Metal-Organic Framework-Based Nano-Activators Facilitating Microwave Combined Therapy via a Divide-and-Conquer Tactic for Triple-Negative Breast Cancer.

Aiming at the clinical problems of high recurrence and metastasis rate of triple-negative breast cancer, a divide-and-conquer tactic is developed. The designed nanoactivators enhance microwave thermo-dynamic-chemotherapy to efficiently kill primary tumors, simultaneously ameliorate the immunosuppressive microenvironment, activate the tumor infiltration of T lymphocytes, and enhance the accumulation and penetration of PD-1/PD-L1 immune agents, ultimately boosting the efficacy of immune checkpoint blocking therapy to achieve efficient inhibition of distal tumors and metastases. Metal-organic framework (MOF)-based MPPT nano-activator is synthesized by packaging chemotherapeutic drug Pyrotinib and immunosuppressant PD-1/PD-L1 inhibitor 2 into MnCa-MOF and then coupling target molecule triphenylphosphine, which significantly improved the accumulation and penetration of Pyrotinib and immunosuppressant in tumors. In addition to the combined treatment of microwave thermo-dynamic-chemotherapy under microwave irradiation, Mn2+ in the nano-activator comprehensively promotes the cGAS-STING pathway to activate innate immunity, microwave therapy, and hypoxia relief are combined to ameliorate the tumor immunosuppressive microenvironment. The released Pyrotinib down-regulates epidermal growth factor receptor and its downstream pathways PI3K/AKT/mTOR and MAPK/ERK signaling pathways to maximize the therapeutic effect of immune checkpoint blocking, which helps to enhance the antitumor efficacy and promote long-term memory immunity. This nano-activator offers a generally promising paradigm for existing clinical triple-negative breast cancer treatment through a divide-and-conquer strategy.

Prepared MW-Immunosensitizers Precisely Release NO to Downregulate HIF-1α Expression and Enhance Immunogenic Cell Death.

Microwave thermotherapy (MWTT) has limited its application in the clinic due to its high rate of metastasis and recurrence after treatment. Nitric oxide (NO) is a gaseous molecule that can address the high metastasis and recurrence rates after MWTT by increasing thermal sensitivity, down-regulating the expression of hypoxia-inducible factor-1 (HIF-1), and inducing the immunogenic cell death (ICD). Therefore, GaMOF-Arg is designed, a gallium-based organic skeleton material derivative loaded with L-arginine (L-Arg), and coupled the mitochondria-targeting drug of triphenylphosphine (TPP) on its surface to obtain GaMOF-Arg-TPP (GAT) MW-immunosensitizers. When GAT MW-immunosensitizers are introduced into mice through the tail vein, reactive oxygen species (ROS) are generated and L-Arg is released under MW action. Then, L-Arg reacts with ROS to generate NO, which not only downregulates HIF-1 expression to improve tumor hypoxia exacerbated by MW, but also enhances immune responses by augment calreticulin (CRT) exposure, high mobility group box 1 (HMGB1) release, and T-cell proliferation to achieve prevention of tumor metastasis and recurrence. In addition, NO can induce mitochondria damage to increase their sensitivity to MWTT. This study provides a unique insight into the use of metal-organic framework MW-immunosensitizers to enhance tumor therapy and offers a new way to treat cancer efficiently.

H2S-Reactivating Antitumor Immune Response after Microwave Thermal Therapy for Long-Term Tumor Suppression.

Microwave thermal therapy (MWTT) is one of the most potent ablative treatments known, with advantages like deep penetration, minimal invasion, repeatable operation, and low interference from bone and gas. However, microwave (MW) is not selective against tumors, and residual tumors after incomplete ablation will generate immunosuppression, ultimately making tumors prone to recurrence and metastasis. Herein, a nano-immunomodulator (Bi-MOF-l-Cys@PEG@HA, BMCPH) is proposed to reverse the immunosuppression and reactivate the antitumor immune effect through responsively releasing H2S in tumor cells for improving MWTT. Under MW irradiation, BMCPH will mediate MWTT to ablate tumors and release l-cysteine (l-Cys) to react with the highly expressed cystathionine ß-synthase in tumor to generate H2S. The generated H2S can inhibit the accumulation of myeloid-derived suppressor cells (MDSCs) and promote the expression of cytotoxic T lymphocytes (CTLs). Moreover, Bi-MOF can also scavenge reactive oxygen species (ROS), a major means of MDSCs-mediated immunosuppression, to further weaken the immunosuppressive effect. Simultaneously, the surface-covered HA will gather CTLs around the tumor to enhance the immune response. This nano gas immunomodulator provides an idea for the sensitive and tunable release of unstable gas molecules at tumor sites. The strategy of H2S gas to reverse immunosuppression and reactivate antitumor immune response introduces a direction to reduce the risk of tumor recurrence and metastasis after thermal ablation.

Logic gate controlled theranostic nanoagents for in situ microwave thermal therapeutic efficacy evaluation.

In vivo monitoring of treatment response is of great significance for tumor therapy in clinical trials, but it remains a formidable challenge. Herein, we demonstrate a logic AND gate theranostic nanoagent that responds to the coexistence of endogenous and exogenous stimuli, namely HAuCl4@1-Tetradecanol@Gd-based metal-organic framework@SiO2 nanocomposites (APGS NCs). Upon microwave (MW) irradiation, HAuCl4 in the inner part of APGS NCs reacts with the tumor-associated glutathione (GSH). Subsequently, it transforms into an active luminescent form of Au@1-Tetradecanol@Gd-MOF@SiO2 nanocomposites (AuPGS NCs). The intensity of generated fluorescence is correlated with the tumor thermal-injury status. Thus, the generation of AuPGS NCs with high intensity fluorescence under the co-activation of MW and GSH can visualize the treatment effects during MW thermal therapy and instantly modulate the irradiation time and range for optimal outcomes. Hence, this logic gate controlled APGS NCs makes MW thermal therapy eliminate tumor cells completely. This research offers an effective strategy for the design and preparation of activatable theranostic nanoagents for precise tumor imaging and therapy.

Boosting Microwave Thermo-Dynamic Cancer Therapy of TiMOF via COF-Coating.

Microwave (MW) dynamic therapy (MDT) can efficiently eliminate tumor residue resulting from MW thermal therapy. However, MDT is currently in its infancy, and luck of effective MDT sensiters severely limits its clinical therapeutic effect. Herein, based on TiMOF (TM), a high-efficiency MW sensitizer is designed for MW thermo-dynamic therapy. TM can generate heat and cytotoxic reacyive oxygen species (ROS) under MW irradiation and has the potential to be used as an MW sensitizer, while the suboptimal MW dynamic sensitization effect of TM limits its application. Inorder to improve the MW dynamic sensitization performance, a covalent organic framework (COF) with good stability and a large conjugate system is used to cover TM, which is conductive to electron and energy transfer, thus increasing the ROS generation rate and prolonging the ROS lifetime. In addition, loading Ni NPs endow nanomaterials with magnetic resonance imaging capabilities. Therefore, this work develops an MW sensitizer based on TM for the first time, and the mechanism of COF coating to enhance the MW dynamic sensitization of TM is preliminarily explored, which provides a new idea for the further development of MW sensitizer with great potential.

Preparation of Janus fluorescent probe based on an asymmetrical silica and its application in glucose and alpha-fetoprotein detection.

Janus particles have been considered suitable for biomedicine owing to their asymmetric structure and unique properties. Although Janus particles have been applied in biosensing for dual-mode sensing, there are almost no reports for the detection of multiple indicators. In fact, many patients require different diagnoses, such as the examination of hepatogenic diseases in diabetics. Here, a Janus particle based on SiO2 was synthesized using a Pickering emulsion method. A novel strategy for detecting glucose and alpha-fetoprotein (AFP) based on different principles using this Janus particle was then constructed as a detection platform. Composed of adjustable dendritic silica loaded with gold nanoclusters (Au NCs) and glucose oxidase (GOx) and spherical SiO2 coupled with AFP antibody, this Janus fluorescent probe achieved the double detection of glucose and AFP. With the protection of dendritic silica, the enzyme temperature stability was enhanced. Moreover, the low limit of detection for glucose (0.5 µM in PBS and 2.5 µM in serum) and AFP (0.5 ng mL-1) illustrated the feasibility of the application of the Janus material in integrated detection. This work not only supported the use of a Janus fluorescent probe as a detection platform toward glucose and AFP but also showed the potential of Janus particles in integrated detection in the future.

Programmed Upregulation of HSP70 by Metal-Organic Frameworks Nanoamplifier for Enhanced Microwave Thermal-Immunotherapy.

Thermotherapy can directly kill tumor cells whilst being accompanied by immune-enhancing effects. However, this immune-enhancing effect suffers from insufficient expression of immune response factors (e.g., heat shock protein 70, HSP70), resulting in no patient benefiting due to the recurrence of tumor cells after thermotherapy. Herein, a nanoengineered strategy of programmed upregulating of the immune response factors for amplifying synergistic therapy is explored. Metal-organic frameworks nanoamplifiers (teprenone/nitrocysteine@ZrMOF-NH2 @L-menthol@triphenylphosphine, GGA/CSNO@ZrMOF-NH2 -LM-TPP nanoamplifier, and GCZMT nanoamplifier) achieve excellent microwave (MW) thermal-immunotherapy by programmed induction of HSP70 expression. After intravenous administration, GCZMT nanoamplifiers target the mitochondria, and then release nitric oxide (NO) under MW irradiation. NO inhibits the growth of tumor cells by interfering with the energy supply of cells. Subsequently, under the combination of MW, NO, and GGA, HSP70 expression can be programmed upregulated, which can induce the response of cytotoxic CD4+ T cells and CD8+ T cells, and effectively activate antitumor immunotherapy. Hence, GCZMT nanoamplifier-mediated MW therapy can achieve a satisfactory therapeutic effect with the tumor inhibition of 97%. This research offers a distinctive insight into the exploitation of metal-organic frameworks nanoamplifiers for enhanced tumor therapy, which provides a new approach for highly effective cancer treatment.

MOF@COF nanocapsule for the enhanced microwave thermal-dynamic therapy and anti-angiogenesis of colorectal cancer.

Microwave thermal therapy (MWTT) shows great prospect in cancer treatments due to its non-invasive or minimally invasive nature and deep penetration through the tissue. However, incomplete ablation and elevated expression of many pro-tumor angiogenesis after MWTT (e.g., vascular endothelial growth factor, VEGF) induced tumor recurrence still remains an obstacle, especially in some tumors prone to recurrence and metastasis, such as colorectal cancer. Herein, we propose a nanocapsule of covalent organic framework cladding metal organic framework (MOF@COF) with microwave (MW) thermal-dynamic sensitization and co-action of tumor anti-angiogenesis. The MOF of Bi-Mn-porphyrin (BM) is designed as MW sensitizer to generate cytotoxic 1O2 and heat for microwave dynamic therapy (MWDT) synergistic MWTT. The COF is covalently coated on BM for further augmenting these two sensitization properties, as well as loading hydrophobic inhibitor of Apatinib to downregulate the expression of VEGF for inhibiting tumor recurrence. Furthermore, the contained Bi and porphyrin endow system with CT and fluorescence imaging (FI) capabilities. In vivo experiments verify that this combination therapy significantly impairs the growth of colorectal cancer with no recurrent carcinoma. Therefore, our work presents an integrated strategy derived from MOF@COF for remarkably augmenting single MWTT to reduce tumor recurrence.

Nanoengineered biomimetic Cu-based nanoparticles for multifunational and efficient tumor treatment.

The microwave dynamic therapy (MDT) mediated by cytotoxic reactive oxygen species (ROS) is a promising anticancer therapeutic method. However, the therapeutic efficiency of MDT is restricted by several limitations including insufficient ROS generation, strong proangiogenic response, and low tumor-targeting efficiency. Herein, we find that Cu-based nanoparticles can produce oxygen under microwave (MW) irradiation to raise the generation of ROS, such as •O2, •OH and 1O2, especially •O2. On this basis, a nanoengineered biomimetic strategy is designed to improve the efficiency of MDT. After intravenous administration, the nanoparticles accumulate to the tumor site through targeting effect mediated by biomimetic modification, and it can continuously produce oxygen to raise the levels of ROS in tumor microenvironment under MW irradiation for MDT. Additionally, Apatinib is incorporated as antiangiogenic drug to downregulate the expression of vascular endothelial growth factor (VEGF), which can effectively inhibit the tumor angiogenesis after MDT. Hence, the tumor inhibition rate is as high as 96.79%. This study provides emerging strategies to develop multifunctional nanosystems for efficient tumor therapy by MDT.

Continuous "Snowing" Thermotherapeutic Graphene.

Finding the best applications of graphene, and the continuous and scalable preparation of graphene with high quality and high purity, are still two major challenges. Herein, a "pulse-etched" microwave-induced "snowing" (PEMIS) process is developed for continuous and scalable preparation of high-quality and high-purity graphene directly in the gas phase, which is found to have excellent thermotherapeutic effects. The obtained graphene exhibits small size (≈180 nm), high quality, low oxygen content, and high purity, together with a high gas-solid conversion efficiency of ≈10.46%. Considering the intrinsic characteristics of this high-purity and small-sized biocompatible graphene, in particular the low-frequency microwave absorption property as well as the good thermal transformation ability, a graphene-based combination therapeutic system is demonstrated for microwave thermal therapy (MTT) for the first time, exhibiting a high tumor ablation rate of ≈86.7%. This is different from the principle of ions vibrating in a confined space used by current MTT sensitization materials. Not limited to this application, it is foreseen that this PEMIS-based high-quality graphene will allow the search for further suitable applications of graphene.

Tumor reoxygenation for enhanced combination of radiation therapy and microwave thermal therapy using oxygen generation in situ by CuO nanosuperparticles under microwave irradiation.

As known, radiation therapy (RT) can exacerbate the degree of hypoxia of tumor cells, which induces serious resistance to RT and in turn, is the greatest obstacle to RT. Reoxygenation can restore the hypoxic state of tumor cells, which plays an important role in reshaping tumor microenviroment for achieving optimal therapeutic efficacy. Herein, we report for the first time that microwave (MW)-triggered IL-Quercetin-CuO-SiO2@ZrO2-PEG nanosuperparticles (IQuCS@Zr-PEG NSPs) have been used to achieve an optimal RT therapeutic outcomes by the strategy of upregulating tumor reoxygenation, i.e. hypoxic cells acquire oxygen and return to normal state. Methods: We prepared a promising multifunctional nanosuperparticle to upregulate tumor reoxygenation by utilizing CuO nanoparticle to generate oxygen under MW irradiation in the tumor microenvironment. The IQuCS@Zr-PEG NSPs were obtained by introducing CuO nanoparticles, MW sensitizer of 1-butyl-3-methylimidazolium hexafluorophosphate (IL), radiosensitizer of Quercetin (Qu) and surface modifier of monomethoxy polyethylene glycol sulfhyl (mPEG-SH, 5k Da) into mesoporous sandwich SiO2@ZrO2 nanosuperparticles (SiO2@ZrO2 NSPs). The release oxygen by IQuCS@Zr-PEG NSPs under MW irradiation was investigated by a microcomputer dissolved oxygen-biochemical oxygen demand detector (DO-BOD) test. Finally, we used the 99mTc-HL91 labeled reoxygenation imaging, Cellular immunofluorescence, immunohistochemistry, and TUNEL experiments to verify that this unique MW-responsive reoxygenation enhancer can be used to stimulate reshaping of the tumor microenvironment. Results: Through experiments we found that the IQuCS@Zr-PEG NSPs can persistently release oxygen under the MW irradiation, which upregulates tumor reoxygenation and improve the combined tumor treatment effect of RT and microwave thermal therapy (MWTT). Cellular immunofluorescence and immunohistochemistry experiments demonstrated that the IQuCS@Zr-PEG NSPs can downregulate the expression of hypoxia-inducible factor 1α (HIF-1α) under MW irradiation. The 99mTc-HL91 labeled reoxygenation imaging experiment also showed that the oxygen generated by IQuCS@Zr-PEG NSPs under MW irradiation can significantly increase the reoxygenation capacity of tumor cells, thus reshaping the tumor microenvironment. The high inhibition rate of 98.62% was achieved in the antitumor experiments in vivo. In addition, the IQuCS@Zr-PEG NSPs also had good computed tomography (CT) imaging effects, which can be used to monitor the treatment of tumors in real-time. Conclusions: The proof-of-concept strategy of upregulating tumor reoxygenation is achieved by MW triggered IQuCS@Zr-PEG NSPs, which has exhibited optimal therapeutic outcomes of combination of RT and MWTT tumor. Such unique MW-responsive reoxygenation enhancer may stimulate the research of reshaping tumor microenvironment for enhancing versatile tumor treatment.

l-Cysteine decorated nanoscale metal-organic frameworks delivering valproic acid/cisplatin for drug-resistant lung cancer therapy.

We design multifunctional CDDP-VPA@ZrMOF-Cys-PEG nanoparticles (CVZP NPs) based on the properties of valproic acid (VPA) that can downregulate the expression of vascular endothelial growth factor (VEGF) to reduce the drug resistance of tumor cells. In vivo experiments confirm that chemotherapy combined with microwave thermal therapy (MWTT) can significantly improve the therapeutic effect of cisplatin-resistant lung cancer.

MOF-derived nano-popcorns synthesized by sonochemistry as efficient sensitizers for tumor microwave thermal therapy.

Microwave (MW) thermal therapy has been vigorously developed in recent years because of its better therapeutic efficiency and smaller side effects compared with traditional tumor treatment methods. In order to promote the tumor cell apoptosis under MW irradiation and achieve better therapeutic effect and prognosis, various microwave sensitizers have been developed. Metal organic frameworks (MOFs) have become one of the most popular materials for microwave sensitization due to their diverse morphology, porous surface and good biodegradability. However, the harsh preparation conditions and long growth time are insurmountable shortcomings of MOFs. Besides, the spongy porous structure of MOFs is not conducive to the retention of ions, leading to insufficient friction and collision between ions under MW radiation. Herein, we synthesized a kind of open-mouthed Zr MOF-derived nano-popcorns (ZDNPs) with the size of about 250 nm by a rapid sonochemical aerosol flow strategy. Compared with UIO-66, the open-mouthed ZDNPs have a better ability to entrap more ions due to their big cracks on the surface, thus improving their MW sensitization performance. The MW heating experiments in vitro present that the net temperature change value of ZDNP was 120% higher than UIO-66 at the same concentration, proving that ZDNP had a higher MW-thermo conversion efficiency than UIO-66, which provided an unprecedented direction for the exploration of more diversified MW sensitizers.

High Biocompatible ZIF-8 Coated by ZrO2 for Chemo-microwave Thermal Tumor Synergistic Therapy.

The zeolitic imidazolate framework-8 (ZIF-8) is a specifically promising drug carrier due to its excellent intrinsic properties. However, the high toxicity of ZIF-8 nanoparticles severely limits their further research and clinical application. In this work, the biocompatibility of ZIF-8 nanoparticles is greatly improved by coating ZrO2 onto the surface. The survival rate of cells and mice in the ZIF-8@ZrO2 nanocomposite group is significantly increased compared with the undecorated ZIF-8 nanoparticle group. Doxorubicin (DOX) as a chemotherapeutic drug is deposited during the ZIF-8 growth by a facile one-pot method. Ionic liquid (IL) is loaded into the pore of the ZIF-8/DOX@ZrO2 nanocomposites for enhancing microwave thermal therapy. The tumor inhibition rate of ZIF-8/DOX@ZrO2@IL nanocomposites with synergistic microwave thermal therapy and chemotherapy is obviously higher than in other groups. In addition, the ZIF-8/DOX@ZrO2@IL nanocomposites are used for real-time monitoring of the therapeutic outcomes due to the excellent computed tomography contrast agent, ZrO2. Therefore, such a ZrO2 coating strategy shows great promise for overcoming high toxicity of ZIF-8 nanoparticles, which offers a new platform for tumor synergistic microwave thermal therapy and chemotherapy using the ZIF-8/DOX@ZrO2@IL nanocomposite as a theranostic nanocarrier.

Oxygen Production of Modified Core-Shell CuO@ZrO2 Nanocomposites by Microwave Radiation to Alleviate Cancer Hypoxia for Enhanced Chemo-Microwave Thermal Therapy.

There are acknowledged risks of metastasis of cancer cells and obstructing cancer treatment from hypoxia. In this work, we design a multifunctional nanocomposite for treating hypoxia based on the oxygen release capability of CuO triggered by microwave (MW). Core-shell CuO@ZrO2 nanocomposites are prepared by confining CuO nanoparticles within the cavities of mesoporous ZrO2 hollow nanospheres. 1-Butyl-3-methylimidazolium hexafluorophosphate (IL) is loaded to the CuO@ZrO2 nanocomposites for improving microwave thermal therapy (MWTT). 1-Tetradecanol (PCM) is introduced to regulate the release of chemotherapeutic drugs of doxorubicin (DOX). Thus, the IL-DOX-PCM-CuO@ZrO2 multifunctional (IDPC@Zr) nanocomposites are obtained. Finally, IDPC@Zr nanocomposites are modified by monomethoxy polyethylene glycol sulfhydryl (mPEG-SH, 5 kDa) (IDPC@Zr-PEG nanocomposites). IDPC@Zr-PEG nanocomposites can produce oxygen in the tumor microenvironment during the course of tumor treatment, thereby alleviating the hypoxic state and improving the therapeutic effect. In vivo antitumor experiments demonstrate a very high tumor inhibition rate of 92.14%. In addition, computed tomography (CT) imaging contrast of the nanocomposites can be enhanced due to the high atomic number of Zr. Therefore, IDPC@Zr-PEG nanocomposites can be applied for monitoring the tumor-treatment process in real time. This combined therapy offers many opportunities, such as the production of oxygen from CuO nanoparticles by MW to alleviate hypoxia, the enhancement of combined treatment of MWTT and chemotherapy, and the potential application of CT imaging to visualize the treatment process, which therefore provides a promising method for the clinical treatment of tumors in the future.

Nanoengineering of nanorattles for tumor treatment by CT imaging-guided simultaneous enhanced microwave thermal therapy and managing inflammation.

Usually the tumor thermal therapy is accompanied with inflammatory reactions, which in turn promote tumor growth and metastasis meanwhile. Herein, we prepared novel trifunctional PEG-IL/ZrO2-Ag@SiO2 nanorattles, which can be used for CT imaging-guided simultaneous tumor microwave thermal therapy and resistance to bacterial infection. Under the microwave irradiation, the nanorattles present excellent microwave thermal properties. Simultaneously, the nanorattles have good antibacterial effect in vitro and in vivo, which can restrain bacterial growth effectively and reduce inflammation response during the microwave thermal therapy. In addition, the nanorattles also have the function of CT imaging, which can monitor the tumor therapy in real time. The strategy of simultaneous microwave thermal therapy and inflammation management effectively inhibits tumor growth in mice with a good anti-tumor effect (96.4%). This proof-of-concept investigation provides a simple and reliable strategy for tumor treatment and inhibiting inflammatory reaction using a multifunctional nanomaterial, indicating the great application prospect in tumor treatment by simultaneous eradicating tumor tissue and managing inflammation.

A tumor treatment strategy based on biodegradable BSA@ZIF-8 for simultaneously ablating tumors and inhibiting infection.

Studies have shown a clear correlation between cancer incidence and infection, and cancer treatment can also trigger infection so as to lead to an inflammatory response. In this case, we have designed a new tumor treatment strategy based on biodegradable BSA@ZIF-8 for simultaneously ablating tumors and inhibiting infection. This biodegradable ZIF contains abundant porous structures, showing increased absorption of ions and inelastic collisions. A large amount of frictional heat produced by the collisions results in increased tumor cell death under microwave irradiation. This can effectively inhibit tumor growth in mice by microwave ablation with a good anti-tumor effect (95.4%). Intriguingly, the Zn2+ released from the degradation of BSA@ZIF-8 causes damage to bacterial cell walls, and destruction of the metabolism and structure of the membrane, leading to bacterial cell death, and ultimately achieving good antibacterial properties. Moreover, BSA@ZIF-8 is biodegradable without long-term toxicity in vivo. The in vivo experimental results show that BSA@ZIF-8 can protect 80% of the mice from lethal challenge with tumors and the accompanying infection. Overall, we present a novel strategy using biodegradable ZIFs for microwave ablation therapy with simultaneous antibacterial and anti-infection effects for the first time, which has achieved good tumor treatment outcomes.