Quantitative Analysis of White Matter Hyperintensities as a Predictor of 1-Year Risk for Ischemic Stroke Recurrence.

INTRODUCTION: This study evaluates the role of quantitative characteristics of white matter hyperintensities (WMHs) in predicting the 1-year recurrence risk of ischemic stroke. METHODS: We conducted a retrospective analysis of 1061 patients with ischemic stroke from January 2018 to April 2021. WMHs were automatically segmented using a cluster-based method to quantify their volume and number of clusters (NoC). Additionally, two radiologists independently rated periventricular and deep WMHs using the Fazekas scale. The cohort was divided into a training set (70%) and a testing set (30%). We employed Cox proportional hazards models to develop predictors based on quantitative WMH characteristics, Fazekas scores, and clinical factors, and compared their performance using the concordance index (C-index). RESULTS: A total of 180 quantitative variables related to WMHs were extracted. A higher NoC in deep white matter and brainstem, advanced age (> 90 years old), specific stroke subtypes, and absence of discharge antiplatelets showed stronger associations with the risk of ischemic stroke recurrence within 1 year. The nomogram incorporating quantitative WMHs data showed superior discrimination compared to those based on the Fazekas scale or clinical factors alone, with C-index values of 0.709 versus 0.647 and 0.648, respectively, in the testing set. Notably, a combined model including both WMHs and clinical factors achieved the highest predictive accuracy, with a C-index of 0.735 in the testing set. CONCLUSION: Quantitative assessment of WMHs provides a valuable neuro-imaging tool for enhancing the prediction of ischemic stroke recurrence risk.

MRI Manifestations of Breast Cancer Stroma and their Role in Predicting Molecular Subtype: A Case-control Study.

OBJECTIVE: This study explored whether breast MRI manifestations could be used to predict the stroma distribution of breast cancer (BC) and the role of tumor stroma-based MRI manifestations in molecular subtype prediction. METHODS: 57 patients with pathologically confirmed invasive BC (non-special type) who had lumpy BC on MRI within one week before surgery were retrospectively collected in the study. Stroma distributions were classified according to their characteristics in the pathological sections. The stromal distribution patterns among molecular subtypes were compared with the MRI manifestations of BC with different stroma distribution types (SDTs). RESULTS: SDTs were significantly different and depended on the BC hormone receptor (HR) (P<0.001). There were also significant differences among five SDTs on T2WI, ADC map, internal delayed enhanced features (IDEF), marginal delayed enhanced features (MDEF), and time signal intensity (TSI) curves. Spiculated margin and the absence of type-I TSI were independent predictors for BC with star grid type stroma. The appearance frequency of hypo-intensity on T2WI in HR- BCs was significantly lower (P=0.043) than in HR+ BCs. Star grid stroma and spiculated margin were key factors in predicting HR+ BCs, and the AUC was 0.927 (95% CI: 0.867-0.987). CONCLUSION: Breast MRI can be used to predict BC's stromal distribution and molecular subtypes.

Pulmonary delivery of nano-particles for lung cancer diagnosis and therapy: Recent advances and future prospects.

Although our understanding of lung cancer has significantly improved in the past decade, it is still a disease with a high incidence and mortality rate. The key reason is that the efficacy of the therapeutic drugs is limited, mainly due to insufficient doses of drugs delivered to the lungs. To achieve precise lung cancer diagnosis and treatment, nano-particles (NPs) pulmonary delivery techniques have attracted much attention and facilitate the exploration of the potential of those in inhalable NPs targeting tumor lesions. Since the therapeutic research focusing on pulmonary delivery NPs has rapidly developed and evolved substantially, this review will mainly discuss the current developments of pulmonary delivery NPs for precision lung cancer diagnosis and therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Noninvasive Monitoring of Immunotherapy in Lung Cancer by Lymphocyte Activation Gene 3 PET Imaging of Tumor-Infiltrating Lymphocytes.

Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

Porous Molybdenum Nitride Nanosphere as Carrier-Free and Efficient Nitric Oxide Donor for Synergistic Nitric Oxide and Chemo/Sonodynamic Therapy.

Given its abundant physiological functions, nitric oxide (NO) has attracted much attention as a cancer therapy. The sensitive release and great supply capacity are significant indicators of NO donors and their performance. Here, a transition metal nitride (TMN) MoN@PEG is adopted as an efficient NO donor. The release process starts with H+-triggered denitrogen owing to the high electronegativity of the N atom and weak Mo-N bond. Then, these active NHx are oxidized by O2 and other reactive oxygen species (ROS) to form NO, endowing specific release to the tumor microenvironment (TME). With a porous nanosphere structure (80 nm), MoN@PEG does not require an extra carrier for NO delivery, contributing to ultrahigh atomic utilization for outstanding release ability (94.1 ± 5.6 µM). In addition, it can also serve as a peroxidase and sonosensitizer for anticancer treatment. To further improve the charge separation, MoN-Pt@PEG was prepared to enhance the sonodynamic therapy (SDT) effect. Accordingly, ultrasound (US) further promotes NO generation due to more ROS generation, facilitating in situ peroxynitrite (·ONOO-) generation with great cytotoxicity. At the same time, the nanostructure also degrades gradually, leading to high elimination (94.6%) via feces and urine within 14-day. The synergistic NO and chemo-/sono-dynamic therapy brings prominent antitumor efficiency and further activates the immune response to inhibit metastasis and recurrence. This work develops a family of NO donors that would further widen the application of NO therapy in other fields.

Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy.

Recently, radiotherapy (RT) has entered a new realm of precision cancer therapy with the introduction of magnetic resonance (MR) imaging guided radiotherapy systems into the clinic. Nonetheless, identifying an optimized radiotherapy time window (ORTW) is still critical for the best therapeutic efficacy of RT. Here we describe pH and O2 dual-sensitive, perfluorooctylbromide (PFOB)-based and glycerol-weighted chemical exchange saturation transfer (CEST) nano-molecular imaging probes (Gly-PFOBs) with dual fluorine and hydrogen proton based CEST MR imaging properties (19F/1H-CEST). Oxygenated Gly-PFOBs ameliorate tumor hypoxia and improve O2-dependent radiotherapy. Moreover, the pH and O2 dual-sensitive properties of Gly-PFOBs could be quantitatively, spatially, and temporally monitored by 19F/1H-CEST imaging to optimize ORTW. In this study, we describe the CEST signal characteristics exhibited by the glycerol components of Gly-PFOBs. The pH and O2 dual-sensitive Gly-PFOBs with19F/1H-CEST MR dual-modality imaging properties, with superior therapeutic efficacy and biosafety, are employed for sensitive imaging-guided lung cancer RT, illustrating the potential of multi-functional imaging to noninvasively monitor and enhance RT-integrated effectiveness.

Correction: DCE-MRI-Derived Parameters in Evaluating Abraxane-Induced Early Vascular Response and the Effectiveness of Its Synergistic Interaction with Cisplatin.

[This corrects the article DOI: 10.1371/journal.pone.0162601.].

Controlled Release of Hydrogen-Carrying Perfluorocarbons for Ischemia Myocardium-Targeting 19 F MRI-Guided Reperfusion Injury Therapy.

Hydrogen gas is recently proven to have anti-oxidative and anti-inflammation effects on ischemia-reperfusion injury. However, the efficacy of hydrogen therapy is limited by the efficiency of hydrogen storage, targeted delivery, and controlled release. In this study, H2 -PFOB nanoemulsions (NEs) is developed with high hydrogen loading capacity for targeted ischemic myocardium precision therapy. The hydrogen-carrying capacity of H2 -PFOB NEs is determined by gas chromatography and microelectrode methods. Positive uptake of H2 -PFOB NEs in ischemia-reperfusion myocardium and the influence of hydrogen on 19 F-MR signal are quantitatively visualized using a 9.4T MR imaging system. The biological therapeutic effects of H2 -PFOB NEs are examined on a myocardial ischemia-reperfusion injury mouse model. The results illustrated that the developed H2 -PFOB NEs can efficaciously achieve specific infiltration into ischemic myocardium and exhibit excellent antioxidant and anti-inflammatory properties on myocardial ischemia-reperfusion injury, which can be dynamically visualized by 19 F-MR imaging system. Moreover, hydrogen burst release induced by low-intensity focused ultrasound (LIFU) irradiation further promotes the therapeutic effect of H2 -PFOB NEs with a favorable biosafety profile. In this study, the potential therapeutic effects of H2 -PFOB NEs is fully unfolded, which may hold great potential for future hydrogen-based precision therapeutic applications tailored to ischemia-reperfusion injury.

Effect of silk fibroin scaffold loaded with 17-ß estradiol on the proliferation and differentiation of BMSCs.

In this study, different concentrations of 17-ß estradiol silk fibroin (SF)porous scaffolds (SFPS) were prepared using freeze-drying technique, with a hope for optimal concentration and apply it locally to the bone defect area. In this study, the porous scaffold morphology structure was characterized by SEM, FTIR and universal capacity testing machines, and the in vitro cytocompatibility and biological activity of scaffold materials were studied by cell adhesion, viability and proliferation experiments. The results showed that SFPS boasts better physicochemical properties, while 17-ß estradiol SF scaffolds with low concentrations of 10-10 mol/L and 10-12 mol/L had more growth and proliferation of SF scaffolds with higher concentrations, and 10-10 mol/L was the optimal concentration of 17-ß estradiol SFPS, which was more conducive to cell adhesion and proliferation. On the other hand, after osteogenesis induction of BMSCs inoculated on 17-ß estradiol SFPS at different concentrations, it was found that the expression of alkaline phosphatase in BMSCs on different concentrations of 17-ß estradiol porous scaffolds was not large. No conflict of interest exits in the submission of this manuscript.

c-Met-Targeting 19F MRI Nanoparticles with Ultralong Tumor Retention for Precisely Detecting Small or Ill-Defined Colorectal Liver Metastases.

Purpose: Precisely detecting colorectal liver metastases (CLMs), the leading cause of colorectal cancer-associated mortality, is extremely important. 1H MRI with high soft tissue resolution plays a key role in the diagnosing liver lesions; however, precise detecting CLMs by 1H MRI is a great challenge due to the limited sensitivity. Even though contrast agents may improve the sensitivity, due to their short half-life, repeated injections are required to monitor the changes of CLMs. Herein, we synthesized c-Met-targeting peptide-functionalized perfluoro-15-crown-5-ether nanoparticles (AH111972-PFCE NPs), for highly sensitive and early diagnosis of small CLMs. Methods: The size, morphology and optimal properties of the AH111972-PFCE NPs were characterized. c-Met specificity of the AH111972-PFCE NPs was validated by in vitro experiment and in vivo 19F MRI study in the subcutaneous tumor murine model. The molecular imaging practicability and long tumor retention of the AH111972-PFCE NPs were evaluated in the liver metastases mouse model. The biocompatibility of the AH111972-PFCE NPs was assessed by toxicity study. Results: AH111972-PFCE NPs with regular shape have particle size of 89.3 ± 17.8 nm. The AH111972-PFCE NPs exhibit high specificity, strong c-Met-targeting ability, and precise detection capability of CLMs, especially small or ill-defined fused metastases in 1H MRI. Moreover, AH111972-PFCE NPs could be ultralong retained in metastatic liver tumors for at least 7 days, which is conductive to the implementation of continuous therapeutic efficacy monitoring. The NPs with minimal side effects and good biocompatibility are cleared mainly via the spleen and liver. Conclusion: The c-Met targeting and ultralong tumor retention of AH111972-PFCE NPs will contribute to increasing therapeutic agent accumulation in metastatic sites, laying a foundation for CLMs diagnosis and further c-Met targeted treatment integration. This work provides a promising nanoplatform for the future clinical application to patients with CLMs.

A new method for predicting the prognosis of ischemic stroke based vascular structure features and lesion location features.

OBJECTIVE: Determining the changes in the prognosis of the cerebral infarction area has an important guiding role in the selection of the treatment plan. The goal of this study is to propose a machine learning-based method that can predict the prognosis of stroke effectively and efficiently. METHODS: 97 cases of stroke were analyzed retrospectively. Firstly, we extracted vascular structural features from computed tomography angiography (CTA) images and stroke location features from diffusion-weighted imaging (DWI) images to comprehensively characterize the lesions, respectively. Then, we performed sparse representation-based feature selection and classification to predict the prognosis of stroke based on the extracted features. Finally, we randomly divided the 97 cases into cross-validation set, independent testing set 1 and independent testing set 2 to validate the proposed model. RESULTS: 464 vascular structure features and 116 positional features were extracted. After feature selection, 52 features were finally applied to build the classification model. The proposed model achieved promising prediction performance on the two independent testing sets, with the classification accuracies of 85.19% and 81.25%, respectively. CONCLUSION: The proposed machine learning approach can effectively mine and accurately quantify the features related to the prognosis, which include the vascular structural features and the stroke location features. In addition, the established prognostic prediction model based on these features has achieved interesting performances, which may provide valuable guidance for the clinical treatment of stroke.

Alveolar Macrophages-Mediated Translocation of Intratracheally Delivered Perfluorocarbon Nanoparticles to Achieve Lung Cancer 19F-MR Imaging.

Recent advances in intratracheal delivery strategies have sparked considerable biomedical interest in developing this promising approach for lung cancer diagnosis and treatment. However, there are very few relevant studies on the behavior and mechanism of imaging nanoparticles (NPs) after intratracheal delivery. Here, we found that nanosized perfluoro-15-crown-5-ether (PFCE NPs, ∼200 nm) exhibite significant 19F-MRI signal-to-noise ratio (SNR) enhancement than perfluorooctyl bromide (PFOB NPs) up to day 7 after intratracheal delivery. Alveolar macrophages (AMs) engulf PFCE NPs, become PFCE NPs-laden AMs, and then migrate into the tumor margin, resulting in increased tumor PFCE concentration and 19F-MRI signals. AMs-mediated translocation of PFCE NPs to lung draning lymph nodes (dLNs) decreases the background PFCE concentration. Our results shed light on the dynamic AMs-mediated translocation of intratracheally delivered PFC NPs for effective lung tumor visualization and reveal a pathway to develop and promote the clinical translation of an intratracheal delivery-based imaging strategy.

Single low-dose INC280-loaded theranostic nanoparticles achieve multirooted delivery for MET-targeted primary and liver metastatic NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC. METHODS: We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens. RESULTS: INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens. CONCLUSIONS: These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.

Histogram-based analysis of diffusion-weighted imaging for predicting aggressiveness in papillary thyroid carcinoma.

BACKGROUND: To assess the potential of apparent diffusion coefficient (ADC) map in predicting aggressiveness of papillary thyroid carcinoma (PTC) based on whole-tumor histogram-based analysis. METHODS: A total of 88 patients with PTC confirmed by pathology, who underwent neck magnetic resonance imaging, were enrolled in this retrospective study. Whole-lesion histogram features were extracted from ADC maps and compared between the aggressive and non-aggressive groups. Multivariable logistic regression analysis was performed for identifying independent predictive factors. Receiver operating characteristic curve analysis was used to evaluate the performances of significant factors, and an optimal predictive model for aggressiveness of PTC was developed. RESULTS: The aggressive and non-aggressive groups comprised 67 (mean age, 44.03 ± 13.99 years) and 21 (mean age, 43.86 ± 12.16 years) patients, respectively. Five histogram features were included into the final predictive model. ADC_firstorder_TotalEnergy had the best performance (area under the curve [AUC] = 0.77). The final combined model showed an optimal performance, with AUC and accuracy of 0.88 and 0.75, respectively. CONCLUSIONS: Whole-lesion histogram analysis based on ADC maps could be utilized for evaluating aggressiveness in PTC.

An Osimertinib-Perfluorocarbon Nanoemulsion with Excellent Targeted Therapeutic Efficacy in Non-small Cell Lung Cancer: Achieving Intratracheal and Intravenous Administration.

Low accumulation of anticancer drugs in tumors and serious systemic toxicity remain the main challenges to the clinical efficiency of pharmaceuticals. Pulmonary delivery of nanoscale-based drug delivery systems offered a strategy to increase antitumor activity with minimal adverse exposure. Herein, we report an osimertinib-loaded perfluoro-15-crown-5-ether (AZD9291-PFCE) nanoemulsion, through intratracheal and intravenous delivery, synergizes with 19F magnetic resonance imaging (19F MRI)-guided low-intensity focused ultrasound (LIFU) for lung cancer therapy. Pulmonary delivery of AZD9291-PFCE nanoemulsion in orthotopic lung carcinoma models achieves quick distribution of the nanoemulsion in lung tissues and tumors without short-term and long-term toxic effects. Furthermore, LIFU can trigger drug release from the AZD9291-PFCE nanoemulsion and specifically increases tumor vascular and tumor tissue permeability. 19F MRI was applied to quantify nanoemulsion accumulation in tumors in real time after LIFU irradiation. We validate the treatment effect of AZD9291-PFCE nanoemulsion in resected human lung cancer tissues, proving the translational potential to enhance clinical outcomes of lung cancer therapy. Thus, this work presents a promising pulmonary nanoemulsion delivery system of osimertinib (AZD9291) for targeted therapy of lung cancer without severe side effects.

Pathophysiological mechanisms of ALPPS: experimental model.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy that may increase hepatic tumour resectability and reduce postoperative liver failure rate by inducing rapid hypertrophy of the future liver remnant (FLR). Pathophysiological mechanisms after the first stage of ALPPS are poorly understood. METHODS: An ALPPS model was established in rabbits with liver VX2 tumour. The pathophysiological mechanisms after the first stage of ALPPS in the FLR and tumour were assessed by multiplexed positron emission tomography (PET) tracers, dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. RESULTS: Tumour volume in the ALPPS model differed from post-stage 1 ALPPS at day 14 compared to control animals. 18F-FDG uptake of tumour increased from day 7 onwards in the ALPPS model. Valid volumetric function measured by 18F-methylcholine PET showed good values in accurately monitoring dynamics and time window for functional liver regeneration (days 3 to 7). DCE-MRI revealed changes in the vascular hyperpermeability function, with a peak on day 7 for tumour and FLR. CONCLUSION: Molecular and functional imaging are promising non-invasive methods to investigate the pathophysiological mechanisms of ALPPS with potential for clinical application.

Correction: Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer.

Correction for 'Novel anilino quinazoline-based EGFR tyrosine kinase inhibitors for treatment of non-small cell lung cancer' by Lili Yang et al., Biomater. Sci., 2021, 9, 443-455. DOI: 10.1039/D0BM00293C.

Multimodality MRI-based radiomics for aggressiveness prediction in papillary thyroid cancer.

OBJECTIVE: To investigate the ability of a multimodality MRI-based radiomics model in predicting the aggressiveness of papillary thyroid carcinoma (PTC). METHODS: This study included consecutive patients who underwent neck magnetic resonance (MR) scans and subsequent thyroidectomy during the study period. The pathological diagnosis of thyroidectomy specimens was the gold standard to determine the aggressiveness. Thyroid nodules were manually segmented on three modal MR images, and then radiomics features were extracted. A machine learning model was established to evaluate the prediction of PTC aggressiveness. RESULTS: The study cohort included 107 patients with PTC confirmed by pathology (cross-validation cohort: n = 71; test cohort: n = 36). A total of 1584 features were extracted from contrast-enhanced T1-weighted (CE-T1 WI), T2-weighted (T2 WI) and diffusion weighted (DWI) images of each patient. Sparse representation method is used for radiation feature selection and classification model establishment. The accuracy of the independent test set that using only one modality, like CE-T1WI, T2WI or DWI was not particularly satisfactory. In contrast, the result of these three modalities combined achieved 0.917. CONCLUSION: Our study shows that multimodality MR image based on radiomics model can accurately distinguish aggressiveness in PTC from non-aggressiveness PTC before operation. This method may be helpful to inform the treatment strategy and prognosis of patients with aggressiveness PTC.

Magnetic Resonance/Infrared Dual-Modal Imaging-Guided Synergistic Photothermal/Photodynamic Therapy Nanoplatform Based on Cu1.96S-Gd@FA for Precision Cancer Theranostics.

Developing new nanoplatforms for dynamically and quantitatively visualizing drug accumulation and targeting within tumors is crucial for precision cancer theranostic. However, achieving efficient tumor therapy via synergistic photothermal/photodynamic therapy (PTT/PDT) using a single excitation light source, remains a challenge. In this work, we designed Gd-surface functionalized copper sulfide nanoparticles that were modified with folic acid (FA) (Cu1.96S-Gd@FA) to overcome the above limitations and promote PTT/PDT therapeutics. Here, Cu1.96S-Gd nanoparticles were synthesized via a coprecipitation method. All samples exhibited high longitudinal relaxivity (up to 12.9 mM-1 s-1) and strong photothermal conversion efficiency (50.6%). Furthermore, the Gd ions promoted electron-hole segregation, inducing the Cu1.96S-Gd nanoparticles to generate more reactive oxygen species (ROS) than pure Cu1.96S nanoparticles. The Cu1.96S-Gd@FA enabled the targeting of folate receptor (FR) and promoted cellular uptake, consequently enhancing oncotherapy efficacy. Compared to non-targeted Cu1.96S-Gd, a higher signal enhancement for magnetic resonance (MR) imaging in vivo by Cu1.96S-Gd@FA was recorded. Given photothermal ability, the nanoparticles also could be visualized in infrared (IR) imaging. Furthermore, the nanoparticles exhibited biodegradation behavior and achieved good drug elimination performance via renal clearance. Our strategy, integrating Cu1.96S-Gd@FA nanoparticles, MR/IR dual-modal imaging, and PTT/PDT into one nanoplatform, demonstrated great potential for anti-breast cancer therapy by effectively targeting FR overexpressed breast cancer cells.

Pulmonary Delivery of Theranostic Nanoclusters for Lung Cancer Ferroptosis with Enhanced Chemodynamic/Radiation Synergistic Therapy.

Inefficient tumor accumulation and penetration remain as the main challenges to therapy efficacy of lung cancer. Local delivery of smart nanoclusters can increase drug penetration and provide superior antitumor effects than systemic routes. Here, we report self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) that enhance in situ ferroptosis and apoptosis with radiotherapy and chemodynamic therapy. After pulmonary delivery in orthotopic lung cancer, SPIONCs disintegrate into smaller nanoparticles and release more iron ions in an acidic microenvironment. Under single-dose X-ray irradiation, endogenous superoxide dismutase converts superoxide radicals produced by mitochondria to hydrogen peroxide, which in turn generates hydroxyl radicals by the Fenton reaction from iron ions accumulated inside the tumor. Finally, irradiation and iron ions enhance tumor lipid peroxidation and induce cell apoptosis and ferroptosis. Thus, rationally designed pulmonary delivered nanoclusters provide a promising strategy for noninvasive imaging of lung cancer and synergistic therapy.