Tumor microenvironment responsive nano-platform for overcoming sorafenib resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously jeopardizes human health. The 5-year relative survival rate of HCC is only about 18%. Sorafenib, a small molecule multi-targeted tyrosine kinase inhibitor (MTKI), has been classified as the first-line treatment scheme for HCC and has significantly extended the median survival time for patients with advanced HCC. Nevertheless, the emergence of sorafenib resistance has substantially hampered its further clinical application. Herein, the nano-platform based on phototherapy and small molecular targeted therapy (SMTT) was devised to overcome the sorafenib resistance and reduce the adverse effects. Hollow mesoporous manganese dioxide (H-MnO2) was prepared by hard template method, and the prepared H-MnO2 was used to load sorafenib and Chlorin e6 (Ce6). Subsequently, the nanoparticle (NPs) were modified with dopamine to optimize biocompatibility. The final prepared NPs (MCS NPs) exhibit regular spherical shape with a hydrated particle size of approximately 97.02 nm. MCS NPs can not only possess tumor microenvironment (TME) stimuli-responsive drug release performance but also can enhance the efficacy of photodynamic therapy and reverse sorafenib resistance by alleviating tumor hypoxia. Under the action of phototherapy (Ce6) combined with molecular targeted therapy (sorafenib), MCS NPs manifest a satisfactory antitumor effect for sorafenib-sensitive or sorafenib-resistant HCC cells, and retain the antiangiogenic properties of sorafenib. In the nude mouse subcutaneous tumor model constructed with sorafenib-resistant cells, MCS NPs demonstrated superior tumor imaging ability and excellent biocompatibility. The tumor inhibition rate of the MCS NPs group without laser irradiation was 53.4 %, while the MCS NPs group with laser irradiation was as high as 100 %. The novel smart TME-responsive nano-platform shows great potential for overcoming sorafenib resistance and realizes multimodality imaging and therapy of HCC.

Current Application of Nanoparticle Drug Delivery Systems to the Treatment of Anaplastic Thyroid Carcinomas.

Anaplastic thyroid carcinomas (ATCs) are a rare subtype of thyroid cancers with a low incidence but extremely high invasiveness and fatality. The treatment of ATCs is very challenging, and currently, a comprehensive individualized therapeutic strategy involving surgery, radiotherapy (RT), chemotherapy, BRAF/MEK inhibitors (BRAFi/MEKi) and immunotherapy is preferred. For ATC patients in stage IVA/IVB, a surgery-based comprehensive strategy may provide survival benefits. Unfortunately, ATC patients in IVC stage barely get benefits from the current treatment. Recently, nanoparticle delivery of siRNAs, targeted drugs, cytotoxic drugs, photosensitizers and other agents is considered as a promising anti-cancer treatment. Nanoparticle drug delivery systems have been mainly explored in the treatment of differentiated thyroid cancer (DTC). With the rapid development of drug delivery techniques and nanomaterials, using hybrid nanoparticles as the drug carrier to deliver siRNAs, targeted drugs, immune drugs, chemotherapy drugs and phototherapy drugs to ATC patients have become a hot research field. This review aims to describe latest findings of nanoparticle drug delivery systems in the treatment of ATCs, thus providing references for the further analyses.

Multifunctional Nanoplatform Based on Sunitinib for Synergistic Phototherapy and Molecular Targeted Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a tumor that poses a serious threat to human health, with an extremely low five-year survival rate due to its difficulty in early diagnosis and insensitivity to radiotherapy and chemotherapy. To improve the therapeutic efficiency of HCC, we developed a novel multifunctional nanoplatform (SCF NPs) with an amphiphilic polymer (Ce6-PEG2000-FA) and a multitarget tyrosine kinase inhibitor sunitinib. SCF NPs showed superior therapeutical efficiency for HCC due to the synergetic effect of molecular targeted therapy and phototherapy. The Ce6-PEG2000-FA not only serves as a nanocarrier with excellent biocompatibility but also can act as a therapeutic reagent for photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, the folic acid group of Ce6-PEG2000-FA enhanced the active targeting performance of SCF NPs. As a multitargeted tyrosine kinase inhibitor, sunitinib in SCF NPs can play a role in molecular targeted therapies, including tumor growth inhibition and anti-angiogenesis. In vivo experiments, SCF NPs showed multimode imaging capabilities, which can be used for tumorous diagnosis and intraoperative navigation. Meanwhile, SCF NPs showed outstanding synergetic tumor inhibition ability. Tumors of SCF NPs group with laser radiation were eradicated without any recrudescence after 14 days of treatment. Such theranostic nanoparticles offer a novel therapeutic tactic for HCC.

Nanomaterials based on phase change materials for antibacterial application.

Bacterial infections seriously threaten human health. Although antibiotics can significantly treat infectious diseases, antibiotics abuse has brought a series of serious problems, such as multidrug-resistant bacteria, adverse effects, and so on. Therefore, it is indispensable to develop alternative therapies with superior efficacy and minor toxicity to enhance the anti-infective outcome, overcome drug resistance and reduce adverse effects. The phase change material (PCM) is a substance that changes its physical properties with elevated temperatures. Nanoparticles based on PCM have been widely used in biomedical research due to their excellent biocompatibility, sustained release, and outstanding targeting properties. In this manuscript, the applications of PCM-based nanoparticles in the treatment of bacterial infections were summarized. Firstly, the composition and biotoxicity of PCM nanocarriers were described. Secondly, various antibacterial strategies based on PCM nanoparticles for combination therapy were highlighted. Finally, the prospects for antibacterial therapy of PCM nanomaterials were summarized.

Thrombin Based Photothermal-Responsive Nanoplatform for Tumor-Specific Embolization Therapy.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

Structural effect of NIR-II absorbing charge transfer complexes and its application on cysteine-depletion mediated ferroptosis and phototherapy.

Second near-infrared (NIR-II) absorbing organic photothermal agents (PTAs) usually suffer from laborious and time-consuming synthesis; therefore, it is of importance to develop a simple and easy-to-handle method for the preparation of NIR-II PTAs. Charge-transfer complexes (CTCs) can be easily used to construct NIR-II absorbing PTAs, although the relationship between their molecular structure and photophysical properties is yet to be uncovered. Herein, three kinds of electron donors with different substitutions (chloroethyl, ethyl, and methyl) were synthesized and assembled with electron-deficient F4TCNQ to afford corresponding CTC nanoparticles (Cl-F4, Et-F4, and Me-F4 NPs). The large energy gap (>0.61 eV) between HOMO of the donor and LUMO of the acceptor made the CTCs exhibit high charge transfer (>0.93) and dramatic differences in photophysical properties. Additionally, Et-F4 NPs possess the highest NIR-II absorption ability and best photothermal effect because of different packing modes (mass extinction coefficient of 11.0 L g-1 cm-1 and photothermal conversion efficiency of 40.2% at 1060 nm). The mixed stacking mode formed strong charge-transfer absorption bands, indicating that the photophysical properties of CTCs can be tailored by changing the molecular structure and aggregate behaviors. Furthermore, Et-F4 NPs with cyano groups could specifically react with cysteine to block the intracellular biosynthesis of GSH and result in ROS accumulation and ferroptosis. Et-F4 NPs possess outstanding antitumor efficacy for the combined actions of NIR-II triggered photothermal killing effect and ferroptosis in vivo.

Fe-Doped Polyoxometalate as Acid-Aggregated Nanoplatform for NIR-II Photothermal-Enhanced Chemodynamic Therapy.

The combination of reactive oxygen species-involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe-doped polyoxometalate (Fe-POM) cluster is fabricated via a simple method. The Fe-POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near-infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less-reactive H2 O2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self-assembling properties at lowered pH values, the Fe-POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe-POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT-enhanced CDT in a NIR-II biowindow.

Near-Infrared Light-Harvesting Fullerene-Based Nanoparticles for Promoted Synergetic Tumor Phototheranostics.

A synergetic phototheranostic system, combining diagnostic photo-imaging and phototherapies [such as photothermal therapy and photodynamic therapy (PDT)], shows great potential in today's tumor precise therapy. Herein, we fabricate near-infrared (NIR) light-harvesting fullerene-based nanoparticles (DAF NPs) for photoacoustic (PA) imaging-guided synergetic tumor photothermal and PDT. The fullerene derivatives (DAF) absorbing in the NIR region have been synthesized by conjugating NIR-absorbing antenna with fullerene. In addition, DAF NPs with good biocompatibility have been fabricated via a nanoprecipitation approach. The as-prepared DAF NPs can accumulate and generate PA signals around the tumor site 6 h post injection via enhanced permeability and retention effect in vivo. More importantly, the DAF NPs exhibit better reactive oxygen species and heat generation efficacy compared with fullerene and antenna nanoparticles (DA NPs), respectively. Further in vitro and in vivo studies demonstrate that DAF NPs can effectively inhibit tumor growth through synergetic photodynamic and photothermal therapies, which provides a new sight of photosensitizer design for enhanced cancer phototheranostics.

Penetration depth tunable BODIPY derivatives for pH triggered enhanced photothermal/photodynamic synergistic therapy.

Improving the deep-tissue phototherapy (PDT) efficiency in the near-infrared (NIR) region has become one of the major challenges in clinics for cancer treatment. Developing intelligent photosensitizers (PSs) responding to tumor-specific signals sensitively to minimize side effects is another major challenge for tumor phototherapy. Herein, three phenyl-based boron dipyrromethene (BODIPY) compounds with different numbers of diethylaminophenyl groups introduced onto the BODIPY core have been designed and synthesized by the Knoevenagel condensation reaction. The absorbance of these compounds (BDPmPh, BDPbiPh, and BDPtriPh) can be controlled easily for realizing the tunable penetration depth. Moreover, the diethylamino groups in these designed PSs can serve as proton acceptors triggered by the low pH in lysosomes which can enhance the efficacy of photodynamic and photothermal therapy. The corresponding nanoparticles (NPs) of the compounds are prepared through a nanoprecipitation method and in vitro studies demonstrate that the ultra-low drug dosage of BDPtriPh NPs (half-maximal inhibitory concentration, IC50 = 4.16 µM) is much lower than that of BDPmPh NPs (50.09 µM) and BDPbiPh NPs (22.4 µM). In vivo fluorescence imaging shows that these NPs can be passively targeted to tumors by the enhanced permeability and retention (EPR) effect, and BDPtriPh NPs exhibit the fastest accumulation (about 4 hours). In vivo phototherapy indicates that BDPtriPh NPs with the longest NIR absorbance (813 nm) and highest photothermal conversion efficiency (60.5%) can effectively inhibit tumor growth and reduce side effects to normal tissues. This study provides a strategy to modulate the photoconversion characteristics of PSs for both penetration-depth-tunable and pH-dependent PDT/PTT synergistic cancer therapy in clinics.

Hydrogen Peroxide Responsive Iron-Based Nanoplatform for Multimodal Imaging-Guided Cancer Therapy.

Cancer multimodal phototherapy triggered by hydrogen peroxide has attracted widespread attention as a dominating strategy to increase phototherapeutic efficiency. Herein, a hydrogen peroxide responsive iron oxide nanoplatform, with the diameter of about 50 nm, is fabricated to intracellularly trigger the Fenton reaction and achieve synergistic photodynamic therapy and photothermal therapy. The nanoplatform based on iron oxide nanoparticles is decorated with indocyanine green (ICG, photosensitizer) and hyaluronic acid (HA, targeting molecular) through electrostatic interaction, thus the as-prepared nanoplatform (IONPs-ICG-HA) exhibits excellent active targeting ability and biocompatibility. More importantly, it can effectively utilize the intratumoral overproduced hydrogen peroxide to generate reactive oxygen species for cancer cell killing via intracellular Fenton reactions. In vitro and in vivo experiments reveal that the IONPs-ICG-HA nanocomposites realize effective photoacoustic/photothermal/fluorescence imaging-guided phototherapy, leading to promising hydrogen peroxide responsive cancer theranostics.

A light-induced nitric oxide controllable release nano-platform based on diketopyrrolopyrrole derivatives for pH-responsive photodynamic/photothermal synergistic cancer therapy.

Emerging treatment approaches, such as gas therapy (GT), photodynamic therapy (PDT) and photothermal therapy (PTT), have received widespread attention. The development of an intelligent multifunctional nano-platform responding to tumor microenvironments for multimodal therapy is highly desirable. Herein, a near-infrared (NIR) light-responsive nitric oxide (NO) photodonor (4-nitro-3-trifluoromethylaniline, NF) and a pH-sensitive group (dimethylaminophenyl) have been introduced into a diketopyrrolopyrrole core (denoted as DPP-NF). The DPP-NF nanoparticles (NPs) can be activated under weakly acidic conditions of lysosomes (pH 4.5-5.0) to generate reactive oxygen species (ROS) and enhance photothermal efficiency. The fluorescence detection demonstrated that NO controllable release can be realized by "on-off" switching of the NF unit under NIR light irradiation or dark conditions. The controllable NO release of DPP-NF NPs can not only trigger tumor cell death by DNA damage, but also overcome PDT inefficiencies caused by hypoxia in tumors. Additionally, DPP-NF NPs displayed 45.6% photothermal conversion efficiency, making them superior to other reported DPP derivatives. In vitro studies showed that DPP-NF NPs possessed low dark toxicity and high phototoxicity with a half-maximal inhibitory concentration of about 38 µg mL-1. In vivo phototherapy indicated that DPP-NF NPs exhibited excellent tumor phototherapeutic efficacy with passive targeting of the tumor site via the enhanced permeability and retention (EPR) effect. These results highlight that the nano-platform has promising potential for NO-mediated multimodal synergistic phototherapy in clinical settings.

Triphenylamine flanked furan-diketopyrrolopyrrole for multi-imaging guided photothermal/photodynamic cancer therapy.

The combination of photodynamic therapy (PDT) and photothermal therapy (PTT) is highly desired to improve the cancer phototherapeutic effect. However, most reported multicomponent therapeutic agents need complex preparation processes and must be excited by using multiple light sources. Herein, triphenylamine flanked furan-diketopyrrolopyrrole (FDPP-TPA) with a donor-acceptor-donor structure has been synthesized and used as a sole-component agent for fluorescence, photoacoustic and photothermal imaging guided photodynamic and photothermal synergistic therapy. FDPP-TPA nanoparticles (NPs) obtained by re-precipitation exhibit a high molar extinction coefficient (ε = 2.13 (±0.2) × 104 M-1 cm-1), excellent photothermal conversion efficiency (η = 47%) and favorable singlet oxygen quantum yield (ΦΔ(X) = 40%). In vitro, the half-maximal inhibitory concentration (IC50) is 13 µg mL-1 determined by cytotoxicity assay. And the apoptosis rate is 67.3% according to flow cytometry analysis. In vivo, the tumor can be completely ablated without recurrence, which suggests that FDPP-TPA NPs can generate considerable poisonous singlet oxygen and hyperthermia for tumor treatment.

Production of fibrinolytic enzyme from Bacillus amyloliquefaciens by fermentation of chickpeas, with the evaluation of the anticoagulant and antioxidant properties of chickpeas.

To develop safe and cheap thrombolytic agents, a fibrinolytic enzyme productive strain of LSSE-62 was isolated from Chinese soybean paste. This strain was identified as Bacillus amyloliquefaciens by 16S rDNA sequence analysis. Nucleotide and amino acid sequence analysis showed that this fibrinolytic enzyme was identical to subtilisin DJ-4. Chickpeas were used as the substrate for fibrinolytic enzyme production from B. amyloliquefaciens in solid-state fermentation. Under the optimized conditions (34 °C and 50% initial moisture content), the fibrinolytic activity of fermented chickpeas reached 39.28 fibrin degradation units (FU)/g. Additionally, the fermented chickpeas showed anticoagulant activity, and the purified anticoagulant component showed higher anticoagulant activity than heparin sodium. After fermentation, the total phenolic and total flavonoid contents increased by 222 and 71%, respectively, and then the antioxidant activities were improved significantly. This study provided a novel method for the preparation of multifunctional food of chickpeas or raw materials for the preparation of functional food additives and potential drugs.