Deep Tumor Therapy Research Articles

An ultrasound-activated piezoelectric sonosensitizer enhances mitochondrial depolarization for effective treatment of orthotopic glioma

Despite the significant advancements in piezoelectric materials for sonodynamic therapy (SDT), the suppression of orthotopic glioma remains challenging, primarily due to the unclear mechanism and the restriction of blood-brain barrier (BBB). Herein, we proposed that layered piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) could effectively depolarize the mitochondrial membrane potential (ΔΨm) of glioma cells under ultrasound (US) exposure. The US-induced band bending in SBTO NPs enhanced redox ability, promoting an increase in reactive oxygen species (ROS) generation. The in vitro results proved that SBTO NPs selectively accumulated in mitochondria under US and induced apoptosis in a mitochondrial depolarization manner mediated by the generation of ROS and free charges. Furthermore, SBTO NPs could cross the BBB and then accumulate in gliomas through US/microbubbles (MBs) procedure and protein-mediated transport. The therapeutic effect of piezoelectric SBTO NPs mediated SDT was proved in the orthotopic glioma mouse model. As validated by the histopathological observation and the long-term evaluation, the good biocompatibility and biosafety of SBTO NPs make it possible for deep tumor therapy, and worthy for further preclinical study. Statement of significanceEmploying piezoelectric sonosensitizers for sonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, the unclear mechanism and blood-brain barrier (BBB) limit the effectiveness of SDT in glioma. Herein, we developed piezoelectric SrBi2Ta2O9 nanoparticles (SBTO NPs) with a built-in electric field for glioma treatment and explored the underlying therapeutic mechanism. Notably, SBTO NPs selectively accumulated in mitochondria under ultrasound (US) and induced apoptosis in a mitochondrial depolarization manner, which is mediated by the generation of reactive oxygen species (ROS) and free charges. In an orthotopic glioma mouse model, SBTO NPs were delivered into the glioma through US/microbubbles and transferrin-mediated transport pathways, inhibiting tumor growth. This work provides a new paradigm for the treatment of orthotopic glioma and other tumor types.

A self-assembled theranostic nanoplatform for efficient tumor sonodynamic-gas therapy

The powerful antioxidant system in tumor tissues limits the efficacy of sonodynamic therapy (SDT) by reducing the availability of the produced reactive oxygen species (ROS). To address this problem, a pH/ultrasound (US) responsive theranostic nanoplatform is elaborately constructed by self-assembly of nitrogen-doped graphene quantum dots (NGQDs), benzothiazole sulfinate (BTS), Gd3+ ions and poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG). The NGQD component with excellent sonodynamic activity wrapped in the resulting Gd-NGQDs/BTS@PLGA-PEG can efficaciously respond to ultrasonic irradiation and cause abundant ROS generation. Importantly, in response to acidic tumor microenvironment, the loaded BTS sustainably releases SO2, which induces the increase of intracellular •O2− level by inhibiting superoxide dismutase activity and further promotes the enrichment of ROS by reducing intracellular glutathione level and suppressing glutathione peroxidase 4 activity. The well-designed SO2 gas therapy-enhanced SDT strategy leads to high oxidative stress in tumor cells and effective inhibition of the growth of bilateral tumors with only a single intravenous injection of the nanomedicine and a subsequent single US irradiation. Gd-NGQDs/BTS@PLGA-PEG can also be employed as a good T1-weighted magnetic resonance imaging contrast agent to guide tumor therapy. This innovative therapeutic strategy developed in our contribution may provide a new paradigm for the exploration of deep tumor therapy.

Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70 ) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70 -mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

An intelligent NIR-IIb-responsive lanthanide@metal-organic framework core-shell nanocatalyst for combined deep-tumor therapy.

The ground-breaking combination of photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted much attention in medical fields as an effective method for fighting cancer. However, evidence suggests that the therapy efficiency is still limited by shallow light penetration depth and poor photosensitizer loading capacity. Herein, we constructed an upconversion nanoparticle@Zr-based metal-organic framework@indocyanine green molecule (UCNPs@ZrMOF@ICG) nanocomposite to integrate 1532 nm light-triggered PDT and 808 nm light-mediated PTT. NaLnF4 nanoparticles are designed to emit upconversion luminescence (UCL) under 1532 nm laser excitation, which is consistent with the absorption spectra of the ZrMOF. Benefiting from the excellent energy transfer efficiency, the ZrMOF can absorb visible light from the UCNPs and then catalyze O2 into 1O2 for deep tissue PDT. To achieve combination therapy, the clinically approved ICG nanocomposite was introduced as a photothermal agent for PTT under 808 nm laser irradiation, and the photothermal conversion efficiency was calculated to be ∼28%. The designed nanosystems facilitate efficient deep-tissue tumor treatment by integrating PDT with PTT. Ultimately, this study creates a multifunctional nanocomposite by combining 1532 nm light-triggered deep tissue PDT and near-infrared (NIR) light-driven PTT for personalized cancer therapy.

Self-Illuminating In Situ Hydrogel with Immune-Adjuvant Amplify Cerenkov Radiation-Induced Photodynamic Therapy.

Cerenkov radiation-induced photodynamic therapy (CR-induced PDT) has shown the potential to overcome the light penetration limitation in conventional PDT. In addition, the tumor-associated antigens (TAAs) produced by PDT can initiate an antitumor immune process but only show a limited immunotherapeutic effect without the use of immunotherapeutic agents. Herein, a CR-induced PDT hydrogel (R837/89Zr-HG-PpIX) has been developed by in situ formation of a hyaluronic acid (HA)-based hydrogel integrated with internal light source 89Zr, photosensitizer protoporphyrin IX (PpIX), and immune adjuvant imiquimod (R837). The obtained R837/89Zr-HG-PpIX hydrogel with long-term tumor retention and low radiation leakage can provide long-lasting photodynamic therapy without phototoxicity in normal tissues. In addition, the loaded R837 improves the immunogenicity of TAAs released after PDT, resulting in considerably enhanced immune responses. At relatively low radioactivity, R837/89Zr-HG-PpIX shows significant inhibition in subcutaneous H22 tumor-bearing BALB/c mice and orthotopic VX2 liver tumor-bearing rabbits. Furthermore, the combination of such a CR-induced PDT hydrogel with anti-PD-L1 exhibits the abscopal effect to inhibit the growth of distant tumors. Therefore, the proposed in situ formed CR-induced PDT hydrogel with long-term photodynamic-immunotherapy provides an effective strategy for deep tumor therapy.

A novel activated NIR-II phototheranostic nanoagent and its application to photothermal therapy

Phototheranostic nanoagent with NIR-II fluorescence imaging and photothermal therapy (PTT) may allow high-quality imaging guided efficient ablation of deep-tissue tumors. Non-specific distribution in vivo may lead to poor imaging results and a risk of damage to normal tissues. However, developing an activable NIR-II nanoagent for photothermal therapy is challenging. Herein, a new polarity-sensitive phototheranostic nanoagent (DC@PEG) is developed for combinational tumor-specific NIR-II fluorescence imaging and photothermal therapy. DC@PEG has a maximum emission exceed 1200 nm at 808 nm excitation. In vivo fluorescence imaging indicated the nanoparticles could accurately distinguish normal tissue (high polarity environment) and tumor tissue (low polarity environment). Furthermore, DC@PEG effectively inhibited the growth of 4T1 tumor under 808 nm laser irradiation with a high photothermal conversion efficiency of 48.1 %. This work provides a promising strategy for development of excellent NIR-II nanoagent with good biocompatibility and deep tissue penetration. This novel nanoagent can served as a robust tool for photothermal therapy of deep tumors.

Ultrasound-Driven Piezoelectrocatalytic Immunoactivation of Deep Tumor.

Tumor heterogeneity makes routine drugs difficult to penetrate solid tumors, limiting their therapy efficacies. Based on high tissue penetrability of hydrogen molecules (H2 ) and ultrasound (US) and the immunomodulation effects of H2 and lactic acid (LA), this work proposes a novel strategy of US-driven piezoelectrocatalytic tumor immunoactivation for high-efficacy therapy of deep tumors by piezoelectrocatalytic hydrogen generation and LA deprivation. A kind of US-responsive piezoelectric SnS nanosheets (SSN) is developed to realize US-triggered local hydrogen production and simultaneous LA deprivation in deep tumors. The proof-of-concept experiments which are executed on an orthotopic liver cancer model have verified that intratumoral SSN-medicated piezoelectrocatalytically generated H2 liberates effector CD8+ T cells from the immunosuppression of tumor cells through down-regulating PD-L1 over-expression, and simultaneous LA deprivation activates CD8+ T cells by inhibiting regulatory T cells, efficiently co-activating tumor immunity and achieving a high outcome of liver tumor therapy with complete tumor eradication and 100% mice survival. The proposed strategy of US-driven piezoelectrocatalytic tumor immunoactivation opens a safe and efficient pathway for deep tumor therapy.

Polymeric Phthalocyanine-Based Nanosensitizers for Enhanced Photodynamic and Sonodynamic Therapies.

Photodynamic therapy and sonodynamic therapy are two highly promising modalities for cancer treatment. The latter holds an additional advantage in deep-tumor therapy owing to the deep penetration of the ultrasonic radiation. The therapeutic efficacy depends highly on the photo/ultrasound-responsive properties of the sensitizers as well as their tumor-localization property and pharmacokinetics. A novel nanosensitizer system based on a polymeric phthalocyanine (pPC-TK) is reported herein in which the phthalocyanine units are connected with cleavable thioketal linkers. Such polymer could self-assemble in water forming nanoparticles with a hydrodynamic diameter of 48nm. The degradable and flexible thioketal linkers could effectively inhibit the π-π stacking of the phthalocyanine units, rendering the resulting nanoparticles an efficient generator of reactive oxygen species upon light or ultrasonic irradiation. The nanosensitizer could be internalized into cancer cells readily, inducing cell death by efficient photodynamic and sonodynamic effects. The potency is significantly higher than that of the monomeric phthalocyanine (PC-4COOH). The nanosensitizer could also effectively inhibit the growth of tumor in liver tumor-bearing mice by these two therapies without causing noticeable side effects. More importantly, it could also retard the growth of a deep-located orthotopic liver tumor in vivo by sonodynamic therapy.

Mesocrystalline ZnS nanoparticles-augmented sonocatalytic full water splitting into H2/O2 for immunoactivating deep tumor

Therapeutic gas molecules have high tissue penetrability, but their sustainable supply and controlled release in deep tumor is a huge challenge. In this work, a concept of sonocatalytic full water splitting for hydrogen/oxygen immunotherapy of deep tumor is proposed, and a new kind of ZnS nanoparticles with a mesocrystalline structure (mZnS) is developed to achieve highly efficient sonocatalytic full water splitting for sustainable supply of H2 and O2 in tumor, achieving a high efficacy of deep tumor therapy. Mechanistically, locally generated hydrogen and oxygen molecules exhibit a tumoricidal effect as well as the co-immunoactivation of deep tumors through inducing the M2-to-M1 repolarization of intratumoral macrophages and the tumor hypoxia relief-mediated activation of CD8+ T cells, respectively. The proposed sonocatalytic immunoactivation strategy will open a new window to realize safe and efficient treatment of deep tumors.

Single-Excitation Triple-Emission Down-/Up-Conversion Nanoassemblies for Tumor Microenvironment-Enhanced Ratiometric NIR-II Fluorescence Imaging and Chemo-/Photodynamic Combination Therapy.

Tumor microenvironment-mediated ratiometric second near-infrared (NIR-II) fluorescence imaging and photodynamic therapy contribute to accurate diagnosis and highly efficient therapy of deep tumors. However, it is challenging to integrate these functions into one nanodrug due to the difficulty in preparing triple-emission nanoprobes. In this work, single-excitation triple-emission (wavelength at 660, 1060, and 1550 nm) down-/up-conversion nanoassemblies were prepared by conjugating dual-ligands-stabilized gold nanoclusters (cgAuNCs) into down-/up-conversion nanoparticles (D/UCNPs), which simultaneously realized ratiometric NIR-II fluorescence imaging and chemo-/photodynamic combination therapy toward tumors upon exposure to an 808 nm laser. The presence of dual ligands endowed cgAuNCs with an enhanced NIR-II fluorescence response to endogenous glutathione, allowing in situ ratiometric NIR-II fluorescence imaging of tumors using the prepared nanoassemblies. Additionally, the stabilizing ligand cyclodextrin of cgAuNCs facilitated the loading of the antitumor drug doxorubicin, and D/UCNPs could be modified with the photosensitizer methylene blue. Such a spatially separated functionalization method enabled chemo-/photodynamic combination therapy. This study provides new insights into the design of multifunctional nanoplatforms for tumor diagnosis and treatment.

Stimuli-responsive ferroptosis for cancer therapy.

Ferroptosis, an iron-dependent programmed cell death mechanism, is regulated by distinct molecular pathways of lipid peroxidation caused by intracellular iron supplementation and glutathione (GSH) synthesis inhibition. It has attracted a great deal of attention as a viable alternative to typical apoptosis-based cancer therapy that exhibits drug resistance. For efficient therapeutic utilization of such a unique and desirable mechanism, precise control using various stimuli to activate the administered nanocarriers is essential. Specific conditions in the tumor microenvironment (e.g., acidic pH, high level of ROS and GSH, hypoxia, etc.) can be exploited as endogenous stimuli to ensure high specificity of the tumor site. Maximized spatiotemporal controllability can be assured by utilizing external energy sources (e.g., magnetic fields, ultrasound, microwaves, light, etc.) as exogenous stimuli that can provide on-demand remote controllability for customized deep tumor therapy with a low inter-patient variation. Strikingly, the utilization of dual endogenous and/or exogenous stimuli provides a new direction for efficient cancer therapy. This review highlights recent advances in the utilization of various endogenous and exogenous stimuli to activate the reactions of nanocarriers for ferroptosis-based cancer therapy that can inspire the field of cancer therapy, particularly for the treatment of intractable tumors.

Photodynamic antitumor activity of tetrahydroxyl-methyl pyropheophorbide-a with improved water-solubility and depth of treatment

Methyl pyropheophorbide-a (MPPa) is a chlorophyll degradation product that possesses excellent photophysical and photochemical properties, yet poor water solubility limits its clinical application. In this paper, a novel MPPa derivative, 31,32,7,8-tetrahydroxy-4 H-MPPa (HMPPa) was synthesized by oxidative hydrolysis of MPPa with potassium osmate. The four hydrophilic hydroxyl groups endow HMPPa with better water solubility (lipid water partition coefficient logP = −0.16), which solve the problem of MPPa aggregation in water. HMPPa has a long-wavelength near-infrared absorption at 740 nm that can achieve a deeper penetration depth in biological tissues, which allows HMPPa to be applied in deep tumor therapy. Moreover, HMPPa possesses a higher singlet oxygen quantum yield (62.65 %) than that of MPPa (56 %). MTT assay verified that HMPPa had a strong ability to inhibit the growth of HepG-2 cells and 4T1 cells, and the PDT effect was superior to that of MPPa. Cell morphology experiments and flow cytometry analysis showed that HMPPa could induce apoptosis via a mitochondrial pathway. In vivo study of HMPPa showed a significant PDT antitumor effect on 4T1 tumor-bearing mice (Balb/C). The tumor cells followed by treatment of HMPPa could be clearly observed under fluorescence microscopy, implying a good fluorescence imaging function of HMPPa.

Bacterial targeted AIE photosensitizers synergistically promote chemotherapy for the treatment of inflammatory cancer

Tumor-associated components, especially extratumoral bacteria (EB) in the form of biofilms, could exacerbate cancer progression and hinder the effectiveness of antitumor drugs by covering the interstitial tumor space. Although photodynamic therapy (PDT) is a promising modality to kill cancer cells and bacteria with high spatiotemporal precision, the low penetration of light limits its potential in deep tumor therapy. Furthermore, current 2D culture-based preclinical in vitro models failed to reflect the complexity of the tumor microenvironment. Here, we developed an unprecedented “1 + 1 > 2″ combinatorial strategy of PDT and chemotherapy by co-delivering a bacterial-targeted photosensitizer with aggregation-induced emission (AIE) property and an anticancer drug, doxorubicin. The theranostic system could selectively visualize and rapidly kill EB, using a microfluidic-based 3D bladder cancer model. The effect of combinatorial therapy was synergistic, resulting in improved efficacy, as evidenced by at least a 2.5-fold reduction in the half-maximal inhibitory concentration of doxorubicin. Validation using a fish wound infection model further demonstrated the feasibility of AIE photosensitizers for efficient fluorescence imaging-guided PDT in vivo. Overall, we proposed a robust AIE PDT/chemotherapy strategy that shows great potential for rapid and concurrent treatment of bacterially infected cancer patients.

Intelligent Bi2Se3@Cu2−xSe heterostructures with enhanced photoabsorption and photoconversion efficiency for tri-modal imaging guided combinatorial cancer therapy by near-infrared Ⅱ light

A novel nanoplatform that supports multimodal imaging has been designed for deep tumor therapy. In this study, Bi2Se3@Cu2−xSe heterojunction nanocomposites with tunable spectral absorption, effective electron–hole separation and high photothermal conversion efficiency were prepared for the combination therapy of phototherapy (PT), chemodynamic therapy (CDT) and radiotherapy (RT). By adjusting the doping ratio, the heterojunction nanoparticles show obvious tunable ability of local surface plasmon resonance and the ability to promote electron-hole separation with significantly enhanced reactive oxygen species production capacity. The band structure and charge density difference calculated by density functional theory further reveal that the change of band gap and the decrease of free carriers can regulate the spectral absorption of nanomaterials and promote electron-hole separation. In addition, the photothermal conversion properties of low carrier density semiconductors are related to their inherent deep level defects. The formation of heterojunctions making the Se atoms deviate from the Bi2Se3 lattice, resulting in more deep level defects and stronger photothermal conversion properties. Meanwhile, this nanoplatform presented features similar to catalase activities and glutathione (GSH) consumption characteristics, which was capable of effectively alleviate the tumor-specific hypoxia environment to enhance the efficacy of O2-dependent photodynamic therapy (PDT) and radiotherapy (RT) and depletion GSH to prevent the reduction of therapeutic efficacy due to the clearance of reactive oxygen species. In addition to therapeutic enhancement, heterojunction nanomaterials have excellent nuclear magnetic resonance imaging (MRI), infrared thermal imaging (IR) and computed tomography (CT) properties due to their significant paramagnetism and excellent photothermal conversion and X-ray attenuation capacities. In conclusion, our findings provide a new strategy for designing multi-function and efficient nanoplatform to treat tumor.

Ultrasound-Responsive Peptide Nanogels to Balance Conflicting Requirements for Deep Tumor Penetration and Prolonged Blood Circulation.

A series of biological barriers need to be overcome for therapeutic nanocarriers accumulating at the tumor site and uptaken by cancer cells. One strategy is to construct switchable nanocarriers to meet the conflicting requirements for various physiology environments. In this work, besides widely studied endogenous stimuli-responsiveness, an exogenous ultrasound responsiveness was additionally embedded into nanocarriers to balance the conflicting needs of prolonged blood circulation and deep tumor penetration. Polylysine and Pluronic F127 were first coassembled and then cross-linked by genipin to form stable nanogel structure. Subsequently, ICAM-1 antibody was grafted onto the nanogel (designated as GenPLPFT) for active tumor targeting. Upon external sonication, the F127 was shed from GenPLPFT to induce swelling of nanogel with reduced stability and accelerated drug release. In detail, sonication leads to GenPLPF swelling from 329 to 516 nm, while its Young's modulus significantly decreased from 336.78 to 3.93 kPa. Through intravenous injection, relatively rigid GenPLPFT was able to achieve a high level of accumulation at tumor site by active targeting and long-term blood circulation. Moreover, under sonication at the tumor site, GenPLPFT became softer with enhanced deformability to achieve deep tumor penetration. In addition, in vivo studies revealed that GenPLPFT was able to penetrate into the deep area of xenografted tumor with enhanced antitumor efficacy and reduced toxicity. Overall, this peptide nanogel with ultrasound-responsive stiffness demonstrates an effective approach to overcome a series of biological barriers for enhanced deep tumor therapy.

Biodegradable Polymer with Effective Near-Infrared-II Absorption as a Photothermal Agent for Deep Tumor Therapy.

Photothermal therapy holds great promise for cancer treatment due to its effective tumor ablation and minimal invasiveness. Herein a new class of biodegradable photothermal agents with effective adsorption in both near-infrared-I (NIR-I) and NIR-II windows is reported for deep tumor therapy. As demonstrated in a deep-seated ovarian cancer model, photothermal therapy using 1064nm irradiation effectively inhibits tumor progression and prolongs survival spans. This work provides a new design of photothermal agents toward a more effective therapy of tumors.

Emerging biocompatible nanoplatforms for the potential application in diagnosis and therapy of deep tumors

AbstractCancer, as one of the most attention‐grabbing medical problems, has been tried to solve with various methods. With the development of nanotechnology, diagnosis and therapy based on nanoplatforms have become new dawn for overcoming cancer problems. Biocompatible nanoplatforms integrating diagnosis and therapy technology for cancer have been extensively studied. Most of the reported works focus on the diagnosis and therapy of subcutaneous tumor. To promote clinical application, it is of great significance to develop efficient methods for deep tumors. This work reviews the latest research progress and future development prospects for the diagnosis and therapy of deep tumors based on biocompatible nanoplatforms. It mainly introduces four cancer diagnostic technologies (fluorescence imaging (FI), computed tomography (CT), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI)) and four tumor treatment methods (phototherapy, ultrasound therapy, radiotherapy (RT), and microwave therapy (MWT)) based on the nanoplatforms. Several diagnostic techniques and treatment methods are systematically summarized and compared, and the advantages and limitations of different methods in tumors are discussed. At last, the application prospects and challenges of the nanoplatforms for the diagnosis and therapy of deep tumors are discussed. It is hoped that this review will provide some useful information for the research in this field.

Water-Soluble Iridic-Porphyrin Complex for Non-invasive Sonodynamic and Sono-oxidation Therapy of Deep Tumors.

Due to conventional photodynamic therapy encountering serious problems of phototoxicity and low tissue-penetrating depth of light, other dynamic therapy-based therapeutic methods such as sonodynamic therapy (SDT) are expected to be developed. To improve the therapeutic response to SDT, more effective sonosensitizers are imperative. In this study, a novel water-soluble iridium(III)-porphyrin sonosensitizer (IrTMPPS) was synthesized and used for SDT. IrTMPPS generated ample singlet oxygen (1O2) under US irradiation and especially showed distinguished US-activatable abilities at more than 10 cm deep-tissue depths. Interestingly, under US irradiation, IrTMPPS sonocatalytically oxidized intracellular NADH, which would enhance SDT efficiency by breaking the redox balance in the tumor. Moreover, IrTMPPS displayed great sonocytotoxicity toward various cancer cells, and in vivo experiments demonstrated efficient tumor inhibition and anti-metastasis to the lungs in the presence of IrTMPPS and US irradiation. This report gives a novel idea of metal-based sonosensitizers for sonotherapy by fully taking advantage of non-invasiveness, water solubility, and deep tumor therapy.

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.