Quantitative analysis of pre-treatment dynamic contrast-enhanced ultrasound for assessing the response of colorectal liver metastases to chemotherapy plus targeted therapy: a dual-institutional study.

OBJECTIVES: To investigate the clinical value of pre-treatment quantitative contrast-enhanced ultrasound (CEUS) in assessing the response of colorectal liver metastases (CRLM) to chemotherapy plus targeted therapy. METHODS: This study retrospectively enrolled 50 CRLM patients from the Zhongshan Hospital, Fudan University as the training cohort and 14 patients from Shanghai Tenth People's Hospital as the testing cohort. Patients underwent the CEUS examination before receiving chemotherapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI) plus targeted therapy (Bevacizumab or Cetuximab). The therapy response was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 based on pre-treatment CT and 3-month follow-up CT after therapy. Dynamic analysis was performed by VueBox® software. Time-intensity curves with quantitative perfusion parameters were obtained. In the training cohort, univariable and multivariable logistic regression analyses were used to develop the predictive model of therapy response. The predictive performance of the developed model was validated in the testing cohort. RESULTS: After the logistic regression analyses, the peak enhancement (PE) (odds ratio = 1.640; 95% confidence intervals [CI] 1.022-2.633) and time to peak (TTP) (odds ratio = 0.495; 95% CI 0.246-0.996) were determined as independent predictive factors. PE and TTP generated from VueBox® were not affected by ultrasound instruments and contrast agent dosage in therapy response evaluation (P > 0.05). The logistic regression model achieved satisfactory prediction performance (area under the curve: 0.923 in the training cohort and 0.854 in the testing cohort). CONCLUSION: CEUS with dynamic quantitative perfusion analysis, which presents high consistency, has potential practical value in predicting the response of CRLM to chemotherapy plus targeted therapy.

Response Evaluation Using Contrast-Enhanced Ultrasound for Unresectable Advanced Hepatocellular Carcinoma Treated With Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy.

OBJECTIVE: The aim of the work described here was to evaluate the role of contrast-enhanced ultrasound (CEUS) in response evaluation for unresectable advanced hepatocellular carcinoma (HCC) treated with tyrosine kinase inhibitors (TKIs) plus anti-programmed cell death protein-1 (PD-1) antibody therapy. METHODS: A prospective cohort of consecutive patients with HCC who received combined TKI/anti-PD-1 antibody treatment for unresectable HCC between January 2022 and October 2022 was included in this study. The patients underwent unenhanced ultrasound (US) and CEUS examinations before treatment and at follow-up. Changes in the largest diameters of the target tumor on unenhanced US and the largest diameters of the enhancing target tumors on CEUS were evaluated. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with unenhanced US and magnetic resonance imaging/computed tomography (MRI/CT) and modified RECIST (mRECIST) with CEUS and CEMRI/CT were used to assess treatment response. RESULTS: A total of 24 HCC patients (23 men and 1 woman; mean age: 56.5 ± 8.5 y; Barcelona Clinic Liver Cancer stage C, 62.5%; 29 intrahepatic target tumors) were studied. Calculations of degree of necrosis in the target tumors revealed no significant differences between CEUS and CEMRI/CT (44.5 ± 36.2% vs. 45.3 ± 36.8%, p = 0.862). As for the differentiation of responders from non-responders, the agreement between RECIST version 1.1 of unenhanced US and mRECIST-CEUS was poor (κ coefficient = 0.233). Meanwhile, there was a high degree of concordance between mRECIST-CEUS and mRECIST-CEMRI/CT (κ coefficient = 0.812). CONCLUSION: CEUS proved to be superior to baseline US and is comparable to CEMRI/CT in defining treatment outcome for combined TKI/anti-PD-1 antibody therapy.

Biomimetic inducer enabled dual ferroptosis of tumor and M2-type macrophages for enhanced tumor immunotherapy.

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe3+. The released Fe3+ is reduced to Fe2+ by consuming intratumoral glutathione (GSH), which promotes abundant free radical generation via triggering Fenton and Fe2+-DHA reactions, thus inducing ferroptosis of both cancer cells and M2-type TAMs. Resultantly, the anticancer immune response is strongly activated by the massive tumor-associated antigens released by ferroptositic cancer cells. Also importantly, the ferroptosis-sensitive M2-type TAMs will be either damaged or gradually domesticated to ferroptosis-resistant M1 TAMs under the ferroptosis stress, favoring the normalization of ITME and finally amplifying cancer ferroptosis immunotherapeutic efficacy. This work provides a novel strategy for ferroptosis immunotherapy of solid tumors featuring TAMs infiltration and immunosuppression by inducing dual ferroptosis of tumor cells and M2-type TAMs.

MnOOH-Catalyzed Autoxidation of Glutathione for Reactive Oxygen Species Production and Nanocatalytic Tumor Innate Immunotherapy.

The antioxidant system, signed with reduced glutathione (GSH) overexpression, is the key weapon for tumor to resist the attack by reactive oxygen species (ROS). Counteracting the ROS depletion by GSH is an effective strategy to guarantee the antitumor efficacy of nanocatalytic therapy. However, simply reducing the concentration of GSH does not sufficiently improve tumor response to nanocatalytic therapy intervention. Herein, a well-dispersed MnOOH nanocatalyst is developed to catalyze GSH autoxidation and peroxidase-like reaction concurrently and respectively to promote GSH depletion and H2O2 decomposition to produce abundant ROS such as hydroxyl radical (·OH), thereby generating a highly effective superadditive catalytic therapeutic efficacy. Such a therapeutic strategy that transforms endogenous "antioxidant" into "oxidant" may open a new avenue for the development of antitumor nanocatalytic medicine. Moreover, the released Mn2+ can activate and sensitize the cGAS-STING pathway to the damaged intratumoral DNA double-strands induced by the produced ROS to further promote macrophage maturation and M1-polarization, which will boost the innate immunotherapeutic efficacy. Resultantly, the developed simple MnOOH nanocatalytic medicine capable of simultaneously catalyzing GSH depletion and ROS generation, and mediating innate immune activation, holds great potential in the treatment of malignant tumors.

5G-Based Telerobotic Ultrasound System Improves Access to Breast Examination in Rural and Remote Areas: A Prospective and Two-Scenario Study.

OBJECTIVE: Ultrasound (US) plays an important role in the diagnosis and management of breast diseases; however, effective breast US screening is lacking in rural and remote areas. To alleviate this issue, we prospectively evaluated the clinical availability of 5G-based telerobotic US technology for breast examinations in rural and remote areas. METHODS: Between September 2020 and March 2021, 63 patients underwent conventional and telerobotic US examinations in a rural island (Scenario A), while 20 patients underwent telerobotic US examination in a mobile car located in a remote county (Scenario B) in May 2021. The safety, duration, US image quality, consistency, and acceptability of the 5G-based telerobotic US were assessed. RESULTS: In Scenario A, the average duration of the telerobotic US procedure was longer than that of conventional US (10.3 ± 3.3 min vs. 7.6 ± 3.0 min, p = 0.017), but their average imaging scores were similar (4.86 vs. 4.90, p = 0.159). Two cases of gynecomastia, one of lactation mastitis, and one of postoperative breast effusion were diagnosed and 32 nodules were detected using the two US methods. There was good interobserver agreement between the US features and BI-RADS categories of the identical nodules (ICC = 0.795-1.000). In Scenario B, breast nodules were detected in 65% of the patients using telerobotic US. Its average duration was 10.1 ± 2.3 min, and the average imaging score was 4.85. Overall, 90.4% of the patients were willing to choose telerobotic US in the future, and tele-sonologists were satisfied with 85.5% of the examinations. CONCLUSION: The 5G-based telerobotic US system is feasible for providing effective breast examinations in rural and remote areas.

Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy.

Reprogramming the tumor immunosuppressive microenvironment is a promising strategy for improving tumor immunotherapy efficacy. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 system can be used to knockdown tumor immunosuppression-related genes. Therefore, here, a self-driven multifunctional delivery vector is constructed to efficiently deliver the CRISPR-Cas9 nanosystem for indoleamine 2,3-dioxygenase-1 (IDO1) knockdown in order to amplify immunogenic cell death (ICD) and then reverse tumor immunosuppression. Lactobacillus rhamnosus GG (LGG) is a self-driven safety probiotic that can penetrate the hypoxia tumor center, allowing efficient delivery of the CRISPR/Cas9 system to the tumor region. While LGG efficiently colonizes the tumor area, it also stimulates the organism to activate the immune system. The CRISPR/Cas9 nanosystem can generate abundant reactive oxygen species (ROS) under the ultrasound irradiation, resulting in ICD, while the produced ROS can induce endosomal/lysosomal rupture and then releasing Cas9/sgRNA to knock down the IDO1 gene to lift immunosuppression. The system generates immune responses that effectively attack tumor cells in mice, contributing to the inhibition of tumor re-challenge in vivo. In addition, this strategy provides an immunological memory effect which offers protection against lung metastasis.

Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy. Herein, we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses. Briefly, a microbiotic nanomedicine, designated as Cu2O@ΔSt, has been constructed by conjugating PEGylated Cu2O nanoparticles on the surface of an engineered Salmonella typhimurium strain (ΔSt). Owing to the natural hypoxia tropism of ΔSt, Cu2O@ΔSt could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu2O@ΔSt generates H2S gas and other acidic substances in the tumor microenvironment (TME), which will in situ trigger the sulfidation of Cu2O to form CuS facilitating tumor-specific photothermal therapy (PTT) under local NIR laser irradiation on the one hand. Meanwhile, the dissolved Cu+ ions from Cu2O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H2O2 into cytotoxic hydroxyl radicals (·OH) on the other hand. Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns, thereby sensitizing tumors to checkpoint blockade (ICB) therapy. The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors, and more importantly, induces a powerful immunological memory effect after the primary tumor ablation.

Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy.

A rationally designed immunostimulant (CC@SiO2-PLG) with a photoactivatable immunotherapeutic function for synergetic tumor therapy is reported. This CC@SiO2-PLG nanoplatform comprises catalase and a photosensitizer (Ce6) co-encapsulated in a silica capsule, to which an immunostimulant is conjugated through a reactive oxygen species-cleavable linker. After accumulating in tumor tissue, CC@SiO2-PLG generates O2 to relieve tumor hypoxia and promotes the production of singlet oxygen (1O2) upon laser irradiation, resulting in not only tumor destruction but also the release of tumor-associated antigens (TAAs). Simultaneously, the linker breakage by the photoproduced 1O2 leads to the remote-controlled release of conjugated indoleamine 2,3-dioxygenase (IDO) inhibitor from CC@SiO2-PLG and consequent immunosuppressive tumor microenvironment reversion. The released TAAs in conjunction with the inhibition of the IDO-mediated tryptophan/kynurenine metabolic pathway induced a boosted antitumor immune response to the CC@SiO2-PLG-mediated phototherapy. Therefore, the growth of primary/distant tumors and lung metastases in a mouse xenograft model was greatly inhibited, which was not achievable by phototherapy alone.

Two-dimensional shear wave elastography with two different systems for the diagnosis of breast lesions.

BACKGROUND: Two-dimensional (2D) - shear wave elastography (SWE) has made promising advances in the diagnostic of breast lesions. However, few studies have assessed whether the diagnostic effectiveness of different platforms employing 2D-SWE is equal or different. OBJECTIVE: To compare the diagnostic effectiveness of 2D-SWE techniques from two different systems in differentiating malignant breast lesions from benign ones. METHODS: A total of 84 breast lesions were retrospectively analyzed by experienced radiologists using 2D-SWE on two ultrasound systems, i.e. system-1 (LOGIQ E9 system, GE Healthcare, Wauwatosa, WI, USA), and system-2 (Aixplorer US system, SuperSonic Imagine, Aix-en-Provence, France). Qualitative and quantitative parameters including color sign, the maximum elasticity modulus values (E-max), the mean elasticity modulus values (E-mean) and standard deviation (E-sd) of elasticity modulus values in two 2D-SWE systems were analyzed. The diagnostic performance between system-1 and system-2 were evaluated in terms of the areas under the receiver operating characteristic curves (AUROCs). RESULTS: Among the 84 lesions in this study, 66 (78.6%) were benign and 18 (21.4%) were malignant. E-max in system-1 showed the best diagnostic performance with a cut-off value of 174.5 kPa with the associated sensitivity and specificity of 100.0% and 80.3% respectively. Meanwhile, E-sd in system-2 displayed the best diagnostic performance with a cut-off value of 12.7 kPa, with the associated sensitivity and specificity of 94.4% and 80.3% respectively. The diagnostic performance of the two 2D-SWE systems was not statistically different according to receiver operating characteristic curve (ROC) analysis of E-max, E-mean, and E-sd. CONCLUSION: For identifying breast lesions, system-1 and system-2 appear to be similar in diagnostic performance. However, different cut-off values for different parameters might be selected to obtain the best diagnostic performance for the two 2D-SWE systems.

Nanomedicine-enabled chemotherapy-based synergetic cancer treatments.

Chemotherapy remains one of the most prevailing regimens hitherto in the fight against cancer, but its development has been being suffering from various fatal side effects associated with the non-specific toxicity of common chemical drugs. Advances in biomedical application of nanomedicine have been providing alternative but promising approaches for cancer therapy, by leveraging its excellent intrinsic physicochemical properties to address these critical concerns. In particular, nanomedicine-enabled chemotherapy has been established as a safer and promising therapeutic modality, especially the recently proposed nanocatalytic medicine featuring the capabilities to generate toxic substances by initiating diverse catalytic reactions within the tumor without directly relying on highly toxic but non-selective chemotherapeutic agents. Of special note, under exogenous/endogenous stimulations, nanomedicine can serve as a versatile platform that allows additional therapeutic modalities (photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), etc.) to be seamlessly integrated with chemotherapy for efficacious synergistic treatments of tumors. Here, we comprehensively review and summarize the representative studies of multimodal synergistic cancer treatments derived from nanomedicine and nanocatalytic medicine-enabled chemotherapy in recent years, and their underlying mechanisms are also presented in detail. A number of existing challenges and further perspectives for nanomedicine-synergized chemotherapy for malignant solid tumor treatments are also highlighted for understanding this booming research area as comprehensively as possible.

Ultrasound-Controlled CRISPR/Cas9 System Augments Sonodynamic Therapy of Hepatocellular Carcinoma.

Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.

Biodegradable and Excretable 2D W1.33 C i-MXene with Vacancy Ordering for Theory-Oriented Cancer Nanotheranostics in Near-Infrared Biowindow.

MXenes, a new class of two-dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W1.33 C i-MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in-plane ordered (W2/3 Y1/3 )2 AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33 C i-MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33 C i-MXene possesses a strong predominance of near-infrared (NIR) absorbance. The constructed ultrathin W1.33 C nanosheets feature excellent photothermal-conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal-imaging properties and photothermal-ablation performance of W1.33 C-BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33 C-BSA nanosheets-induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i-MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.

Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy.

The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal-organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1 O2 )-generating MOF structures anchored with CRISPR-Cas9 systems via 1 O2 -cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1 O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1 O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.

Starvation-Sensitized and Oxygenation-Promoted Tumor Sonodynamic Therapy by a Cascade Enzymatic Approach.

The therapeutic outcomes of noninvasive sonodynamic therapy (SDT) are always compromised by tumor hypoxia, as well as inherent protective mechanisms of tumor. Herein, we report a simple cascade enzymatic approach of the concurrent glucose depletion and intratumoral oxygenation for starvation-sensitized and oxygenation-amplified sonodynamic therapy using a dual enzyme and sonosensitizer-loaded nanomedicine designated as GOD/CAT@ZPF-Lips. In particular, glucose oxidase- (GOD-) catalyzed glycolysis would cut off glucose supply within the tumor, resulting in the production of tumor hydrogen peroxide (H2O2) while causing tumor cells starvation. The generated H2O2 could subsequently be decomposed by catalase (CAT) to generate oxygen, which acts as reactants for the abundant singlet oxygen (1O2) production by loaded sonosensitizer hematoporphyrin monomethyl ether (HMME) upon the US irradiation, performing largely elevated therapeutic outcomes of SDT. In the meantime, the severe energy deprivation enabled by GOD-catalyzed glucose depletion would prevent tumor cells from executing protective mechanisms to defend themselves and make the tumor cells sensitized and succumbed to the cytotoxicity of 1O2. Eventually, GOD/CAT@ZPF-Lips demonstrate the excellent tumoral therapeutic effect of SDT in vivo without significant side effect through the cascade enzymatic starvation and oxygenation, and encouragingly, the tumor xenografts have been found completely eradicated in around 4 days by the intravenous injection of the nanomedicine without reoccurrence for as long as 20 days.

Dual Size/Charge-Switchable Nanocatalytic Medicine for Deep Tumor Therapy.

Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor-specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)-triggered dual size/charge-switchable nanocatalytic medicine, designated as Cu-LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer-layer of the nanomedicine enables much-prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton-like catalyst Cu-LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co-released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen (1O2) generation upon the US irradiation, and deep-tumoral infiltrated Cu-LDH catalyzes the H2O2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton-like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine.

Transitional Metal-Based Noncatalytic Medicine for Tumor Therapy.

Nanocatalytic medicine has been emerging as a highly promising strategy for cancer therapeutics since it enables tumor suppression by in situ generating toxic agents within tumors through catalytic reactions without using conventional highly toxic and nonselective chemodrugs. In the last several years, a number of nanocatalytic medicines have been used to steer catalytic reactions in endogenous or exogenous stimuli-activated cancer therapy, such as chemodynamic therapy, photodynamic therapy, and sonodynamic therapy. In particular, transitional metal-based nanocatalytic medicines with excellent catalytic activity and selectivity show significant clinical potentials, and significant progress has been achieved very recently. In this review, three types of typical transitional metal (Fe, Mn, and Cu)-based nanocatalytic medicines are summarized, followed by detailed discussions on their catalytic mechanisms. Of note, the obstacles and challenges that will be encountered in the design and further clinical conversion of transitional metal-based nanocatalytic medicine in the future are also outlooked.

Tyrosinase-activated prodrug nanomedicine as oxidative stress amplifier for melanoma-specific treatment.

Malignant melanoma is one of the most aggressive skin cancers, posing severe threat to human health. Tyrosinase, overexpressed in melanoma cells, is a specific in-situ weapon to augment the therapeutic efficacy of melanoma-specific treatment by in-situ accelerating the activation of anti-melanoma prodrugs. Herein, we developed a tyrosinase-triggered oxidative stress amplifier, denoted as APAP@PEG/HMnO2, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO2 nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO2 nanostructures. After tumor accumulation of APAP@PEG/HMnO2 amplifier, substantial amounts of oxygen (O2) was generated through reaction between HMnO2 and excessive H2O2 present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O2 to produce cytotoxic benzoquinone metabolites (AOBQ). On the basis of the combinational effect of AOBQ-triggered reactive oxygen species (ROS) generation and synergistic glutathione (GSH) depletion as promoted by HMnO2 and AOBQ, the APAP@PEG/HMnO2 administration augmented the therapeutic efficacy of chemotherapy by amplifying the intratumoral oxidative stress, thus inducing remarkable cell apoptosis in vitro and tumor suppression in vivo. Therefore, the constructed prodrug nanomedicine represents a prospective tumor-specific therapeutic nanoagent for melanoma treatment.

In situ phase-changeable 2D MXene/zein bio-injection for shear wave elastography-guided tumor ablation in NIR-II bio-window.

Localized tumor photothermal cancer ablation is a minimally invasive therapeutic modality for combating cancer, but it often suffers from low therapeutic efficacy and poor precision due to the poor accumulation and non-uniform distribution of used photothermal-conversion agents in tumor tissue via the typical intravenous administration. To address this, an injectable and phase-changeable composite bio-injection consisting of biocompatible two-dimensional (2D) niobium carbide (Nb2C) MXene and the plant-originating protein, zein, has been engineered for near infrared (NIR)-II-triggered tumor photothermal ablation. Zein can respond to aqueous microenvironments and also external photo-triggers from the NIR-II bio-window (1064 nm), and transforms into a solid bio-implant after solvent exchange between ethanol and water. Which, thus, traps Nb2C MXene and heat, improving ablation efficiency and enabling the precise and complete eradication of 4T1 breast tumor cells without additional safety concerns. More significantly, shear wave elastography (SWE) as a deep-penetration imaging mode that can reflect the ablated outcomes via monitoring tissue density variation, has been employed to guide the photo-thermal ablation process to further improve the ablation precision. Thus, this compatible and phase-changeable bio-injection capable of improving photo-thermal ablation efficiency holds great potential in clinical applications.

Copper-Enriched Prussian Blue Nanomedicine for In Situ Disulfiram Toxification and Photothermal Antitumor Amplification.

In situ toxification of less toxic substance for the generation of effective anticarcinogens at the specific tumor tissue has been a novel paradigm for combating cancer. Significant efforts have been recently dedicated to turning clinical-approved drugs into anticancer agents in specific tumor microenvironment by chemical reactions. Herein, a hollow mesoporous Prussian blue (HMPB)-based therapeutic nanoplatform, denoted as DSF@PVP/Cu-HMPB, is constructed by encapsulating alcohol-abuse drug disulfiram (DSF) into the copper-enriched and polyvinylpyrrolidone (PVP)-decorated HMPB nanoparticles to achieve in situ chemical reaction-activated and hyperthermia-amplified chemotherapy of DSF. Upon tumor accumulation of DSF@PVP/Cu-HMPB, the endogenous mild acidity in tumor condition triggers the biodegradation of the HMPB nanoparticle and the concurrent co-releases of DSF and Cu2+ , thus forming cytotoxic bis(N,N-diethyl dithiocarbamato)copper(II) complexes (CuL2 ) via DSF-Cu2+ chelating reaction. Moreover, by the intrinsic photothermal-conversion effect of PVP/Cu-HMPBs, the anticancer effect of DSF is augmented by the hyperthermia generated upon near-infrared irradiation, thus inducing remarkable cell apoptosis in vitro and tumor elimination in vivo on both subcutaneous and orthotopic tumor-bearing models. This strategy of in situ drug transition by chemical chelation reaction and photothermal-augmentation provides a promising paradigm for designing novel cancer-therapeutic nanoplatforms.