Noninvasive Tumor Therapy Research Articles

Tumor Microenvironment-Responsive Zn(II)-Porphyrin Nanotheranostics for Targeted Sonodynamic Therapy.

As a novel noninvasive tumor therapy, sonodynamic therapy (SDT) attracts booming concerns. However, the limited water solubility, inadequate biocompatibility, and low targeting ability of conventional sonosensitizers significantly hinder their potential for clinical application. Herein, novel zinc(II)-porphyrin nanotheranostics (HA@Zn-TCPP) were fabricated in which the zinc(II)-porphyrin (TCPP) metal-organic framework was first constructed by a simple thermal reaction, followed by the addition of hyaluronic acid (HA) for modification. The specific targeting ability of HA facilitated the internalization of HA@Zn-TCPP within tumor cells, resulting in its preferential accumulation in tumor tissues that exhibit CD44 receptor overexpression. The acidic tumor microenvironment induced the rapid decomposition of HA@Zn-TCPP, releasing free TCPP for activating SDT. This controllable generation of reactive oxygen species (ROS) could effectively decrease damage to normal tissues. The HA@Zn-TCPP exhibited remarkable antitumor effects in experiments, achieving a tumor inhibition rate of up to 82.1% when under ultrasound. This finding provides an imperative strategy to develop novel sonosensitizers for enhanced SDT.

Curcumin Nanoparticles-related Non-invasive Tumor Therapy, and Cardiotoxicity Relieve.

Non-invasive antitumor therapy can treat tumor patients who cannot tolerate surgery or are unsuitable. However, tumor resistance to non-invasive antitumor therapy and cardiotoxicity caused by treatment seriously affect the quality of life and prognosis of patients. As a kind of polyphenol extracted from herbs, curcumin has many pharmacological effects, such as anti-inflammation, antioxidation, antitumor, etc. Curcumin plays the antitumor effect by directly promoting tumor cell death and reducing tumor cells' invasive ability. Curcumin exerts the therapeutic effect mainly by inhibiting the nuclear factor-κB (NF-κB) signal pathway, inhibiting the production of cyclooxygenase-2 (COX-2), promoting the expression of caspase-9, and directly inducing reactive oxygen species (ROS) production in tumor cells. Curcumin nanoparticles can solve curcumin's shortcomings, such as poor water solubility and high metabolic rate, and can be effectively used in antitumor therapy. Curcumin nanoparticles can improve the prognosis and quality of life of tumor patients by using as adjuvants to enhance the sensitivity of tumors to non-invasive therapy and reduce the side effects, especially cardiotoxicity. In this paper, we collect and analyze the literature of relevant databases. It is pointed out that future research on curcumin tends to alleviate the adverse reactions caused by treatment, which is of more significance to tumor patients.

Nitrogen-doped carbon dots as a highly efficient photosensitizer for photodynamic therapy to promote apoptosis in oral squamous cell carcinoma

Photodynamic (PDT) is a new strategy for non-invasive tumor therapy and has been studied for the treatment of oral cancer. PDT has the advantages of low damage and high therapeutic efficiency. However, conventional photosensitizers have defects in different degrees, such as low stability and solubility, and low oxygen quantum yield of singlet oxygen. These defects greatly limit the efficiency of PDT. Several studies have shown that carbonaceous nanomaterials, carbon dots (CDs), are promising as a novel nanoscale photosensitizer to mediate PDT for cancer treatment. In this study, we utilized fluorescent CDs doped with nitrogen to optimize their photosensitizing activity to enhance PDT in oral squamous cell carcinoma (OSCC). Nitrogen-doped CDs were able to generate a large amount of reactive oxygen species (ROS) under 660-nm laser irradiation after uptake by cancer cells, effectively inducing apoptosis in the mitochondrial pathway. The in vivo and in vivo experiments verified that CDs-mediated PDT was able to promote apoptosis of tumor cells in terms of DNA damage, inhibition of angiogenesis and cell proliferation, etc. CDs, as a novel photosensitizer, is expected to be an outstanding tool for clinical PDT in the treatment of OSCC.

Two-dimensional MXene-based nano-prodrug for synergistic chemo-photothermal therapy on cancer treatment

In cancer treatment, although prodrugs have been developed to overcome obstacles such as undesirable pharmacokinetic performance and serious off-target toxicity of most chemotherapeutics, the combination of prodrugs with nanotechnology could be used to overcome the shortcomings of conventional prodrug strategies and facilitate more efficient drug delivery and accumulation of anticancer prodrugs at specific sites/tissues. Phototherapy is a method that uses near-infrared (NIR) light to achieve local and non-invasive tumor therapy. The combination of chemotherapy and phototherapy has shown many therapeutic advantages, including synergistic therapeutic effects and the reduction of toxic and side effects of drugs through dose reduction. In this work, a hydrazone linkage was reported to conjugate Ti3C2Tx MXene nanosheets with doxorubicin hydrochloride (DOX) and methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) through a chemical surface modification to form a two-dimensional (2D) nano-prodrug Ti3C2Tx-DOX/PEG (TDP) for synergistic chemo-photothermal therapy. First, hydrazide functionalized Ti3C2Tx was obtained. Then, the carbonyl group of DOX and the aldehyde group of mPEG-CHO can form a pH-responsive hydrazone bond with hydrazide-functionalized Ti3C2Tx. The high surface area of Ti3C2Tx could overcome the reduced drug loading caused by conjugation. Aqueous stability and biocompatibility were enhanced by the introduction of PEG, making the material capable of prolonged circulation in the body's bloodstream. By achieving excellent antitumor results with this nano-prodrug, we have added another brick to the edifice of Ti3C2Tx MXene as an anticancer drug carrier, and given new vitality to the study of anticancer prodrugs combined with nanotechnology.

Nanoscale Metal-Organic Frameworks Combined with Metal Nanoparticles and Metal Oxide/Peroxide to Relieve Tumor Hypoxia for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) is a clinically approved noninvasive tumor therapy that can selectively kill malignant tumor cells, with promising use in the treatment of various cancers. PDT is typically composed of three important parts: the specific wavelength of light, photosensitizer (PS), and oxygen. With the progressing investigation on PDT treatment, the most recent attention has focused on improving photodynamic efficiency. Tumor hypoxia has always been a critical factor hindering the efficacy of PDT. Nanoscale metal-organic frameworks (nMOF), the fourth generation of PS, present great potential in photodynamic therapy. In particular, nMOF combined with metal nanoparticles and metal oxide/peroxide has demonstrated unique properties for enhanced PDT. The metal and metal oxide nanoparticles can catalyze H2O2 to generate oxygen or automatically produces oxygen, alleviating the hypoxia and improving the photodynamic efficiency. Metal peroxide nanoparticles can spontaneously produce oxygen in water or under acidic conditions. Therefore, this Review summarizes the recent development of nMOF combined with metal nanoparticles (platinum nanoparticles and gold nanoparticles) and metal oxide/peroxide (manganese dioxide, ferric oxide, cerium oxide, calcium peroxide, and magnesium peroxide) for enhanced photodynamic therapy by alleviating tumor hypoxia. Finally, future perspectives of nMOF combined nanomaterials in PDT are put forward.

Self-assembled peptide nanoparticles for photodynamic therapy: morphological and mechanical effects on hepatocellular carcinoma cells

Self-assembling peptides, offering favorable biocompatibility, high stability, and easy incorporation of various functionalities, have demonstrated enormous potential for the precise design of next-generation nanodrugs for non-invasive tumor therapy. Peptide-based supramolecular photodynamic therapy (PDT) has shown great promise as an emerging modality for cancer treatment, achieving substantially-enhanced photosensitizer delivery selectivity and treatment efficacy, based on peptide biological activity and self-assembly potential. Although considerable research has been conducted toward fabricating self-assembling peptide-based smart nanodrugs for PDT, few studies have investigated cellular biophysical responses as indicators of tumor function and metabolic state. Here, via atomic force microscopy (AFM)-based morphological and mechanical measurements, including optical microscopy and scanning electron microscopy, we observed, for the first time, variation in membrane stiffness of human liver (HepG2) cancer cells treated with self-assembling peptides serving as a PDT nanodrug. This biophysical information will help to establish a comprehensive understanding of the anticancer effect of peptide-based smart nanodrugs, and highlight the exceptional ability of AFM in determining cell-surface properties.

Focused ultrasound restrains the growth of orthotopic colon cancer via promoting pyroptosis.

Focused ultrasound (FUS) is a non-invasive tumor therapy technology emerging in recent years, which can treat various solid tumors. However, it is unclear whether FUS can affect the pyroptosis of colon cancer (CC) cells. Here, we analyzed the effect of FUS on pyroptosis in the orthotopic CC model. After an orthotopic CC mouse model was constructed by injecting CT26-Luc cells, BABL/C mice were allocated to the normal, tumor, FUS, and FUS + BAY11-7082 (pyroptosis inhibitor) groups. We monitored the tumor status of the mice through in vivo fluorescence image analysis. The histopathological injury of the intestinal tissue and the expression of IL-1β, IL-18, caspase-recruitment domain (ASC), cleaved caspase-1, gasdermin D (GSDMD), and NLRP3 of the CC tumors were examined utilizing hematoxylin and eosin staining, immunohistochemical assay, and Western blot. FUS restrained the fluorescence intensity of the tumors in orthotopic CC mice, while FUS-mediated suppression of the bioluminescent signal of the tumors was alleviated by BAY11-7082. FUS was found to relieve the injury of the intestinal tissues in CC mice as revealed by morphology. Furthermore, the expressions of IL-1β, IL-18, GSDMD, ASC, cleaved caspase-1, and NLRP3 of the CC tumors in the FUS group were higher than those in the tumor group, while BAY11-7082 addition partly reversed the FUS's effects on orthotopic CC model mice. Our results pointed out that FUS presented anti-tumor activity in experimental CC, and its mechanism was correlated with the promotion of pyroptosis.

Facile preparation of a novel hyaluronic acid-modified metal-polyphenol photothermal nanoformulation for tumor therapy

Photothermal therapy (PTT) is a potentially effective and non-invasive tumor therapy that has attracted the attention of many researchers. This study systematically investigated the formation of metal-polyphenol nanoparticles and their photothermal properties. A simple physical self-assembly method was used to embed hyaluronic acid (HA) into metal-polyphenol nanoparticles, and a novel type of HA-modified ferrous baicalein nanoparticle (HFBNP) was successfully prepared for the first time. Unlike most current methods that utilize positive and negative charge attraction or chemical bonding, the method proposed in this study is to embed HA into nanostructures to reduce the risk of HA shedding in the circulation, thereby improving the tumor targeting efficiency while avoiding the use of other chemical reagents. HFBNP had a suitable size distribution and good biosafety meanwhile efficiently converting near-infrared (NIR) laser energy into thermal energy. The active targeting capability mediated by HA significantly increased the uptake of nanoparticles by tumor cells, and HFBNP exhibited a strong growth inhibitory effect on tumor cells under NIR laser irradiation. With the combination of PTT and chemotherapy, HFBNP significantly inhibited tumor growth in tumor-bearing mice. In conclusion, the nanosystem prepared in this study provides a new strategy for tumor therapy.

Self-assembling peptides-based nano-cargos for targeted chemotherapy and immunotherapy of tumors: recent developments, challenges, and future perspectives

Self-assembling peptides (SAPs) have enormous potential in medical and biological applications, particularly noninvasive tumor therapy. SAPs self-assembly is governed by multiple non-covalent interactions and results in the formation of a variety of morphological features. SAPs can be assembled in a variety of ways, including chemical conjugation and physical encapsulation, to incorporate multiple bioactive motifs. Peptide-based nanomaterials are used for chemotherapy, delivery vehicles, immunotherapy, and noninvasive tumor therapies (e.g. photodynamic therapy) by employing the self-assembling properties of peptides. The recent increase of SAPs is almost entirely due to their excellent biocompatibility, responsiveness toward tumor microenvironment, multivalency, and structural versatility. Synergistic therapy is a more effective and powerful approach to treat the tumor. Notably, SAPs can be used to subtly combine various treatments. Importantly, SAPs are capable of subtly making the combination of various treatments. This review describes mechanisms of peptides self-assemble into various structures and their biomedical applications with a focus on possible treatments.

Computational Study Regarding CoxFe3-xO4 Ferrite Nanoparticles with Tunable Magnetic Properties in Superparamagnetic Hyperthermia for Effective Alternative Cancer Therapy.

The efficacy in superparamagnetic hyperthermia (SPMHT) and its effectiveness in destroying tumors without affecting healthy tissues depend very much on the nanoparticles used. Considering the results previously obtained in SPMHT using magnetite and cobalt ferrite nanoparticles, in this paper we extend our study on CoxFe3−xO4 nanoparticles for x = 0–1 in order to be used in SPMHT due to the multiple benefits in alternative cancer therapy. Due to the possibility of tuning the basic observables/parameters in SPMHT in a wide range of values by changing the concentration of Co2+ ions in the range 0–1, the issue explored by us is a very good strategy for increasing the efficiency and effectiveness of magnetic hyperthermia of tumors and reducing the toxicity levels. In this paper we studied by computational simulation the influence of Co2+ ion concentration in a very wide range of values (x = 0–1) on the specific loss power (Ps) in SPMHT and the nanoparticle diameter (DM) which leads to the maximum specific loss power (PsM). We also determined the maximum specific loss power for the allowable biological limit (PsM)l which doesn’t affect healthy tissues, and how it influences the change in the concentration of Co2+ ions. Based on the results obtained, we established the values for concentrations (x), nanoparticle diameter (DM), amplitude (H) and frequency (f) of the magnetic field for which SPMHT with CoxFe3−xO4 nanoparticles can be applied under optimal conditions within the allowable biological range. The obtained results allow the obtaining a maximum efficacy in alternative and non-invasive tumor therapy for the practical implementation of SPMHT with CoxFe3−xO4 nanoparticles.

Graphene Oxide Nanoparticle–Loaded Ginsenoside Rg3 Improves Photodynamic Therapy in Inhibiting Malignant Progression and Stemness of Osteosarcoma

Osteosarcoma serves as a prevalent bone cancer with a high metastasis and common drug resistance, resulting in poor prognosis and high mortality. Photodynamic therapy (PDT) is a patient-specific and non-invasive tumor therapy. Nanoparticles, like graphene oxide have been widely used in drug delivery and PDT. Ginsenoside Rg3 is a principal ginseng component and has presented significant anti-cancer activities. Here, we constructed the nanoparticles using GO linked with photosensitizer (PS) indocyanine green (ICG), folic acid, and polyethylene glycol (PEG), and loaded with Rg3 (PEG–GO–FA/ICG–Rg3). We aimed to explore the effect of PEG–GO–FA/ICG–Rg3 combined with PDT for the treatment of osteosarcoma. Significantly, we found that Rg3 repressed proliferation, invasion, and migration, and enhanced apoptosis and autophagy of osteosarcoma cells, while the PEG–GO–FA/ICG–Rg3 presented a higher activity, in which NIR laser co-treatment could remarkably increase the effect of PEG–GO–FA/ICG–Rg3. Meanwhile, stemness of osteosarcoma cell–derived cancer stem cells was inhibited by Rg3 and PEG–GO–FA/ICG–Rg3, and the combination of PEG–GO–FA/ICG–Rg3 with NIR laser further significantly attenuated this phenotype in the system. Moreover, NIR laser notably improved the inhibitor effect of PEG–GO–FA/ICG–Rg3 on the tumor growth of osteosarcoma cells in vivo. Consequently, we concluded that PEG–GO–FA/ICG–Rg3 improved PDT in inhibiting malignant progression and stemness of osteosarcoma cell. Our finding provides a promising and practical therapeutic strategy for the combined treatment of osteosarcoma.

Noninvasive Tumor Therapy: A Graphene‐Based Flexible Device as a Specific Far‐Infrared Emitter for Noninvasive Tumor Therapy (Adv. Therap. 3/2020)

Noninvasive Tumor Therapy: A Graphene‐Based Flexible Device as a Specific Far‐Infrared Emitter for Noninvasive Tumor Therapy (Adv. Therap. 3/2020)

A Graphene‐Based Flexible Device as a Specific Far‐Infrared Emitter for Noninvasive Tumor Therapy

AbstractNoninvasive treatments are emerging as a promising strategy not only due to their non‐invasive nature, but also due to their additive effects to traditional radiotherapy and chemotherapy. Herein, specific far‐infrared rays generated from single‐layer, graphene‐based devices are applied to tumors as a novel noninvasive therapeutic strategy. In MDA‐MB‐231 breast cancer cell xenograft and metastasis models, irradiation generated from this flexible device reduces the rate of tumor growth and the number of metastatic nodules per lung by 42% and 55%, respectively. This result might be induced by the similarity between the emission spectra of the device and the absorption spectra of the living tissue. With its high energy conversion and safety, the graphene‐based device can serve as an adjuvant therapeutic instrument for combined tumor treatment.

An Ultrasound-Guided Robotic HIFU Ablation System with Respiration Induced Displacement and Time Delay Compensation

IntroductionIn recent years, high-intensity focused ultrasound (HIFU) has commonly been applied in non-invasive tumor therapy, such as to treat uterine fibroids or prostate tumors. However, respiration may cause tumor displacement, such as liver tumor displacement, which may lead to errors in localization or inadequate thermal effects on the tumor. Therefore, a compensating mechanism for target localization is important.MethodsThis paper introduces an ultrasound imaging-assisted robotic HIFU ablation system with a displacement compensatory mechanism. According to the correlation between the measured displacements of the heaving chest and the target tumor, a respiration simulation device was designed, which used a tumor phantom and a cam-driving mechanism to simulate displacements of the tumor and of the heaving chest. Then, a polynomial function of the tumor position relative to the position of the heaving chest was generated. After the coordinate frames of the robotic arm, optical tracker and tumor phantom had been registered, the robotic arm was able to guide the HIFU probe to track and ablate the target tumor automatically and synchronously by inputting the displacement values of the heaving chest.ResultsThe average positioning error in the single-point tracking experiment was 1.72 ± 1.26 mm, while the ablation temperature was stabilized at 80 °C. Furthermore, the average positioning error in the cross-section ablation experiment was 3.04 ± 1.24 mm.

Nanogold Flower-Inspired Nanoarchitectonics Enables Enhanced Light-to-Heat Conversion Ability for Rapid and Targeted Chemo-Photothermal Therapy of a Tumor.

Chemo-photothermal therapy has become a promising tool for clinical noninvasive tumor therapy, which is able to efficiently avoid drug resistance and other side effects from chemical anticarcinogenic drugs. The ability to selectively fast-heat tumor tissues over surrounding compartments is of fundamental importance and makes effective treatment of tumor margins and complex tumor geometries. Currently existing chemo-photothermal methods mainly show slow light-to-heat conversion with increased temperature up to around 45-57 °C for 5-20 min or a longer time in vitro under regular near-infrared laser irradiation, and during tumor therapy, worse performance in temperature changes are obtained due to the much longer penetration distance in vivo. Herein, nanoarchitectonics with excellent chemo-photothermal performance are first proposed for tumors via in situ decoration of nanogold flowers on graphene oxide surface with further modification of the aptamer molecule. Even with simple synthesis processes, these nanoarchitectonics demonstrate impressive increased temperatures up to 85 °C in just 2 min under 808 nm laser irradiation with regular power density. Due to the fast light-to-heat conversion ability and specific binding effect between the aptamer and tumor cells, the designed nanocarrier shows a rapid and target therapy system with a targeted chemo-photothermal tumor treatment.

Smart Peptide-Based Supramolecular Photodynamic Metallo-Nanodrugs Designed by Multicomponent Coordination Self-Assembly.

Supramolecular photosensitizer nanodrugs that combine the flexibility of supramolecular self-assembly and the advantage of spatiotemporal, controlled drug delivery are promising for dedicated, precise, noninvasive tumor therapy. However, integrating robust blood circulation and targeted burst release in a single photosensitizer nanodrug platform that can simultaneously improve the therapeutic performance and reduce side effects is challenging. Herein, we demonstrate a multicomponent coordination self-assembly strategy that is versatile and potent for the development of photodynamic nanodrugs. Inspired by the multicomponent self-organization of polypeptides, pigments, and metal ions in metalloproteins, smart metallo-nanodrugs are constructed based on the combination and cooperation of multiple coordination, hydrophobic, and electrostatic noncovalent interactions among short peptides, photosensitizers, and metal ions. The resulting metallo-nanodrugs have uniform sizes, well-defined nanosphere structures, and high loading capacities. Most importantly, multicomponent assembled nanodrugs have robust colloidal stability and ultrasensitive responses to pH and redox stimuli. These properties prolong blood circulation, increase tumor accumulation, and enhance the photodynamic tumor therapeutic efficacy. This study offers a new strategy to harness robust, smart metallo-nanodrugs with integrated flexibility and multifunction to enhance tumor-specific delivery and therapeutic effects, highlighting opportunities to develop next-generation, smart photosensitizing nanomedicines.

Chemiluminescence-Guided Cancer Therapy Using a Chemiexcited Photosensitizer

Summary Image-guided therapy is one of the most promising strategies for efficiently curing a tumor. Here, a novel nanomaterial with chemiexcited far-red/near-infrared (FR/NIR) emission and singlet oxygen ( 1 O 2 ) generation is reported for precise diagnosis and treatment of tumors. Bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO) and a specially designed photosensitizer TBD with aggregation-induced FR/NIR emission were co-encapsulated by pluronic F-127 and soybean oil to form C-TBD nanoparticles (C-TBD NPs). These NPs serve as a specific H 2 O 2 probe to precisely track tumors in vivo through chemiluminescence imaging. In addition, effective 1 O 2 generation by C-TBD NPs in response to tumor H 2 O 2 was observed, which could efficiently induce tumor cell apoptosis and inhibit tumor growth. Both the chemiluminescence response and the therapeutic function were further enhanced when β-phenylethyl isothiocyanate was used to enhance the H 2 O 2 production at the tumor site. Our results prove that C-TBD NPs provide a new strategy for intelligent, accurate, and non-invasive tumor therapy.

Non-Invasive Tumor Therapy with Indocyanine Green and Paclitaxel Doubly Loaded Nanoparticles Using Photoacoustic Imaging

Non-Invasive Tumor Therapy with Indocyanine Green and Paclitaxel Doubly Loaded Nanoparticles Using Photoacoustic Imaging

Folic acid-modified and functionalized CuS nanocrystal-based nanoparticles for combined tumor chemo- and photothermal therapy

Recent studies have identified that CuS nanocrystal (CuS NCs) could be used as a new class of promising photo-thermal agents due to their excellent plasmonic absorption abilities in a wide near-infrared (NIR) region. However, most of nanocarriers lack target capacity for combining chemotherapy and photothermal therapy effects. Herein, we reported chitosan (CS)-encapsulated and folic acid (FA)-modified nanoparticles (NPs) simultaneously loading with functionalized CuS NCs and docetaxel (DTX) (FA-DTX-PVP/CuS-NPs). Compared with free DTX, the photothermal agent CuS NCs and DTX not only could be specially targeted to deliver into MCF-7 cancer cells via a receptor-mediated endocytosis pathway, but also could be effectively transferred into tumor tissues of S180 tumor-bearing mice in vivo. More important, when combination with NIR laser irradiation, FA-DTX-PVP/CuS-NPs showed a higher antitumor efficacy than the individual therapies. Thus, as a remote and noninvasive tumor therapy strategy, these active targeting NPs may provide a great potential for tumor synergistic therapy.

In vitro and in vivo evaluation of [ 123I]-VEGF 165 as a potential tumor marker

One of the research challenges in oncology is to develop new biochemical methods for noninvasive tumor therapy evaluation to determine whether the chemotherapeutics is effective. Vascular endothelial growth factor (VEGF) was labeled with radioiodine and evaluated in vitro as well as in vivo, using A2058, a melanoma cell line overexpressing VEGFR-1 and -2. Saturation binding analysis with [ 125I]-VEGF resulted in a K d of 0.1 nM. Internalization assays indicate the preserved ligand induced internalization and metabolization of the tracer. Biodistribution studies with [ 123I]-VEGF in wild type and A2058 tumor-bearing athymic mice showed low background activity and a tumor to reference tissue ratio of maximum 6.12. These results suggest that [ 123I]-VEGF is a potentially suitable tracer for tumor therapy evaluation.