Tumor-specific Imaging Research Articles

18F]FAPI-42 PET/CT versus [18F]FDG PET/CT for imaging of recurrent or metastatic gastrointestinal stromal tumors.

PET has been important for monitoring recurrence and metastasis of Gastrointestinal Stromal Tumors (GISTs) and the selection of therapeutic strategies. A significant portion of GISTs lesions show negative FDG uptake and therefore calls for more tumor-specific imaging biomarkers. This study compared the imaging performance of [18F]FAPI-42 PET/CT and [18F]FDG PET/CT in recurrent or metastatic gastrointestinal stromal tumors (R/M GISTs). This study retrospectively included 35 patients with R/M GISTs who underwent both FAPI PET/CT and FDG PET/CT. The definite diagnosis was confirmed by pathology or follow-up drug treatment effects. The differences in detection rates and tumor-to-background SUVmax ratio (SUVTBR) of different locations between dual-tracer PET/CT were compared. Factors including tumor size, degree of enhancement, type of gene mutation, and targeted treatment potentially influencing the uptake of both tracers were assessed. The excised lesions (n = 3) underwent immunohistochemical staining to verify FAP expression in the tissue. A total of 106 lesions in 35 patients were identified, out of which 38/106 (35.8%) lesions (FAPI + /FDG -) were additionally detected by FAPI PET/CT as compared to that by FDG, including 26 liver metastases, ten peritoneal metastases, one gastrointestinal recurrence, and one bone metastasis. The positive detection rate of FAPI PET/CT for recurrent or metastatic GISTs was higher than that of FDG (80.2% vs. 53.8%, P< 0.001), especially in liver metastases (87.5% vs. 33.3%, P< 0.001). Moreover, the SUVTBR of liver metastases of GISTs in FAPI PET/CT was higher than that in FDG [2.4 (0.3 to 11.2) vs. 0.9 (0.3 to 6.5), P< 0.001]. The longest diameter of tumors in the FDG-positive group was higher than that of the FDG-negative group (P= 0.005); still, it did not differ between the FAPI-positive group and the FAPI-negative group. No difference in the degree of enhancement was observed between both tracers' positive and negative groups. Besides, the SUVTBR of FDG but not FAPI differed significantly among various gene mutations (P< 0.001) as well as the targeted therapy and no targeted therapy groups (P= 0.001). FAP was expressed in R/M GISTs, and the uptake of FAPI corresponded to the level of FAP expression. In conclusion, FAPI for imaging of R/M GISTs could be superior to FDG, specifically for liver metastases. The uptake of FAPI could reflect the level of FAP expression, and it was independent of tumor size, degree of enhancement, type of gene mutation, and targeted therapy as compared to FDG.

Mesoporous Nanoparticles for Diagnosis and Treatment of Liver Cancer in the Era of Precise Medicine.

Primary liver cancer is the seventh-most-common cancer worldwide and the fourth-leading cause of cancer mortality. In the current era of precision medicine, the diagnosis and management of liver cancer are full of challenges and prospects. Mesoporous nanoparticles are often designed as specific carriers of drugs and imaging agents because of their special morphology and physical and chemical properties. In recent years, the design of the elemental composition and morphology of mesoporous nanoparticles have greatly improved their drug-loading efficiency, biocompatibility and biodegradability. Especially in the field of primary liver cancer, mesoporous nanoparticles have been modified as highly tumor-specific imaging contrast agents and targeting therapeutic medicine. Various generations of complexes and structures have been determined for the complicated clinical management requirements. In this review, we summarize these advanced mesoporous designs in the different diagnostic and therapeutic fields of liver cancer and discuss the relevant advantages and disadvantages of transforming applications. By comparing the material properties, drug-delivery characteristics and application methods of different kinds of mesoporous materials in liver cancer, we try to help determine the most suitable drug carriers and information media for future clinical trials. We hope to improve the fabrication of biomedical mesoporous nanoparticles and provide direct evidence for specific cancer management.

Two-dimensional silicene photodynamic tumor-targeting nanomedicine.

Since the innovative development of photosensitizers (PSs) is pivotal prerequisite for the successful clinical translation of photodynamic therapy (PDT), the unresolved challenges of classical PSs such as photobleaching, poor bioavailability, lack of tumor selectivity encourage the exploitation of new-generation PSs. In this work, we develop silicene nanosheets with unparalleled physiochemical nature and intriguing biocompatibility as the distinct two-dimensional (2D) nanoscale photosensitizer based on the mechanism of wet-chemical synthetic approach to achieve effective PDT-based tumor nanotherapy. The generation capacities of singlet oxygen (1O2) in different atmospheres have been systematically explored in depth. Furthermore, the conjunction of c (RGDyC) onto 2D silicene nanosheets (denoted as SRGD) endows the SRGD nanomedicines with specific targeting properties to αvβ3 integrin-overexpressed cancer cells, accomplishing in vivo and in vitro potent tumor growth inhibition efficiency. More notably, the excellent light absorption capacity of 2D silicene enables the tumor-specific photoacoustic imaging for potentiating the therapeutic guidance and monitoring. This paradigm can inspire the future design and applications of 2D silicene-based cancer-theranostic nanoplatform in biology and medicine.

In vivo Preclinical Tumor-Specific Imaging of Superparamagnetic Iron Oxide Nanoparticles Using Magnetic Particle Imaging for Cancer Diagnosis.

PurposeMagnetic particle imaging (MPI) is an emerging radiation-free, non-invasive three-dimensional tomographic technology that can visualize the concentrations of superparamagnetic iron oxide nanoparticles (SPIONs). To verify the applicability of the previously proposed point-of-care testing MPI (PoCT-MPI) in medical diagnosis and therapeutics, we imaged SPIONs in animal tumor models.MethodsCT26 or MC38 mouse colon carcinoma cells (2 × 106 cells) were subcutaneously injected into the right flank of BALB/c mice. SPIONs were either injected directly into the tumor lesions in the intratumoral group or through tail veins in the intravenous group. CT26 and MC38 tumor models were examined both intratumorally and intravenously to confirm the biological availability of SPIONs using PoCT-MPI.ResultsSignals were observed in the tumor lesions from day 1 to day 7. This is the first study to successfully image the pathological region and show the biodistribution of SPIONs in CT26 tumor models using the recently developed PoCT-MPI technology. Furthermore, MC38 tumor models were examined, resulting in similar images to those of the CT26 tumor model in both intratumoral and intravenous groups.ConclusionThe present study demonstrates the biological applicability of PoCT-MPI, which promises to be a powerful diagnostic and therapeutic technique in biomedical imaging.

Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops predominantly in the inflammatory environment of a cirrhotic liver caused by hepatitis, toxin exposure, or chronic liver disease. A targeted therapeutic approach is required to enable cancer killing without causing toxicity and liver failure. Poly(beta-amino-ester) (PBAE) nanoparticles (NPs) were used to deliver a completely CpG-free plasmid harboring mutant herpes simplex virus type 1 sr39 thymidine kinase (sr39) DNA to human HCC cells. Transfection with sr39 enables cancer cell killing with the prodrug ganciclovir and accumulation of 9-(4-18F-fluoro-3-hydroxymethylbutyl)guanine (18F-FHBG) for in vivo imaging. Targeting was achieved using a CpG-free human alpha fetoprotein (AFP) promoter (CpGf-AFP-sr39). Expression was restricted to AFP-producing HCC cells, enabling selective transfection of orthotopic HCC xenografts. CpGf-AFP-sr39 NP treatment resulted in 62% reduced tumor size, and therapeutic gene expression was detectable by positron emission tomography (PET). This systemic nanomedicine achieved tumor-specific delivery, therapy, and imaging, representing a promising platform for targeted treatment of HCC.

PET/NIR-II fluorescence imaging and image-guided surgery of glioblastoma using a folate receptor α-targeted dual-modal nanoprobe.

The surgery of glioblastoma (GBM) requires a maximal resection of the tumor when it is safe and feasible. The infiltrating growth property of the GBM makes it a challenge for neurosurgeons to identify the tumor tissue even with the assistance of the surgical microscope. This highlights the urgent requirement for imaging techniques that can differentiate tumor tissues during surgery in real time. Fluorescence image-guided surgery of GBM has been investigated using several non-specific fluorescent probes that emit light in the visible and the first near-infrared window (NIR-I, 700-900nm), which limit the detection accuracy because of the non-specific targeting mechanism and spectral characteristics. Targeted NIR-II (1000-1700nm) fluorescent probes for GBM are thus highly desired. The folate receptor (FR) has been reported to be upregulated in GBM, which renders it to be a promising target for specific tumor imaging. In this study, the folic acid (FA) that can target the FR was conjugated with the clinically approved indocyanine green (ICG) dye and DOTA chelator for radiolabeling with 64Cu to achieve targeted positron emission tomography (PET) and fluorescence imaging of GBM. Surprisingly it was found that the resulted bioconjugate, DOTA-FA-ICG and non-radioactive natCu-DOTA-FA-ICG, were both self-assembled into nanoparticles with NIR-II emission signal. The radiolabeled DOTA-FA-ICG, 64Cu-DOTA-FA-ICG, was found to specifically accumulate in the orthotopic GBM models using in vivo PET, NIR-II, and NIR-I fluorescence imaging. The best time window of fluorescence imaging was demonstrated to be 24h after DOTA-FA-ICG injection. NIR-II fluorescence image-guided surgery was successfully conducted in the orthotopic GBM models using DOTA-FA-ICG. All the fluorescent tissue was removed and proved to be GBM by the H&E examination. Overall, our study demonstrates that the probes, 64Cu-DOTA-FA-ICG and DOTA-FA-ICG, hold promise for preoperative PET examination and intraoperative NIR-II fluorescence image-guided surgery of GBM, respectively.

Nanobubbles as theranostic platforms for tumour-specific imaging and therapy

Effective disease the executives relies upon precise diagnostics alongside explicit treatment conventions. Current analytic procedures should be improved towards give prior discovery abilities, also customary chemotherapy ways towards deal with disease treatment are restricted by absence of explicitness also foundational harmfulness. This audit features propels in nanotechnology that have permitted the improvement of multifunctional stages for malignant growth discovery, treatment, also checking. Nanomaterial’s can be utilized as MRI, optical imaging, furthermore, photo acoustic imaging contrast specialists. When utilized as medication transporters, Nano formulations can increment growth openness towards remedial specialists also result in superior treatment impacts by dragging out flow times, shielding entangled drugs from corruption, also improving cancer take-up through the upgraded porousness also maintenance impact also as receptor-interceded endocytosis. Numerous restorative specialists like chemotherapy, antiangiogenic, or quality treatment specialists can be all the while conveyed by Nano carriers towards growth locales towards improve the adequacy of treatment. Moreover, imaging also treatment specialists can be co-conveyed towards give consistent combination of diagnostics, treatment, also follow-up, also different helpful modalities, for example, chemotherapy also hyperthermia can be co-controlled towards exploit synergistic impacts.

Tumor-Specific Imaging with Angiostamp800 or Bevacizumab-IRDye 800CW Improves Fluorescence-Guided Surgery over Indocyanine Green in Peritoneal Carcinomatosis

Complete surgical removal of lesions improves survival of peritoneal carcinomatosis and can be enhanced by intraoperative near-infrared fluorescence imaging. Indocyanine green (ICG) is the only near-infrared fluorescent dye approved for clinical use, but it lacks specificity for tumor cells, highlighting the need for tumor-selective targeting agents. We compared the tumor-specific near-infrared fluorescent probes Bevacizumab-IRDye 800CW and Angiostamp800, which target tumor angiogenesis and cancer cells, to ICG for fluorescence-guided surgery in peritoneal carcinomatosis of ovarian origin. The probes were administered to mice with orthotopic peritoneal carcinomatosis prior to conventional and fluorescence-guided surgery. The influence of neoadjuvant chemotherapy was also assessed. Conventional surgery removed 88.0 ± 1.2% of the total tumor load in mice. Fluorescence-guided surgery allowed the resection of additional nodules, enhancing the total tumor burden resection by 9.8 ± 0.7%, 8.5 ± 0.8%, and 3.9 ± 1.2% with Angiostamp800, Bevacizumab-IRDye 800CW and ICG, respectively. Interestingly, among the resected nodules, 15% were false-positive with ICG, compared to only 1.4% with Angiostamp800 and 3.5% with Bevacizumab-IRDye 800CW. Furthermore, conventional surgery removed only 69.0 ± 3.9% of the total tumor burden after neoadjuvant chemotherapy. Fluorescence-guided surgery with Angiostamp800 and Bevacizumab-IRDye 800CW increased the total tumor burden resection to 88.7 ± 4.3%, whereas ICG did not improve surgery at all. Bevacizumab-IRDye 800CW and Angiostamp800 better detect ovarian tumors and metastases than the clinically used fluorescent tracer ICG, and can help surgeons completely remove tumors, especially after surgery neoadjuvant chemotherapy.

Manganous-manganic oxide nanoparticle as an activatable microwave-induced thermoacoustic probe for deep-located tumor specific imaging in vivo

Deep-located tumor specific imaging has broad clinical applications in improving the accuracy of tumor diagnosis. Microwave-induced thermoacoustic imaging (MTAI), combining the high-contrast of microwave imaging with the high-resolution of ultrasound imaging, is a potential candidate for noninvasive tumor detection. Herein, a deep-located tumor specific MTAI method by tumor microenvironment (TME) activated nanoprobe is reported. In principle, manganous-manganic oxide-based nanoprobe can be triggered by TME with overexpressed glutathione and weak acidity, causing to release manganese ions and increase conductivity. With pulsed microwaves, manganese ions move repeatedly in gigahertz alternating electric field, resulting in a transient heating and thermoelastic expansion through the Joule effect, which yields a strong thermoacoustic (TA) wave in tumor site. In vitro and in vivo experiments demonstrate that manganous-manganic oxide-based nanoprobe could high-selectively amplify the TA signal in deep-located tumor. Our proposed tumor-specific MTAI method based on TME activation provides a potential approach for deep-located tumor detection.

NIR fluorochrome labeled anti-carcinoembryonic antigen monoclonal antibody for gastric cancer-specific image guided surgery.

340 Background: Carcinoembryonic antigen (CEA) is a widely known tumor marker that is clearly expressed in gastrointestinal tract cancer. We utilized a CEA-specific chimeric antibody conjugated to a near infrared (NIR) fluorophore to facilitate CEA-targeted fluorescence image–guided surgery (FGS) of gastric cancer. The anti-CEA antibody, SGM-101 is conjugated with NIR dye BM-105, which has an absorbance band centered at 705 nm. Methods: RNA sequencing data of 34 gastric cancer cell lines from Cancer Cell Line Encyclopedia were screened and validated by qPCR and western blotting. Flow cytometry and confocal microscopy were performed by SGM-101, Alexa Fluor-680, Isotype-101 and Isotype-680 to quantify fluorescence intensity. SGM-101(n = 5) or Isotype-101(n = 2) was injected to mouse xenografts through a tail vein which had been subcutaneously implanted with MKN-45, SNU-16, and SNU-668. IVIS Spectrum quantified radiant efficiency of fluorescence in the region of interest at serial time points. The extracted tumor in peak time was analyzed by confocal imaging for microdistribution. In addition, 85As2mLuc were injected intraperitoneally in 6-week-old female BALB/c-nu mice for peritoneal carcinomatosis. Bioluminescence/fluorescence imaging was performed with IVIS Spectrum at peak time and analyzed via Living Image. Histologic evaluations were processed with H&amp;E and Immunohistochemistry (IHC) data by a pathologist. Results: RNA expression of ceacam5 and protein expression of CEA in gastric cell lines was measured by RNA sequencing, qPCR, and western blotting. CEA expression patterns displays similar with fluorescence intensity patterns which were quantified through flow cytometry and immunocytochemistry show that CEA localized in membranes. In subcutaneously implanted model, the radiant efficiency of each group shows that the accumulation of SGM-101 has significantly higher fluorescence signal in the high CEA expressing group (MKN-45) and medium expressing group (SNU-16) while no fluorescence signal was observed in the CEA negative group (SNU-668) via IVIS Spectrum. Biodistribution of SGM-101 indicates that the maximum peak accumulation point was 48 hours after tail vein injection. Frozen tissue which was extracted at peak detection time shows micro-distribution of SGM-101 and expression of extracted tissue CEA expression was validated with IHC by pathological analysis. In the peritoneal carcinomatosis model, the imaging of fluorescence detection patterns corresponds with bioluminescence imaging and histological evaluation. Conclusions: CEA expression corresponded with intensity of in vitro fluorescence immunodetection and a tumor area accumulation in gastric cancer xenografts by SGM-101. This study indicates that NIR tumor specific imaging can be a feasible tool for image-guided surgery.

Self-quenched liposomal probes for tumor imaging based on cellular on/off system

Near-infrared fluorophores have been widely used in tumor imaging due to superior resolution and sensitivity, high penetration depth and low auto-fluorescence. However, the tumor imaging efficacy of fluorophores in vivo is impeded by the background signals and the delivery efficiency of the fluorophores. To realize sensitive tumor imaging, we developed self-quenched liposomal probes DiR-LP-C and DiR-LP-B as tumor-specific imaging probes with cellular on/off system. To prepare DiR-LP-C probes, hydrophobic DiR was solubilized in DMSO and actively loaded into the aqueous interior of liposomes. Based on the structure, DiR-LP-C showed high self-quenching (46-fold at 1.0% loading ratio) that is ‘off’ state with weak fluorescence signal but recovered fluorescence after cellular uptake. DiR-LP-B was prepared where the hydrophobic DiR molecules were dispersed in the hydrophobic lipid bilayer of liposomes and showed weaker self-quenching (5.4-fold at 1.0% loading ratio). Importantly, DiR-LP-C showed brighter cell imaging than DiR-LP-B. For in vivo imaging, both probes showed excellent tumor targeting with signal to background ratio around 5 at 24 h post-injection, with DiR-LP-C had much lower background. These results proved that the tumor-homing cellular ‘on/off’ nanoparticle system of DiR-LP-C has a great potential for tumor imaging and phototherapeutics.

In situ formation of J-aggregate in the tumor microenvironment using acidity responsive polypeptide nanoparticle encapsulating galactose-conjugated BODIPY dye for NIR-II phototheranostics.

Through the activation of packing arrangements of dyes to modulate their photophysical and/or photochemical properties, not only new NIR-II dyes but tumor-specific NIR-II imaging and therapy can also be achieved. Herein, we designed an acid-responsive polypeptide nanoparticle (P-ipr@Gal) encapsulated with a pH-sensitive amphiphilic polypeptide (P-ipr) as a carrier for the galactose-conjugated BODIPY (Gal-BDP) dye. When P-ipr@Gal NPs are enriched in tumor regions by the EPR effect, the acidic microenvironment (pH 6.4-6.8) promotes the disintegration of P-ipr@Gal nanomicelles and the release of sufficient Gal-BDP. The protonation of the julolidine nitrogen of the Gal-BDP dye switched on the molecular stacking transformation from the H-aggregate to J-aggregate. The J-aggregate significantly enhanced the redshift absorption and emission intensity, which enhanced the fluorescence brightness and photothermal therapeutic effect in the tumor region. We also prepared J-aggregates PAsp@Gal with non-acidic responsive polyaspartic acid benzyl esters (PAsp) encapsulated Gal-BDP, which remained "always-on" with J-aggregate characteristics. The P-ipr@Gal (or PAsp@Gal) J-aggregate has a maximum emission peak redshifted to nearly 1064 nm, with a 3.5-fold increase in the emission intensity compared to the H-aggregate at pH 7.4. Based on the effective accumulation of tumor sites and considerable PCE (>40%), P-ipr@Gal nanoparticles have a lower background and higher tumor background ratio, which makes them a potential NIR-II imaging-guided photothermal therapy agents.

Photosensitive AgBr@PLGA Nanoprobes for Near-Infrared Second Region Tumor-Specific Photoacoustic Imaging

Photosensitive AgBr@PLGA Nanoprobes for Near-Infrared Second Region Tumor-Specific Photoacoustic Imaging

Peptides Radiofluorination: Main Methods and Highlights

Peptides have an important role in organism and its high quantity present in tumors leading to development of radiolabeled peptides for tumor-specific imaging. Once the traditional methodologies used for radiofluorination do not work with peptides, due to their harsh conditions, other radiolabeling strategies had to be developed to supply the need. Direct radiofluorination is either an inefficient method, and the use of bidirectional groups, or prosthetic groups, is needed to enable the binding between the radionuclide fluorine-18 and a peptide functionalized. New peptides radiolabeling strategies have been developed sourcing increase the synthesis yield, its chemoselectivity, and the binding stability, and reduce the total process time and the number of steps required. The progress of radiofluorination methodologies led to development of the amidation, acylation, imidation, and alkylation techniques, the use of thiol groups, photochemical conjugation, chemoselective reactions, and “click chemistry”, in addition to use of FDG molecule and heteroatoms as linkers. This paper presents the main strategies used for peptides radiofluorination, presenting their positive and negative points, and the prosthetic groups most used in each method.

Intracellular Enzyme-Responsive Profluorophore and Prodrug Nanoparticles for Tumor-Specific Imaging and Precise Chemotherapy.

Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.

Tumor microenvironment-responsive dynamic inorganic nanoassemblies for cancer imaging and treatment.

Dynamic inorganic nanoassemblies (DINAs) have emerged as smart nanomedicine platforms with promising potential for bioimaging and targeted drug delivery. In this review, we keep abreast of the advances in development of tumor microenvironment (TME)-responsive DINAs to meet the challenges associated with precise cancer therapy. TME-responsive DINAs are designed to achieve precise switches of structures/functions in response to TME-specific stimuli including reactive oxygen species (ROS), reduced pH and hypoxia, so as to enhance the tumor accumulation of nanoassemblies, overcome the biological barriers during intratumoral penentration of therapeutics, and achieve tumor-specific imaging and therapy. This progress report will summarize various types of recently reported smart DINAs for TME-responsive tumor imaging and therapy. Their future development towards potential clinical translation will also be discussed.

Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions.

Simple SummaryVulvar tumors are sometimes difficult to distinguish from adjacent healthy tissue during surgery, causing recurrence rates of up to 40% and co-morbidity. Fluorescence-guided surgery illuminating neoplastic tissue is increasingly being used to assist surgeons for various types of cancers. As no suitable tracers are known yet for vulvar tumors, we have evaluated which proteins could be targeted for fluorescence-guided surgery. Immunohistochemistry was used to study the distribution of nine membrane proteins in healthy and (pre)malignant tissues that were consequently analyzed using quantitative image analysis. Integrin αvβ6 allowed for the most robust discrimination of VSCCs and adjacent premalignant lesions compared with surrounding healthy tissue. The use of an αvβ6 targeted near-infrared fluorescent probe for FGS of vulvar (pre)malignancies should be evaluated in future studies.Surgical removal of vulvar squamous cell carcinoma (VSCC) is associated with significant morbidity and high recurrence rates. This is at least partially related to the limited visual ability to distinguish (pre)malignant from normal vulvar tissue. Illumination of neoplastic tissue based on fluorescent tracers, known as fluorescence-guided surgery (FGS), could help resect involved tissue and decrease ancillary mutilation. To evaluate potential targets for FGS in VSCC, immunohistochemistry was performed on paraffin-embedded premalignant (high grade squamous intraepithelial lesion and differentiated vulvar intraepithelial neoplasia) and VSCC (human papillomavirus (HPV)-dependent and -independent) tissue sections with healthy vulvar skin as controls. Sections were stained for integrin αvβ6, CAIX, CD44v6, EGFR, EpCAM, FRα, MRP1, MUC1 and uPAR. The expression of each marker was quantified using digital image analysis. H-scores were calculated and percentages positive cells, expression pattern, and biomarker localization were assessed. In addition, tumor-to-background ratios were established, which were highest for (pre)malignant vulvar tissues stained for integrin αvβ6. In conclusion, integrin αvβ6 allowed for the most robust discrimination of VSCCs and adjacent premalignant lesions compared to surrounding healthy tissue in immunohistochemically stained tissue sections. The use of an αvβ6 targeted near-infrared fluorescent probe for FGS of vulvar (pre)malignancies should be evaluated in future studies.

A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. Statement of significanceFerroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.

A metabolic acidity-activatable calcium phosphate probe with fluorescence signal amplification capabilities for non-invasive imaging of tumor malignancy

Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer. Tumor cells, which are characterized by abnormal glycolysis, exhibit a lower extracellular pH (6.5–7.0) than normal tissues (7.2–7.4), providing a promising target for tumor-specific imaging and therapy. However, most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range. In this study, we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate (CaP) fluorescent probe (termed MACaP9). Unlike traditional CaP-based biomedical nanomaterials, which only work within more acidic organelles, such as endosomes and lysosomes (pH 4.0–6.0), MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually distinguish tumor from normal tissues. The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors, as well as small tumor lesions.

A Cooperatively Activatable DNA Nanoprobe for Cancer Cell-Selective Imaging of ATP.

DNA-based nanoprobes have attracted extensive interest in the field of bioanalysis. Notably, engineered DNA nanoprobes that can respond to multiple pathological parameters are desirable to detect targets precisely. Here we design a split aptamer/DNAzyme (aptazyme)-based DNA probe for fluorescence detection of ATP and further develop a cooperatively activatable DNA nanoprobe for tumor-specific imaging of ATP in vivo. The DNA nanoprobes comprising split aptazyme-coated MnO2 nanovectors have high stability and are synergistically activated by multiple biomarkers, GSH and ATP. Upon stimuli by overexpressed GSH in tumor cells, this DNA nanoprobe can release the aptazyme and self-supply cofactor Mn2+ of the DNAzyme. Sequentially, intracellular ATP induces the proper folding of the split ATP aptamer and Mn2+-dependent DNAzyme, which activates the specific cleavage of substrate and generates the optical readout signal. This nanoprobe exhibits remarkable resistance to enzymatic degradation, satisfactory biosafety, identifies ATP specifically within cancer cells, and selectively lights up solid tumors. Our research provides a reliable method for ATP imaging in cancer cells and opens a new avenue for biochemical research and highly accurate disease diagnosis.