LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.

BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the "constantly active" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy.

Midterm Outcomes of Multicenter Castor Single-Branch Stent Graft Use in the Treatment of Thoracic Aortic Diseases.

PURPOSE: The aim of this study was to evaluate the midterm efficacy and safety of a single-branch Castor stent graft in the treatment of thoracic aortic disease. MATERIALS AND METHODS: Clinical data of 106 patients with thoracic aortic disease treated with Castor single-branch stent graft at 3 centers were collected between May 2018 and June 2023. The indicators included technical success, stent-related complication, reintervention, retrograde dissection, endoleak, distal stent graft-induced entry (dSINE), branch patency, and mortality. The outcomes of the Castor stent graft for multibranch reconstruction above the arch was also analyzed. RESULTS: The technical success was 98.1% (104/106), while the surgical success was 93.4% (99/106). The reintervention was 2.8% (3/106), consisting of a case of retrograde type A dissection, an endoleak, and a dSINE. The retrograde dissection was 1.9% (2/106), while type I endoleak was 1.9% (2/106). The new dSINE was 2.8% (3/106), and the branch patency rate was 100%. The mortality was 1.9% (2/106). The mean follow-up time was 29.1±17.7 months. The 2-year post-surgery cumulative survival rate was 91.0%±3.1%, while the cumulative branch patency rate was 96.2%±2.2%. In addition, the cumulative freedom from stent-related reintervention rate was 93.2%±2.8%. A comparison showed no significant difference in the stent-related complication, branch patency, endoleak, reintervention, and mortality when the proximal end of the Castor stent graft was anchored to zones 1 or 2 of the aorta. CONCLUSION: Castor single-branch stent graft showed favorable early and midterm outcomes in the treatment of thoracic aortic disease. In addition, it was feasible to combine Castor stent graft with other advanced techniques for multibranch aortic arch reconstruction. CLINICAL IMPACT: The Castor single-branch stent graft was approval by the Chinese Food and Drug Administration in 2017. However, there were few studies on the mid-term outcomes for thoracic aortic disease after launching, which mainly focused on small single-center retrospective study. In the study, we assessed the mid-term outcomes of Castor stent graft through multi-center cases, Castor stent graft combined with other advanced techniques (such as fenestration and hybrid) for multi-branch reconstruction of aortic arch were also conducted. We found Castor single-branch stent graft showed favorable early and mid-term outcomes in the treatment of thoracic aortic disease. Additionally, it was feasible to combine Castor stent graft with other advanced technique for multi-branch aortic arch reconstruction. As an off-the-shelf branched stent graft with a wide range of models, it could be also used in most emergent situation. The Castor stent graft was expected to become more widely used in the future.

PTC-MAS: A Deep Learning-Based Preoperative Automatic Assessment of Lymph Node Metastasis in Primary Thyroid Cancer.

BACKGROUND: Identifying cervical lymph node metastasis (LNM) in primary thyroid cancer preoperatively using ultrasound is challenging. Therefore, a non-invasive method is needed to assess LNM accurately. PURPOSE: To address this need, we developed the Primary Thyroid Cancer Lymph Node Metastasis Assessment System (PTC-MAS), a transfer learning-based and B-mode ultrasound images-based automatic assessment system for assessing LNM in primary thyroid cancer. METHODS: The system has two parts: YOLO Thyroid Nodule Recognition System (YOLOS) for obtaining regions of interest (ROIs) of nodules, and LMM assessment system for building the LNM assessment system using transfer learning and majority voting with extracted ROIs as input. We retained the relative size features of nodules to improve the system's performance. RESULTS: We evaluated three transfer learning-based neural networks (DenseNet, ResNet, and GoogLeNet) and majority voting, which had the area under the curves (AUCs) of 0.802, 0.837, 0.823, and 0.858, respectively. Method III preserved relative size features and achieved higher AUCs than Method II, which fixed nodule size. YOLOS achieved high precision and sensitivity on a test set, indicating its potential for ROIs extraction. CONCLUSIONS: Our proposed PTC-MAS system effectively assesses primary thyroid cancer LNM based on preserving nodule relative size features. It has potential for guiding treatment modalities and avoiding inaccurate ultrasound results due to tracheal interference.

Imageological/Structural Study regarding the Improved Pharmacokinetics by 68Ga-Labeled PEGylated PSMA Multimer in Prostate Cancer.

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series 68Ga/177Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [68Ga]Ga-DOTA-(1P-PEG4), [68Ga]Ga-DOTA-(2P-PEG0), [68Ga]Ga-DOTA-(2P-PEG4), and [68Ga]Ga/[177Lu]Lu-DOTA-(2P-PEG4)2, which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe's tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes' affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG4 and PSMA dimer optimizations enhanced the probes' tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [68Ga]Ga-DOTA-(2P-PEG4)2 exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG4)2 was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG4)2 is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice.

Tumor-penetrating nanoplatform with ultrasound "unlocking" for cascade synergistic therapy and visual feedback under hypoxia.

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.

Peptide Supramolecular Assembly-Instructed In Situ Self-Aggregation for Stratified Targeting Sonodynamic Therapy Enhancement of AIE Luminogens.

The emergence of aggregation-induced emission luminogens (AIEgens) has attracted substantial scientific attention. However, their antitumor efficacy in photodynamic therapy (PDT) is significantly restricted by the poor water solubility and limited treatment depth. Therefore, a novel AIEgens-involved therapeutic platform with good permeability and bioavailability is urgently required. Herein, supramolecular chemistry is combined with the AIEgen bis-pyrene (BP) to construct a peptide-AIEgen hybrid nanosystem (PAHN). After intravenous injection, the versatile nanoplatform not only improved the hydrophilicity of BP but also achieved stratified targeting from tumor to mitochondrial and induced mitochondrial dysfunction, thus activating caspase-3 upregulation. Then, sonodynamic therapy (SDT), an alternative modality with high tissue penetrability, is performed to evoke reactive oxygen species (ROS) generation for BP. More importantly, since the hydrophilic shell is separated from the nanosystem by the specific cleavage of caspase-3, the resulting decrease in hydrophilicity induced tight self-aggregation of PAHN residues in situ, further allowing more absorbed energy to be used for ROS generation under ultrasound irradiation and enhancing SDT efficacy. Moreover, severe oxidative stress resulting from ROS imbalance in the mitochondria initiates the immunogenic cell death process, thus evoking antitumor immunogenicity. This PAHN provides prospective ideas into AIE-involved antitumor therapy and design of peptide-AIEgens hybrids.

Biomimetic, pH-Responsive Nanoplatforms for Cancer Multimodal Imaging and Photothermal Immunotherapy.

Photothermal therapy (PTT), by converting light to thermal energy, has become a novel and noninvasive technique for tumor thermal ablation in clinical practice. However, as a result of phagocytosis of reticuloendothelial cells, current photothermal agents (PTAs) derived from exogenous materials suffer from incompetent tumor targeting and brief internal circulation time. The resulting poor accumulation of PTAs in the target area severely reduces the efficacy of PTT. In addition, the potential toxicity of PTAs, excessive laser exposure, and possibilities of tumor recurrence and metastasis following PTT are still intractable problems that severely influence patients' quality of life. Herein, a biomimetic pH-responsive nanoprobe was prepared via cancer cell membrane coating polydopamine (PDA)-CaCO3 nanoparticles (CPCaNPs) for photoacoustic (PA)/ultrasonic (US)/thermal imaging-guided PTT. When CPCaNPs targeted and infiltrated into the tumor's acidic microenvironment, the decomposed CO2 bubbles from homologous targeting CPCaNPs enhanced ultrasonic (US) signals obviously. At the same time, the PDA of CPCaNPs not only performed efficient PTT of primary tumors but also generated photoacoustic (PA) signals. In addition, an immune checkpoint pathway blockade was combined, which inhibited tumor recurrence and metastasis significantly and improved the immunosuppressive microenvironment after PTT to a large extent. Thus, these proposed biomimetic pH-responsive CPCaNPs provide a promising strategy for precise PTT immunotherapy under the intelligent guidance of PA/US/thermal imaging and show great potential for clinical translation.

Effect of 131I with and without artificial liver support system in patients with Graves' disease and severe liver dysfunction: A retrospective study.

Objective: Treatment decision-making in Graves' disease (GD) with severe liver dysfunction (LD) is a clinical challenge. This research was carried out to evaluate the effect of radioiodine (131I) with or without an artificial liver support system (ALSS) in GD patients with severe LD. Methods: In total, 45 patients diagnosed with GD and severe LD were enrolled and allocated to two groups: patients treated with 131I alone (n=30) (Group A)and patients by a combination of 131I and ALSS (n=15)(Group B). Liver function, thyroid hormone concentrations, therapeutic efficacy, and the cost of treatment were compared between the two groups. Results: Thyroid hormone concentrations were lower 2 weeks after 131I treatment, but no deterioration in liver function was identified. There was no statistically significant difference in the treatment efficacy between the two groups. The hospital stay, total cost, and daily cost were lower in patients treated with 131I alone than in those treated with 131I and an ALSS (p<0.05). Conclusion: The key point of treating GD patients with severe LD is to control the GD.131I is recommended as an effective and safe and should be applied as soon as possible once the diagnosis is clarified; however, when used in combination with an ALSS, there was no substantial improvement in therapeutic efficacy.

A Cohort Study of Surgical Indexes, Postoperative Complications, Recovery Speed, and Prognosis of Stanford Type A Aortic Dissection Compared with Traditional Sun's Operation.

Objective: The objective is to explore the surgical index, postoperative complications, recovery speed, and prognosis of Stanford type A aortic dissection (AD) compared with traditional 'Sun's operation. Methods: One hundred patients with Stanford type A AD treated from February 2018 to February 2021 were enrolled in our hospital. Patients were randomly divided into control and research group. The former group underwent traditional Sun's surgery, and the latter group underwent combined debranching surgery. The general data, surgical indexes, total amount of blood transfusion, renal function 72 hours after operation, postoperative indexes during hospitalization, and follow-up results after discharge were compared between the two groups. Results: The CPB time, ACC time, operation time, and postoperative total drainage volume of the study group were all lower than those of the control group, and the intraoperative urine volume of the study group was higher than that of the control group (P < 0.05). The total amount of RBC infused in the study group was higher than that in the control group, while the total amount of PLT, cryoprecipitate, and plasma infusion in the study group was lower than that in the control group (P < 0.05). At 72 hours after operation, BUN, Scr, and UA in the study group were significantly lower than those in the control group (P < 0.05). The number of the secondary intubation, hemodialysis, neurological complications, and deaths in the study group was significantly lower than that in the control group (P < 0.05). Conclusion: Both Sun's operation and branch removal are more effective treatment methods, and the two different surgical methods have different indications, advantages, and disadvantages, so different surgical methods can be chosen according to different conditions for Stanford AD. The possible postoperative complications should be comprehensively analyzed in the clinical work in order to reduce the occurrence of postoperative complications and improve the cure rate.

Low Intensity Focused Ultrasound Ignited "Deep-Penetration Nanobomb" (DPNB) for Tetramodal Imaging Guided Hypoxia-Tolerant Sonodynamic Therapy Against Hypoxic Tumors.

Background: Sonodynamic therapy (SDT) has been regarded as a novel therapeutic modality for killing tumors. However, the hypoxic tumor microenvironment, especially deep-seated tumors distant from blood vessels, severely restricts therapeutic efficacy due to the oxygen-dependent manner of SDT. Methods: Herein, we report a novel ultrasonic cavitation effect-based therapeutic modality that is able to facilitate the hypoxia-tolerant SDT for inducing hypoxic tumor death. A tLyP-1 functionalized liposomes is fabricated, composed of hematoporphyrin monomethyl ether gadolinium as the sonosentizer and perfluoropentane (PFP) as the acoustic environment regulator. Moreover, the tLyP-1 functioned liposomes could achieve active tumor homing and effective deep-penetrating into hypoxic tumors. Upon low intensity focused ultrasound (LIFU) irradiation, the acoustic droplet vaporization effect of PFP induced fast liquid-to-gas transition and quick bubbles explosion to generate hydroxyl radicals, efficiently promoting cell death in both normoxic and hypoxic microenvironment (acting as deep-penetration nanobomb, DPNB). Results: The loading of PFP is proved to significantly enhance the therapeutic efficacy of hypoxic tumors. In particular, these DPNB can also act as ultrasound, photoacoustic, magnetic resonance, and near-infrared fluorescence tetramodal imaging agents for guiding the therapeutic process. Conclusion: This study is the first report involving that liquid-to-gas transition based SDT has the potential to combat hypoxic tumors.

Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy.

Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells. Methods: In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin (PDOX) were used to prepare a theranostic nanocomposite (Ag-TF@PDOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration. Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe3+ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@PDOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance. Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.

Near-Infrared II Nanoadjuvant-Mediated Chemodynamic, Photodynamic, and Photothermal Therapy Combines Immunogenic Cell Death with PD-L1 Blockade to Enhance Antitumor Immunity.

The efficacy of immune checkpoint inhibition in inducing death of cancer cells is affected by the immunosuppressive "cold" tumor microenvironment, which results in a poor response by the patient's antitumor immune system. However, the immunomodulatory effects of immunogenic cell death in response to irritation by heat energy and reactive oxygen species (ROS) can switch the tumor microenvironment from "cold" to "hot." This study has developed a nanoadjuvant for immune therapy using iron tungsten oxide (FeWOx)-based nanosheets with surface PEGylation (FeWOx-PEG). This FeWOx-PEG nanoadjuvant serves as a chemodynamic reagent via the Fenton reaction and acts as a photosensitizer for photodynamic and photothermal therapy under near-infrared II laser irradiation; however, it could also be used to augment tumor-infiltrating T-cells and provoke a systemic antitumor immune response by combining the immunogenic cell death triggered by ROS and photothermal therapy with the immune checkpoint blockade. This research demonstrates that application of the FeWOx-PEG nanoadjuvant under the guidance of magnetic resonance/computed tomography/photoacoustic imaging can eliminate the primary tumor and suppress the growth of distant tumors.

[Progression on Multifunctional Nanoparticles Interfering with Cell Membrane Transporters-associated Drug Resistance].

Multi-drug resistance(MDR)refers to the loss of sensitivity of tumor cells to traditional chemotherapeutics agents under the mediation of various mechanisms,resulting in the reduction of chemotherapy efficacy.Current studies suggest that a variety of factors,including cell membrane transporter-mediated efflux of anti-tumor drugs,special microenvironment in tumor tissue,DNA self-repair and anti-apoptotic process,and epithelial-mesenchymal cell transformation,may contribute to the formation of MDR.Cell membrane transporter-mediated drug efflux refers to an increase in the amount of anti-tumor drug pumped out of the cell through the up-regulation of the ATP-binding cassette transporter on tumor cell membrane,which reduces the concentration of the drug in the cell,thus forming MDR.An effective method to inhibit the efflux pump caused by overexpression of membrane transporters plays an important role in overcoming MDR.As a promising drug delivery system,multifunctional nanoparticles have demonstrated many advantages in antitumor therapy.Meanwhile,nanoparticles with tailored design are capable of overcoming MDR when combined with a variety of strategies.This paper described in detail the studies relevant to the use of multifunctional nano-sized drug delivery system combined with different strategies,such as co-delivery of agents,external responsiveness or target modification for intervention with efflux pump in order to reverse MDR.This paper provides reference for the development of nano-sized drug delivery system and the formulation of reversal strategy in the future.

iRGD Peptide-Mediated Liposomal Nanoparticles with Photoacoustic/Ultrasound Dual-Modality Imaging for Precision Theranostics Against Hepatocellular Carcinoma.

PURPOSE: Prepare a multifunctional ultrasound molecular probe, cell-penetrating peptide-modified 10-hydroxycamptothecin-loaded phase-transformation lipid nanoparticles (iRGD-ICG-10-HCPT-PFP-NPs), and to combine iRGD-ICG-10-HCPT-PFP -NPs with low-intensity focused ultrasound (LIFU) for precision theranostics against hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The morphology of nanoparticles (NPs) and iRGD-ICG-10-HCPT-PFP-NPs was detected. In vitro, we examined targeting ability by flow cytometry and confocal laser scanning microscopy (CLSM), assessed penetration ability into hepatoma cells, and assessed killing ability. In vivo, we examined the targeting ability of the NPs with a photoacoustic (PA) imager and fluorometer (FL), while LIFU irradiation was used to trigger the release of chemotherapeutic drugs, which had a therapeutic effect on tumors. RESULTS: The particle size of iRGD-ICG-10-HCPT-PFP-NPs was 298.4 ± 10.42 nm. In vitro, iRGD-ICG-10-HCPT-PFP-NPs bound more to SK-Hep1 cells than ICG-10-HCPT-PFP-NPs. iRGD-ICG-10-HCPT-PFP-NPs could achieve PA/ultrasound imaging. The percentage of antiproliferative and apoptotic cells in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly higher. In vivo, iRGD-ICG-10-HCPT-PFP-NPs can target tumor sites and achieve PA/ultrasound imaging. The tumor volume in the iRGD-ICG-10-HCPT-PFP-NPs+LIFU group was significantly smaller, and the antiproliferative and proapoptotic effects were higher. CONCLUSION: We successfully prepared a novel molecular probe that has good targeting, can perform ultrasound/PA dual-modality imaging, and can penetrate deep into tumors to achieve better therapeutic tumor effects, providing a new idea and method for theranostics of HCC.

Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based "combo" nanoagent together with PD-L1 blockade in reversing multidrug resistance.

BACKGROUND: Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. RESULTS: In this study, we fabricated a "combo" nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. CONCLUSION: This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.

Radiomics Score Combined with ACR TI-RADS in Discriminating Benign and Malignant Thyroid Nodules Based on Ultrasound Images: A Retrospective Study.

This study aimed to explore the ability of combination model of ultrasound radiomics score (Rad-score) and the thyroid imaging, reporting and data system by the American College of Radiology (ACR TI-RADS) in predicting benign and malignant thyroid nodules (TNs). Up to 286 radiomics features were extracted from ultrasound images of TNs. By using the lowest probability of classification error and average correlation coefficients (POE + ACC) and the least absolute shrinkage and selection operator (LASSO), we finally selected four features to establish Rad-score (Vertl-RLNonUni, Vertl-GLevNonU, WavEnLH-s4 and WavEnHL-s5). DeLong's test and decision curve analysis (DCA) showed that the method of combining Rad-score and ACR TI-RADS had the best performance (the area under the receiver operating characteristic curve (AUC = 0.913 (95% confidence interval (CI), 0.881-0.939) and 0.899 (95%CI, 0.840-0.942) in the training group and verification group, respectively), followed by ACR TI-RADS (AUC = 0.898 (95%CI, 0.863-0.926) and 0.870 (95%CI, 0.806-0.919) in the training group and verification group, respectively), and followed by Rad-score (AUC = 0.750 (95%CI, 0.704-0.792) and 0.750 (95%CI, 0.672-0.817) in the training group and verification group, respectively). We concluded that the ability of ultrasound Rad-score to distinguish benign and malignant TNs was not as good as that of ACR TI-RADS, and the ability of the combination model of Rad-score and ACR TI-RADS to discriminate benign and malignant TNs was better than ACR TI-RADS or Rad-score alone. Ultrasound Rad-score might play a potential role in improving the differentiation of malignant TNs from benign TNs.