsion copolymerization of glycidyl methacrylate (GMA), poly(ethylene glycol) methyl ether methacrylate (PEGMA), N-rhodamine 6G-ethyl-acrylamide (Rh6GEAm) with N,N-bis(acyloyl)cystamine) (BACy) as disulfide crosslinker and functionalization. The final PGMA-DMMA microspheres showed excellent cytocompatibility, pH-triggered surface charge reversal at pH 5-6, strong fluorescence only in acidic media, and bioreducible degradation with high reductant level, indicating their promising application as theranostic nanoplatforms for precise imaging-guided diagnosis and chemotherapy. The DOX-loaded PGMA-DMMA microspheres with a drug-loading capacity of 18% and particle size of about 150 nm possessed unique pH/reduction dual-responsive controlled release, with a cumulative DOX release of 60.5% within 54 h at the simulated tumor microenvironment but a premature leakage of < 8.0% under the simulated physiological condition. Enhanced inhibition efficacy against HepG2 cells was achieved than the free DOX.
关键词： tumor-microenvironment bioreducible degradation,pH-triggered “off-on” fluorescence,pH-triggered drug release,theranostic nanoplatforms,pH-activated surface charge-reversal,polymeric microspheres
更新于2025-09-09 09:28:46