Multimode Therapy Research Articles

Pillar[5]arene based glyco-targeting nitric oxide nanogenerator for hyperthermia-induced triple-mode cancer therapy

Nitric oxide (NO)-mediated gas therapy (GT) and alkyl radical (R•) therapy (ART) are emerging cancer therapy modes, and multi-mode therapy has been recognized as an attractive strategy for enhancing anti-cancer efficacy. In this work, a thermal-responsive R• initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIBI)-loaded glycol-targeting NO nanogenerator was constructed by first the covalent conjugation of thermal-responsive NO donor of S-nitrosothiols (RSNO) on the surface of mesoporous silica-coated gold nanorods (AuNRs@MSN), then the coating of a supramolecular complex of amino pillar[5]arene (NP5) and galactose derivative (G), and finally the loading of AIBI. The glycol-targeting NO nanogenerator demonstrated specific targeting ability to HepG2 cells owing to the recognition between galactose residues and asialoglycoprotein receptors (ASGPR). Specially, upon 808 nm near-infrared (NIR) irradiation, the AIBI-loaded NO nanogenerator generated hyperthermia to achieve photothermal therapy (PTT), and further GT and ART resulted from the thermal responsiveness of RSNO and AIBI, respectively. In vitro experiments revealed that the AIBI-loaded glyco-targeting NO nanogenerator had good biocompatibility and exhibited effective inhibition to the proliferation of HepG2 cells. This work provides a novel way to supramolecular hybrid drug delivery systems for triple-mode targeting therapy of PTT/GT/ART.

Clinical observation of intravascular multi-mode combined therapy for severe cerebral venous sinus thrombosis

Clinical observation of intravascular multi-mode combined therapy for severe cerebral venous sinus thrombosis

A Novel Multi-Mode Thermal Therapy for Colorectal Cancer Liver Metastasis: A Pilot Study.

A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic effects of the new therapy with conventional radiofrequency ablation (RFA) on patients with colorectal cancer liver metastasis (CRCLM). From August 2016 to September 2019, thirty-one patients with CRCLM received either multi-mode thermal therapy (n = 17) or RFA (n = 14). Triphasic contrast-enhanced magnetic resonance imaging (MRI), routine blood tests, and peripheral blood immune responses were evaluated before the treatment and in 1, 3, 6, and 12 months after. Local tumor response and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and pre- and post-treatment immune cell counts were analyzed using Mann-Whitney U and Wilcoxon tests. A significantly longer PFS was observed in the multi-mode thermal therapy group in comparison to that of the conventional RFA group (median, 11.4 versus 3.4 months, p = 0.022). It was found that multi-mode therapy induced the functional maturation of dendritic cells, promoted CD4+ T cell-mediated antitumor responses, and decreased regulatory T cells, contributing to better therapeutic efficacy in CRCLM patients.

A Cu-based nanoplatform for near-infrared light amplified multi-mode prostate cancer specific therapy.

Chemodynamic therapy (CDT), as a new method for oncotherapy, can convert less reactive hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH) in the tumor microenvironment (TME) to kill tumor cells and inhibit tumor growth. However, the TME usually presents a low content of endogenous H2O2 and weak acidity, which weakens the therapeutic effect of CDT to a certain extent. Here, we developed a multifunctional nanoplatform based on Cu-doped mesoporous carbon nanospheres loaded with free radical generator 2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and polyacrylic acid (Cu-MNCS-AIPH@PAA). Cu-MNCS-AIPH@PAA exhibited high photothermal conversion efficiency, and could not only act as a good photothermal agent for photothermal therapy (PTT) but also trigger AIPH to produce alkyl radicals. In response to the specificity of the TME, Cu-MNCS-AIPH@PAA could generate ˙OH through a Fenton-like reaction for CDT and enhance the efficacy of CDT by a photothermal effect. The excellent anticancer efficiency by the synergistic effect of CDT, PTT and free radicals, high biocompatibility and low adverse effects of Cu-MNCS-AIPH@PAA make it an ideal nanoplatform for tumor therapy.

White light-induced AIEgen polyurethane films containing Schiff base copper(ii) complexes for synergistic chemo/photodynamic antibacterial therapy

Polyurethane films containing AIEgens and copper complexes can act as a potential antibacterial agent for multi-mode combined antibacterial therapy.

A biofilm microenvironment-responsive one-for-all bactericidal nanoplatform for photothermal-augmented multimodal synergistic therapy of pathogenic bacterial biofilm infection.

Multimodal synergistic bactericidal agents display great potential for fighting biofilm infections. However, the rational design of biofilm microenvironment (BME)-activatable therapeutic agents with excellent specificities, effective eradications and minimal side effects remains a great challenge. Herein, we show a BME-responsive one-for-all bactericidal nanoplatform consisting of Fe3+-doped polydopamine (Fe/PDA)-capped ZnO nanoparticles with a successive assembly of methylene blue (MB) and poly(ethylene glycol) (PEG). In an acidic BME (pH 5.5), the constructed nanoagent (ZnPMp) can realize the co-delivery of dual metal ions (Zn2+ and Fe3+) and MB, and the latter shows an activated photodynamic antibacterial activity when irradiated with 635 nm laser. Zn2+ produced from acid-sensitive dissolution of ZnO is an effective chemical antibacterial agent. Additionally, the released Fe3+ is reduced to Fe2+ by glutathione (GSH) overexpressed in the BME to generate Fe2+/Fe3+ redox couples, which exhibit Fenton catalytic activity to convert endogenous H2O2 to hydroxyl radicals (˙OH) for chemodynamic sterilization and GSH depletion ability to improve ˙OH-induced oxidative damage. Interestingly, the hyperthermia caused by the Fe/PDA layer assisted with 808 nm laser can damage directly bacterial cells, accelerate the release of Zn2+, Fe3+and MB, and promote the catalytic activity of Fe2+/Fe3+ redox couples for photothermal-augmented multimodal antibiofilm therapy. With the help of dual lasers, ZnPMp displays the broad-spectrum antibacterial effect, inhibits effectively the formation of biofilms, and more importantly eliminates bacteria deep in mature biofilms. In addition, ZnPMp can be used to treat biofilm-related infections in vivo with excellent therapeutic performance and minimal toxicity. Overall, the developed ZnPMp may serve as a potential nano-antibacterial agent for intensive anti-infective therapy.

Primary tumor location in lung cancer: the evaluation and administration.

Lung cancer continues to be the leading cause of cancer-related death in the world, which is classically subgrouped into two major histological types: Non-small cell lung cancer (NSCLC) (85% of patients) and small-cell lung cancer (SCLC) (15%). Tumor location has been reported to be associated with the prognosis of various solid tumors. Several types of cancer often occur in a specific region and are more prone to spread to predilection locations, including colorectal cancer, prostate cancer, gastric cancer, ovarian cancer, cervical cancer, bladder cancer, lung tumor, and so on. Besides, tumor location is also considered as a risk factor for lung neoplasm with chronic obstructive pulmonary disease/emphysema. Additionally, the primary lung cancer location is associated with specific lymph node metastasis. And the recent analysis has shown that the primary location may affect metastasis pattern in metastatic NSCLC based on a large population. Numerous studies have enrolled the “location” factor in the risk model. Anatomy location and lobe-specific location are both important in prognosis. Therefore, it is important for us to clarify the characteristics about tumor location according to various definitions. However, the inconsistent definitions about tumor location among different articles are controversial. It is also a significant guidance in multimode therapy in the present time. In this review, we mainly aim to provide a new insight about tumor location, including anatomy, clinicopathology, and prognosis in patients with lung neoplasm.

W-Doped TiO2 Nanorods for Multimode Tumor Eradication in Osteosarcoma Models under Single Ultrasound Irradiation.

Sonosensitizers play crucial roles in the controlled production of reactive oxygen species (ROS) under ultrasound (US) irradiation with high tissue-penetration depth for noninvasive solid tumor therapy. It is desirable to fabricate structurally simple yet multifunctional sonosensitizers from ultrafine nanoparticles for ROS-based multimode therapy to overcome monomode limitations such as low ROS production yields and endogenous reductive glutathione (GSH) to ROS-based treatment resistance. We report the facile high-temperature solution synthesis of ultrafine W-doped TiO2 (W-TiO2) nanorods for exploration of their sonodynamic, chemodynamic, and GSH-depleting activities in sonodynamic-chemodynamic combination tumor therapy. We found that W5+ and W6+ ions doped in W-TiO2 nanorods play multiple roles in enhancing their ROS production. First, W doping narrows the band gap from 3.2 to 2.3 eV and introduces oxygen and Ti vacancies for enhancing their sonodynamic performance. Second, W5+ doping endows W-TiO2 nanorods with Fenton-like reaction activity to produce •OH from endogenous H2O2 in the tumor. Third, W6+ ions reduce endogenous GSH to glutathione disulfide (GSSG) and, in turn, form W5+ ions that further enhance their chemodynamic activity, which greatly modifies thae oxidation-reduction tumor microenvironment in the tumor. In vivo experiments display the excellent ability of W-TiO2 nanorods for enhanced tumor eradication in human osteosarcoma models under single US irradiation. Importantly, the ultrafine nanorod morphology facilitates rapid excretion from the body, displaying no significant systemic toxicity. Our work suggests that multivalent metal doping in ultrafine nanomaterials is an effective and simple strategy for the introduction of new functions for ROS-based multimode therapy.

Near-infrared light triggered multi-mode synergetic therapy for improving antibacterial and osteogenic activity of titanium implants

Reducing bacterial infection and improving osseointegration are critical for the long-term use of orthopedic implants, especially for the infection related surgery. Here, mesoporous dopamine (MPDA) nanoparticles were loaded with nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), and they were immobilized on the surface of titanium (Ti). When bacterial infections occurred, a large amount of NO was rapidly released and triggered by the thermal effect of MPDA after the near-infrared (NIR) light irradiation, which could damage the permeability and integrity of the bacterial membrane, leading to the leakage of bacterial DNA, proteins and ATP. Thus, bacteria was synergistically eliminated by NO and photothermal therapy (PTT) under NIR irradiation. While without NIR irradiation, the low concentration of NO was slowly released into the environment from GSNO, which promoted the proliferation and differentiation of osteoblasts. In addition, the in vivo results also demonstrated good osteogenic and antibacterial effects. Therefore, this study demonstrated a multi-mode synergetic therapy for promoting the antibacterial property and osseointegration of titanium implants.

Promoted intramolecular photoinduced-electron transfer for multi-mode imaging-guided cancer photothermal therapy

Promoted intramolecular photoinduced-electron transfer for multi-mode imaging-guided cancer photothermal therapy

Designer exosomes enabling tumor targeted efficient chemo/gene/photothermal therapy

Exosomes, endogenous nanosized particles (50–150 nm) secreted and absorbed by cells, have been recently used as diagnostic and therapeutic platforms in cancer treatment. The integration of exosome-based delivery with multiple therapeutic modalities could result in better clinical outcomes and reduced-sided effects. Here, we combined the targeting and biocompatibility of designer exosomes with chemo/gene/photothermal therapy. Our platform consists of exosomes loaded with internalized doxorubicin (DOX, a model cancer drug) and coated with magnetic nanoparticles conjugated with molecular beacons capable of targeting miR-21 for responsive molecular imaging. The coated magnetic nanoparticle enables enrichment of the exosomes at the tumor site by external magnetic field guidance. After the exosomes are gathered at the tumor site, the application of near-infrared radiation (NIR) induces localized hyperthermia and triggers the release of cargoes loaded inside the exosome. The released molecular beacon can target the miR-21 for both imaging and gene silencing. Meanwhile, the released doxorubicin serves to kill the cancer cells. About 91.04 % of cancer cells are killed after treatment with Exo-DOX-Fe3O4@PDA-MB under NIR. The ability of the exosome-based method for cancer therapy has been demonstrated by animal models, in which the tumor size is reduced dramatically by 97.57 % with a magnetic field-guided tumor-targeted chemo/gene/photothermal approach. Thus, we expected this designer exosome-mediated multi-mode therapy to be a promising platform for the next-generation precision cancer nanomedicines.

Multifunctional Magnetic Nanoagents for Bioimaging and Therapy.

Multifunctional magnetic nanoagents (MMNs) have drawn increasing attention in cancer precision therapy, attributed to their good biocompatibility and the potential applications for multimodal imaging and multidisciplinary therapy. The noble metal or isotopes contained in MMNs could not only perform superparamagnetism, providing an outstanding magnetic targeting property for drug delivery, but also endow the MMNs with a magnetocaloric effect, photothermal performance, and radiotherapy sensitization, arriving at a multimode combination therapy for cancer. Also, the composite component can endow MMNs with various imaging performance, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), thereby achieving accurate image-guided therapy for cancer. However, the joint function of MMNs is closely correlated with their functional nanocomponents and nanostructures. In this article, we will systematically discuss the design, synthesis, and structure optimization of MMNs, as well as their potential in multimodal diagnosis and therapy, scientifically providing an integrated diagnosis and treatment of nanomedicine for the future cancer therapy.

4-in-1 Fe3O4/g-C3N4@PPy-DOX nanocomposites: Magnetic targeting guided trimode combinatorial chemotherapy/PDT/PTT for cancer

At present, cancer has become a major disease threatening human health worldwide. Therefore, developing targeting guided multimode synergetic therapy has become one of the hot spots in current antitumor research and is also a great challenge. Herein, a new Fe3O4/g-C3N4@PPy-DOX nanocomposite containing magnetic iron oxide (Fe3O4) nanoparticles (NPs), lamellar structure of graphite-like carbon nitride (g-C3N4) and polypyrrole (PPy) shell with the loaded anti-tumor drug doxorubicin hydrochloride (DOX) was designed and prepared. The monodisperse Fe3O4 nanoparticles (NPs) with the diameter of 20 nm endowed the nanocomposite with the magnetic targeting ability, reducing damage to normal tissues. It is very interesting that the Fe3O4 NPs also possessed photosensitizer function for photodynamic therapy (PDT). The g-C3N4 sheets as the photocatalysis towards the degradation of water for generating O2 could effectively improve the hypoxia of solid tumors and increase the efficiency of PDT. In addition, PPy has high light-to-heat conversion efficiency, so was chosen for the cancer photothermal therapy (PTT). Finally, an anticancer drug (DOX) was loaded on the nanocomposite because the presence of mesoporous structure. Thus, the prepared Fe3O4/g-C3N4@PPy-DOX nanocomposites exhibit synergetic chemotherapy/PTT/enhanced PDT antitumor effect. This study provides an inspiration for combining targeting and multimodality to improve the anticancer efficiency.

A New Model for Estimation of Individual Blood Flow Effect during Multimode Thermal Therapy of Tumor.

An accurate temperate control is the key during multimode thermal therapy of tumor. However, the tumor tissue temperature is greatly influenced by local blood flow changes of individuals. A simple but effective method is proposed for estimation of the local blood flow and its impact on the ablation boundary temperature. The proposed model is focused on the tumor domain, namely the targeted treatment region. In the natural thawing process post tumor freezing during the therapy, the main energy transferring to the tumor tissue comes from the blood flow of the surrounding normal tissue on the tumor boundary. By fitting the rewarming temperature measured in the tissue, the inversed problem is solved by the model to calculate the boundary convection condition and thus to predict the corresponding blood perfusion rate. The model is validated by the animal experimental data. The calculated blood perfusion rates are within the published range, but differ individually. The results prove that the new model and the estimated personalized convection coefficient can better predict the tissue temperature distribution during the therapy.Clinical Relevance-The model estimates the local blood flows around the tumor of individuals and the influence on heat transfer process. It can be used to better predict and control the temperature on the tumor boundary during the therapy that is critical to the therapeutic effect. The model also greatly cuts down the calculation time which facilitates the possibility of intraoperative real time monitoring.

Near-infrared triggered Ti3C2/g-C3N4 heterostructure for mitochondria-targeting multimode photodynamic therapy combined photothermal therapy

Abstract g-C3N4 is promising photosensitizer (PS) for photodynamic therapy (PDT) because of its reactive oxygen species (ROS) generation ability. However, satisfactory photocatalytic activity and visible light response limit its effectiveness in in vivo therapy. Herein, we report a near-infrared (NIR)-responsive two-dimensional Ti3C2/g-C3N4 heterostructure for in situ oxygen-generating enhanced multimode PDT and photothermal therapy (PTT). We demonstrate that the assembly of Ti3C2 to g-C3N4 significantly extend the absorption of g-C3N4 to NIR region and enhance the photocatalytic activity owing to the improved photogenerated carrier separation compared to free g-C3N4. After further modification of triphenylphosphonium bromide (TPP) on Ti3C2/g-C3N4, and the mitochondria-targeting Ti3C2/g-C3N4-TPP enables produce oxygen-independent ·O2−- and ·OH through electron transfer. Moreover, it also achieves oxygen self-supplement 1O2 generation through energy transfer on account of its ability of photocatalytic split endogenous water. As a result, a multimode enhanced PDT is performed under both normoxic and hypoxic conditions. Ti3C2/g-C3N4-TPP also shows good photothermal performance derived from Ti3C2 for PTT. This work expands the g-C3N4-based PDT application, contributing to design photocatalytic nanomaterials with desired absorption to overcome the limitation of tumor hypoxia.

Multimode tumor ablation therapy induced different diffusion and microvasculature related parameters change on functional magnetic resonance imaging compared to radiofrequency ablation in liver tumor: An observational study.

To explore different posttreatment changes between multimode tumor ablation therapy (MTAT) and radiofrequency ablation (RFA) using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and diffusion kurtosis imaging (DKI) in patients with hepatic malignancies.Eighty - seven patients with one hundred and twenty eight hepatic lesions receiving MTAT or RFA underwent IVIM-DWI and DKI before and after treatment. The mean value of apparent diffusion coefficient (ADC), IVIM-DWI parameters, including true diffusion coefficient (D), pseudo-diffusion coefficient (DP), perfusion fraction (f), and DKI parameters including diffusion coefficient (DK), apparent diffusional kurtosis (K) were retrospectively compared prior to and following treatment as well as between treatment groups. The degree of parameters change after ablation was compared between 2 treatment modalities.The mean value of ADC, D, and DK increased while f, and K decreased significantly in MTAT group. In RFA group, just ADC and K showed significantly change following treatment. The ADC and D value were higher in MTAT group than in RFA group 1 month after treatment. While f was lower in MTAT group after treatment compared with RFA group. The ADC, D and DK increased (21.89 ± 24.95% versus 8.76 ± 19.72%, P = .04 for ADC, 33.78 ± 54.01% versus 7.91 ± 25.16%, P = .03 for D, 25.91 ± 36.28% versus 1.75 ± 46.42%, P = .01 for DK) while f declined (-32.62 ± 41.48% versus 6.51 ± 44.16%, P < .001) more in MTAT group.The MTAT induced different posttreatment changes on water molecule diffusion and microvasculature related functional MR parameters compared to RFA in patients with liver tumors.

Co-delivery of hydrophilic/hydrophobic drugs by multifunctional yolk-shell nanoparticles for hepatocellular carcinoma theranostics

Co-delivery of hydrophilic/hydrophobic drugs in separate rooms and bimodal triggered drugs release from independent channels without mutual effect, coupled with multi-mode imaging are vitally significative for overcoming drug resistance and enhancing the therapeutic effects. Herein, we report the polydopamine@upconversion nanoparticle@mesoporous silica yolk-shell nanoparticles (PDA@UCNP@mSiO2 NPs) to simultaneously load the hydrophilic doxorubicin (DOX) and hydrophobic hydroxycamptothecin (HCPT) in their distinct domains for combinational chemotherapy. The oleic acid-coated UCNPs attaching onto the surface of polydopamine (PDA) exhibited the multi-mode upconversion luminescence (UCL)/computed tomography (CT)/magnetic resonance (MR) imaging and the hydrophobic environment held great ability for storage of the hydrophobic HCPT. While the mSiO2 shell was used for loading the hydrophilic DOX and ensuring the good water dispersibility of the NPs. Additionally, the NPs with near-infrared (NIR) excitation possessed an efficient photothermal efficiency of 31.1% achieving through the PDA. In a word, the resulted NPs were successfully employed for multi-mode imaging-guided synergistic dual drug chemo-photothermal therapy of hepatocellular carcinoma.

ROI-Based Intraoperative MR-CT Registration for Image-Guided Multimode Tumor Ablation Therapy in Hepatic Malignant Tumors

Image-guided ablation therapy has been widely used as a minimally invasive treatment for hepatic malignant tumors. Image registration is very useful during such operations, especially for multimode tumor ablation therapy. This research proposes a novel idea for performing MR-CT registration in multimode tumor ablation therapy based on liver segmentation. First, the liver is segmented from the preoperative 3D MR image and the intraoperative 3D CT image using a deep learning method based on a modified UNet++ architecture. Then, the preoperative MR image and the intraoperative CT image are coregistered using rigid and nonrigid registration methods with the segmented liver as the region of interest. The segmented binary images, rather than gray-level images, are aligned in the rigid registration step, which proves to be faster and more accurate than the registration method based on gray information. For the nonrigid registration, a multilevel free-form deformation method is applied to correct tiny misalignments. Finally, our method was validated using clinical data from 15 patients. The proposed method achieved an average Dice coefficient and target registration error of 93.36±1.21% and 4.42±2.35 mm, respectively, and it can help interventional radiologists adjust the probe position in clinical work.

Multi-responsive drug delivery nanoplatform for tumor-targeted synergistic photothermal/dynamic therapy and chemotherapy

“From one to all” multi-mode therapy using an integrated nanoplatform of multi-responsive GFCDH nanoparticles for tumor-targeted synergistic photothermal, photodynamic and chemotherapy.

A neutrophil membrane-functionalized black phosphorus riding inflammatory signal for positive feedback and multimode cancer therapy

Neutrophil membrane-functionalized black phosphorus achieved a positive feedback loop in a continuous “administrated-therapy” circle to progressively improve the tumor therapeutic efficiency.