Nanoheterostructure by Liquid Metal Sandwich-Based Interfacial Galvanic Replacement for Cancer Targeted Theranostics.

Nanoheterostructures with exquisite interface and heterostructure design find numerous applications in catalysis, plasmonics, electronics, and biomedicine. In the current study, series core-shell metal or metal oxide-based heterogeneous nanocomposite have been successfully fabricated by employing sandwiched liquid metal (LM) layer (i.e., LM oxide/LM/LM oxide) as interfacial galvanic replacement reaction environment. A self-limiting thin oxide layer, which would naturally occur at the metal-air interface under ambient conditions, could be readily delaminated onto the surface of core metal (Fe, Bi, carbonyl iron, Zn, Mo) or metal oxide (Fe3 O4 , Fe2 O3 , MoO3 , ZrO2 , TiO2 ) nano- or micro-particles by van der Waals (vdW) exfoliation. Further on, the sandwiched LM layer could be formed immediately and acted as the reaction site of galvanic replacement where metals (Au, Ag, and Cu) or metal oxide (MnO2 ) with higher reduction potential could be deposited as shell structure. Such strategy provides facile and versatile approaches to design and fabricate nanoheterostructures. As a model, nanocomposite of Fe@Sandwiched-GaIn-Au (Fe@SW-GaIn-Au) is constructed and their application in targeted magnetic resonance imaging (MRI) guided photothermal tumor ablation and chemodynamic therapy (CDT), as well as the enhanced radiotherapy (RT) against tumors, have been systematically investigated.

Polypyrrole modification on BiVO4 for photothermal-assisted photoelectrochemical water oxidation.

The bismuth vanadate (BiVO4) photoanode receives extensive attention in photoelectrochemical (PEC) water splitting. However, the high charge recombination rate, low electronic conductivity, and sluggish electrode kinetics have inhibited the PEC performance. Increasing the reaction temperature for water oxidation is an effective way to enhance the carrier kinetics of BiVO4. Herein, a polypyrrole (PPy) layer was coated on the BiVO4 film. The PPy layer could harvest the near-infrared light to elevate the temperature of the BiVO4 photoelectrode and further improve charge separation and injection efficiencies. In addition, the conductive polymer PPy layer acted as an effective charge transfer channel to facilitate photogenerated holes moving from BiVO4 to the electrode/electrolyte interface. Therefore, PPy modification led to a significantly improved water oxidation property. After loading the cobalt-phosphate co-catalyst, the photocurrent density reached 3.64 mA cm-2 at 1.23 V vs the reversible hydrogen electrode, corresponding to an incident photon-to-current conversion efficiency of 63% at 430 nm. This work provided an effective strategy for designing a photothermal material assisted photoelectrode for efficient water splitting.

Synthesis of a Thermal-Responsive Dual-Modal Supramolecular Probe for Magnetic Resonance Imaging and Fluorescence Imaging.

Dual-modal imaging can integrate the advantages of different imaging technologies, which could improve the accuracy and efficiency of clinical diagnosis. Herein, a novel amphiphilic thermal-responsive copolymer obtained from three types of monomers, N-isopropyl acrylamide, 2-(acetoacetoxy) ethyl methacrylate, and propargyl methacrylate, by RAFT copolymerization, is reported. It can be grafted with ß-cyclodextrin and aggregation-induced emission (AIE) luminogens tetraphenylethylene by click chemistry and Biginelli reaction. The multifunctional supramolecular polymer (P4) can be constructed by host-guest inclusion between the copolymer and the Gd-based contrast agent (CA) modified by adamantane [Ad-(DOTA-Gd)]. And it can form vesicles with a bilayer structure in aqueous which will enhance the AIE and magnetic resonance imaging effects. As fluorescent thermometer, P4 can enter HeLa cells for intracellular fluorescence imaging (FI) and is sensitive to temperature with detection limit value of 1.5 °C. As magnetic resonance CA, P4 exhibits higher relaxation compared to Magnevist, which can prolong the circulation time in vivo. In addition, Gd3+ in the polymer can be quickly released from the body by disassembly that reduced the biological toxicity. This work introduces new synthetic ideas for dual-modal probe, which has great potential for clinical diagnostic applications in bioimaging.

Non-Magnetic Injectable Implant for Magnetic Field-Driven Thermochemotherapy and Dual Stimuli-Responsive Drug Delivery: Transformable Liquid Metal Hybrid Platform for Cancer Theranostics.

Transformable liquid metal (LM)-based materials have attracted considerable research interest in biomedicine. However, the potential biomedical applications of LMs have not yet been fully explored. Herein, for the first trial, the inductive heating property of gallium-indium eutectic alloy (EGaIn) under alterative magnetic field is systematically investigated. By virtue of its inherent metallic nature, LM possesses excellent magnetic heating property as compared to the conventional magnetite nanoparticles, therefore enabling its unique application as non-magnetic agents in magnetic hyperthermia. Moreover, the extremely high surface tension of LM could be dramatically lowered by a rather facile PEGylation approach, making LM an ideal carrier for other theranostic cargos. By incorporating doxorubicin (DOX)-loaded mesoporous silica (DOX-MS) within PEGylated LM, a magnetic field-driven transformable LM hybrid platform capable of pH/AFM dual stimuli-responsive drug release and magnetic thermochemotherapy are successfully fabricated. The potential application for breast cancer treatment is demonstrated. Furthermore, the large X-ray attenuation ability of LM endows the hybrid with the promising ability for CT imaging. This work explores a new biomedical use of LM and a promising cancer treatment protocol based on LM hybrid for magnetic hyperthermia combined with dual stimuli-responsive chemotherapy and CT imaging.

A Fully Biodegradable Battery for Self-Powered Transient Implants.

Biodegradable transient devices represent an emerging type of electronics that could play an essential role in medical therapeutic/diagnostic processes, such as wound healing and tissue regeneration. The associated biodegradable power sources, however, remain as a major challenge toward future clinical applications, as the demonstrated electrical stimulation and sensing functions are limited by wired external power or wireless energy harvesters via near-field coupling. Here, materials' strategies and fabrication schemes that enable a high-performance fully biodegradable magnesium-molybdenum trioxide battery as an alternative approach for an in vivo on-board power supply are reported. The battery can deliver a stable high output voltage as well as prolonged lifetime that could satisfy requirements of representative implantable electronics. The battery is fully biodegradable and demonstrates desirable biocompatibility. The battery system provides a promising solution to advanced energy harvesters for self-powered transient bioresorbable implants as well as eco-friendly electronics.

CD300LG improves the cytotoxic activity of CIK.

To investigate the effect of CD300LG-γ induction on the cytotoxic activity of CIK. Eukaryotic expression plasmid hCD300LG-γ/pEGFP-C3, which can express human CD300LG-γ, was constructed and transfected into CHO cells by lipofectamine. The expression of CD300LG-γ was confirmed by immunofluorescence, RT-PCR, and Western Blot. To produce CIK cells, human peripheral blood mononuclear cells (PBMC) were isolated and induced, respectively, by cell lysates extracted from hCD300LG-γ/CHO cells, pEGFP-C3/CHO cells, and CHO cells, concurrently with the standard CIK inductive agent. The cytotoxic activity of these CIK cells against hCD300LG-γ/CHO cells, pEGFP-C3/CHO cells, CHO cells, and K562 cells was tested. The results showed that eukaryotic expression of plasmid hCD300LG-γ/pEGFP-C3 was constructed and transfected into CHO cells successfully. After being induced by cell lysates, the cytotoxicity of hCD300LG-γ/CHO-CIK was improved compared with the other CIK cells. In particular, the activity of killing pEGFP-C3/CHO and CHO cells was improved significantly. Meanwhile, the activity of hCD300LG-γ/CHO-CIK killing K562 was improved significantly compared with the other CIK cells. The results indicated that hCD300LG-γ induction can significantly improve the killing activity of CIK cells.

Aggregation Induced Emission Fluorogens Based Nanotheranostics for Targeted and Imaging-Guided Chemo-Photothermal Combination Therapy.

Nanotheranostics for biomedical imaging-guided cancer therapy have attracted increasing interest due to their capabilities of both precise tumor diagnosis and high therapeutic efficacy. Among the diverse imaging models, fluorescence imaging have been extensively researched for their high sensitivity, simple operation, and low cost. In this work, aggregation induced emission (AIE) fluorogens based targeted nanotheranostics are facilely fabricated via paclitaxel (PTX) induced assembly of proteins for the first time. Thanks to the unique fluorescence property of AIE fluorogens PhENH2 , the prepared theranostic nanoplatforms can emit bright fluorescence even after being incorporated with the photothermal therapy agent polypyrrole (PPy), which will often decrease or quench the emission of common fluorescence dyes. The target moiety of cyclic arginine-glycine-aspartic acid (cRGD) endows the nanotheranostics with outstanding targeting ability, which can further facilitate the targeted imaging and cancer treatment. As revealed by the in vitro and in vivo experiments, the prepared nanotheranostics human serum albumin-PhENH2 -PPy-PTX-cRGD shows impressive performance in the targeted fluorescence imaging even after intravenous injection for 48 h, and their combined chemo-photothermal therapy is also very effective. These results indicate that AIE fluorogens based nanotheranostics would find a promising prospect in further improved multimodal imaging and imaging guided cancer treatment.

2-Deoxy-D-Glucose Modified Magnetic Nanoparticles with Dual Functional Properties: Nanothermotherapy and Magnetic Resonance Imaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) with appropriate surface chemistry have attracted wild attention in medical and biological application because of their current and potential usefulness such as magnetic resonance imaging (MRI) contrast enhancement, magnetic mediated hyperthermia (MMH), immunoassay, and in drug delivery, etc. In this study, we investigated the MRI contrast agents and MMH mediators properties of the novel 2-deoxy-D-glucose (2-DG) modified SPIONs. As a non-metabolizable glucose analogue, 2-DG can block glycolysis and inhibits protein glycosylation. Moreover, SPIONs coated with 2-DG molecules can be particularly attractive to resource-hungry cancer cells, therefore to realize the targeting strategy for the SPIONs. SPIONs with amino silane as the capping agent for amino-group surface modification were synthesized by the chemical co-precipitation method with modification. Glutaraldehyde was further applied as an activation agent through which 2-DG was conjugated to the amino-coated SPIONs. Physicochemical characterizations of the 2-DG-SPIONs, such as surface morphology, surface charge and magnetic properties were investigated by Transmission Electron Microscopy (TEM), ζ-Potential and Vibrating Sample Magnetometer (VSM), etc. Magnetic inductive heating characteristics of the 2-DG-SPIONs were analyzed by exposing the SPIONs suspension (magnetic fluid) under alternative magnetic field (AMF). U-251 human glioma cells with expression of glucose transport proteins type 1 and 3 (GLUT1 and GLUT 3), and L929 murine fibroblast cell as negative control, were employed to study the effect of 2-DG modification on the cell uptake for SPIONs. TEM images for ultra-thin sections as well as ICP-MS were applied to evaluate the SPIONs internalization within the cells. In vitro MRI was performed after cells were co-incubated with SPIONs and the T2 relaxation time was measured and compared. The results demonstrate that 2-DG-SPIONs were supermagnetic and in spherical shape with -10 nm diameter. Possessing ideal magnetic inductive heating characteristics, which can generate very rapid and efficient heating while upon AMF exposure, 2-DG-SPIONs can be applied as novel candidature of magnetic nanothermotherapy for cancer treatment. Modification of 2-DG can greatly promote the cell uptake of SPIONs and such cellular uptake of 2-DG-SPIONs was time dependent. Surface coating by 2-DG can remarkably enhance the MR imaging ability for the SPIONs on the cells of U251 cancer cells. In summary, our investigation provides a novel glucose analogue modified SPIONs with potential application in the targeting cancer nanothermotherapy and MR imaging.

GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy.

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP-Van@IR780 NPs). SP-Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP-Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP-Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection.

Drug delivery systems for enhanced tumour treatment by eliminating intra-tumoral bacteria.

Cancer remains one of the serious threats to human health. The relationship between bacteria and various tumours has been widely reported in recent years, and studies on intra-tumoral bacteria have become important as intra-tumoral bacteria directly affect the tumorigenesis, progression, immunity and metastatic processes. Therefore, eliminating these commensal intra-tumoral bacteria while treating tumour is expected to be a potential strategy to further enhance the clinical outcome of tumour therapy. Drug delivery systems (DDSs) are widely used to deliver antibiotics and chemotherapeutic drugs for antibacterial and anticancer applications, respectively. Thus, this review firstly provides a comprehensive summary of the association between intra-tumoral bacteria and a host of tumours, followed by a description of advanced DDSs for improving the therapeutic efficacy of cancer treatment through the elimination of intra-tumoral bacteria. It is hoped that this review will provide guidelines for the therapeutic and "synergistic antimicrobial and antitumour" drug delivery strategy.

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis.

Cell necroptosis has presented great potential, acting as an effective approach against tumor apoptotic resistance, and it could be further enhanced via accompanying reactive oxygen species (ROS) overexpression. However, whether overproduced ROS assists the necroptotic pathway remains unclear. Thus, iron-palladium nanozyme (FePd NZ)- and shikonin (SKN)-encapsulated functional lipid nanoparticles (FPS-LNPs) were designed to investigate the ROS overexpression-enhanced SKN-induced necroptosis. In this system, SKN acts as an effective necroptosis inducer for cancer cells, and FePd NZ, a sensitive Fenton reaction catalyst, produces extra-intracellular ROS to reinforce the necroptotic pathway. Both in vitro and in vivo antitumor evaluation revealed that FPS-LNPs presented the best tumor growth inhibition efficacy compared with FP-LNPs or SKN-LNPs alone. Meanwhile, induced necroptosis by FPS-LNPs can further trigger the release of damage-associated molecular patterns (DAMPs) and antigens from dying tumor cells to activate the innate immune response. Taking biosafety into consideration, this study has provided a potential nanoplatform for cancer nanotherapy via inducing necroptosis to avoid apoptosis resistance and activate CD8+ T cell immune response.

Poly(d-amino acid) Nanoparticles Target Staphylococcal Growth and Biofilm Disassembly by Interfering with Peptidoglycan Synthesis.

d-Amino acids are signals for biofilm disassembly. However, unexpected metabolic pathways severely attenuate the utilization of d-amino acids in biofilm disassembly, resulting in unsatisfactory efficiency. Herein, three-dimensional poly(d-amino acid) nanoparticles (NPs), which possess the ability to block intracellular metabolism, are constructed with the aim of disassembling the biofilms. The obtained poly(α-N-acryloyl-d-phenylalanine)-block-poly(ß-N-acryloyl-d-aminoalanine NPs (denoted as FA NPs) present α-amino groups and α-carboxyl groups of d-aminoalanine on their surface, which guarantees that FA NPs can effectively insert into bacterial peptidoglycan (PG) via the mediation of PG binding protein 4 (PBP4). Subsequently, the FA NPs trigger the detachment of amyloid-like fibers that connect to the PG and reduce the number of polysaccharides and proteins in extracellular polymeric substances (EPS). Finally, FA NPs damage the structural stability of EPS and lead to the disassembly of the biofilm. Based on this feature, FA NPs significantly enhance the killing efficacy of encapsulated sitafloxacin sesquihydrate (Sita) by facilitating the penetration of Sita within the biofilm, achieving complete elimination of Staphylococcal biofilm in mice. Therefore, this study strongly demonstrates that FA NPs can effectively improve biofilm disassembly efficacy and provide great potential for bacterial biofilm infection treatment.

Intracellular Criegee's mechanism-based synergistic ozone therapy mediated by oleogels for cancer treatment.

Broad cellular components-initiated efficient chemical reactions that occur in malignant cells may contribute to exploring emerging strategies for cancer treatment. Herein, an ozonated oleogel (OG(O)) was developed to achieve cancer ozone therapy (O3-T) based on intracellular Criegee's reaction. By integrating the chemo-drug, the ozone-loaded oleogel (Dox@OG(O)) was prepared as a chemotherapeutic agent for local O3-T, associated with chemotherapy (CT)/radiotherapy (RT)/immunotherapy and wound healing. The in vitro results showed that, Dox@OG(O) could achieve high ozone loading efficiency and ensure its stability. This Oleogel-mediated O3-T could directly destroy tumor cells via intracellular Criegee's reaction occurred on cell membranes, as well as the effects of tumor microenvironment (TME) regulation by the generation of oxygen/reactive oxygen species (ROS) and depletion of glutathione (GSH). Meanwhile, under the stimulation of X-ray, an accelerated free radical's production was observed, further combined with the radio-sensitivity after TME regulation, an effective anti-tumor effect would be achieved. Further on, in vivo results demonstrated that the locally implanted Dox@OG(O) could effectively inhibit the growth of both primary and secondary tumors. Considering these results above, it will serve as inspiration for future studies investigating of O3-T, especially for postoperative skin diseases.

Cancer nutritional-immunotherapy with NIR-II laser-controlled ATP release based on material repurposing strategy.

Enlightened by the great success of the drug repurposing strategy in the pharmaceutical industry, in the current study, material repurposing is proposed where the performance of carbonyl iron powder (CIP), a nutritional intervention agent of iron supplement approved by the US FDA for iron deficiency anemia in clinic, was explored in anti-cancer treatment. Besides the abnormal iron metabolic characteristics of tumors, serving as potential targets for CIP-based cancer therapy under the repurposing paradigm, the efficacy of CIP as a catalyst in the Fenton reaction, activator for dihydroartemisinin (DHA), thus increasing the chemo-sensitivity of tumors, as well as a potent agent for NIR-II photothermal therapy (PTT) was fully evaluated in an injectable alginate hydrogel form. The CIP-ALG gel caused a rapid temperature rise in the tumor site under NIR-II laser irradiation, leading to complete ablation in the primary tumor. Further, this photothermal-ablation led to the significant release of ATP, and in the bilateral tumor model, both primary tumor ablation and inhibition of secondary tumor were observed simultaneously under the synergistic tumor treatment of nutritional-photothermal therapy (NT/PTT). Thus, material repurposing was confirmed by our pioneering trial and CIP-ALG-meditated NT/PTT/immunotherapy provides a new choice for safe and efficient tumor therapy.

Apoptosis and Paraptosis Induced by Disulfiram-Loaded Ca2+/Cu2+ Dual-Ions Nano Trap for Breast Cancer Treatment.

Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)-copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.

In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor.

Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.

Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase.

1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.

Acidity-Triggered Charge-Convertible Conjugated Polymer for Dihydroartemisinin Delivery and Tumor-Specific Chemo-Photothermal Therapy.

Since the nonspecificity and nonselectivity of traditional treatment models lead to the difficulty of cancer treatment, nanobased strategies are needed to fill in the gaps of current approaches. Herein, a tumor microenvironment (TME)-responsive chemo-photothermal treatment model was developed based on dihydroartemisinin (DHA)-loaded conjugated polymers (DHA@PLGA-PANI). The synthesized DHA@PLGA-PANI exhibited enhanced photothermal properties under mild-acidic conditions and thus triggered local heat at the tumor site. Meanwhile, these iron-doped conjugated polymers of PLGA-PANI were used as the source of Fe, and benefiting from the Fe-dependent cytotoxicity of DHA, the burst of free radicals could be generated in tumors. Therefore, the combination of TME-responsive chemo-photothermal therapy could achieve effective tumor efficacy.

Physical Dissolution Combined with Photodynamic Depletion: A Two-Pronged Nanoapproach for Deoxygenation-Driven and Hypoxia-Activated Prodrug Therapy.

Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic-co-glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, in vivo experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.

Ultrafast Fabrication of Iron/Manganese Co-Doped Bismuth Trimetallic Nanoparticles: A Thermally Aided Chemodynamic/Radio-Nanoplatform for Low-Dose Radioresistance.

Low-dose radioresistance continues to be one of the major limitations for clinical curative treatment of cancer. Luckily, nanotechnology mediated by multifunctional nanomaterials provides potential opportunity to relieve the radioresistance via increasing the radiosensitivity of cancer cells. Herein, an ultrafast fabrication strategy is reported to prepare iron/manganese co-doped bismuth trimetallic nanoparticles (pFMBi NPs) as a multifunctional radiosensitizer for combined therapy. The bismuth matrix provides the intrinsic radiosensitization effect under the low and safe radiation dose via Auger electrons, photoelectrons, and Rayleigh scattering. Meanwhile, co-doping of iron and manganese ions endows pFMBi NPs with both the Fenton reaction property for reactive oxygen species (ROS) generation and photothermal conversion performance for heat production. Additional ROS generation enhances the radiosensitization effect by collaborating with Rayleigh scattering-mediated water radiolysis, and endogenous heat production under near-infrared 808 nm laser irradiation makes DNA more sensitive to radiation and ROS damage. Both in vitro and in vivo evaluations demonstrate the effective antitumor and radiosensitization effects via thermally aided chemodynamic/radiotreatment with a low radiation dose (6 Gy). Therefore, this work provides a potential strategy for overcoming the low-dose radioresistance in cancer therapy.