Synergistic Tumor Therapy Research Articles

Tumor-targeted glycogen nanoparticles loaded with hemin and glucose oxidase to promote tumor synergistic therapy

Strategies which are used to address the low levels of intracellular hydrogen peroxide and the development of biocompatible catalysts still need to be fulfilled in tumor chemodynamic therapy. Therefore, a novel tumor-targeted glycogen-based nanoparticle system (GN/He/GOx/HA) was developed to co-deliver hemin (He) and GOx, which can self-supply glucose formed upon degradation of glycogen by α-glycosidase in the lysosome environment, in order to achieve synergistic antitumor therapy. Hyaluronic acid (HA) was selected as the outer shell to protect the activity of GOx, and to increase the uptake by tumor cells via CD44 receptor-mediated endocytosis. GN/He/GOx/HA NPs had a good stability in the blood circulation, but fast release of the therapeutic cargos upon intracellular uptake. Hemin had a cascade catalytic reaction with GOx. Furthermore, GN/He/GOx/HA NPs had the strongest cytotoxicity in Hela cells in a glucose concentration dependent manner. The NPs could efficiently produce reactive oxygen species in tumor cells, resulting in a decrease in the mitochondrial membrane potential and apoptosis of tumor cells. The in vivo results showed that the drug-loaded nanoparticles had good safety, biocompatibility, and efficacious antitumor effect. Therefore, the glycogen-based nanoparticle delivery system provides potential application for self-enhancing CDT, which can be used for effective antitumor therapy.

α-Fe2O3@Au-PEG-Ce6-Gd Nanoparticles as Acidic H2O2-Driven Oxygenators for Multimodal Imaging and Synergistic Tumor Therapy.

Nanoparticles with visual imaging capabilities and synergistic therapeutics have a bright future in antitumor applications. However, most of the current nanomaterials lack multiple imaging-guided therapeutic capabilities. In this study, a novel enhanced photothermal photodynamic antitumor nanoplatform with photothermal imaging, fluorescence (FL) imaging, and MRI-guided therapeutic capabilities was constructed by grafting gold, dihydroporphyrin Ce6, and Gd onto α-iron trioxide. This antitumor nanoplatform can convert NIR light into local hyperthermia at a temperature of up to 53 °C under NIR light irradiation, while Ce6 can generate singlet oxygen, which further synergizes the tumor-killing effect. At the same time, α-Fe2O3@Au-PEG-Ce6-Gd can also have significant photothermal imaging effect under light irradiation, which can guide to see the temperature change near the tumor tissue. It is worth noting that α-Fe2O3@Au-PEG-Ce6-Gd can have obvious MRI and FL imaging effects after tail vein injection in mice with blood circulation, realizing imaging-guided synergistic antitumor therapy. α-Fe2O3@Au-PEG-Ce6-Gd NPs provide a new solution for tumor imaging and treatment.

Disulfide-Bridged Dendritic Organosilicas-Based Biodegradable Molecularly Imprinted Polymers for Multiple Targeting and pH/Redox-Responsive Drug Release toward Chemical/Photodynamic Synergistic Tumor Therapy.

In this study, a sialic acid (SA) and transferrin (TF) imprinted biodegradable disulfide bridging organosilicas-based drug delivery system (SS-DMONS/DOX-Ce6@MIPs) for targeted cancer therapy is constructed, for the first time. Disulfide bridged dendritic mesoporous organosilicas nanoparticles (SS-DMONs) not only enhance drug loading as the drug repository, but also provide enough specific surface area for the molecular imprinting shell to expose more degradation and imprinted sites on the surface. In addition, SS can be disturbed in a highly reducing tumor microenvironment to achieve degradation. The biodegradable imprinting film, prepared with customized 2-amino-N-(3,4-dihydroxyphenethyl)-3-mercaptopropanamide and 4-mercaptophenylboronic acid as functional monomers, endows SS-DMONs with active targeting capacity, and responsive drug release through degradation under acidic and highly reductive tumor microenvironment. SS-DMONS/DOX-Ce6@MIPs after binding of TF can target tumor cells actively through multiple interactions, including the affinity between antigen and antibody, and the specific recognition between molecularly imprinted polymers and template molecules. Under laser irradiation the loaded chlorin e6 (Ce6) that can produce toxic reactive oxygen, combined with the doxorubicin (DOX), achieves chemical/photodynamic synergistic anticancer effects. SS-DMONS/DOX-Ce6@MIPs present excellent tumor targeting and dual-responsive drug release, which provides an effective strategy for chemical/photodynamic antitumor therapy.

Multiple in-situ reactions induced by biodegradable iodides: A synergistically chemodynamic-photothermal therapy platform

Integrating multifunctional nanostructures and effectively modulating the tumor microenvironment (TME) is a need for precision nanotherapy. In this work, cuprous iodide-palladium iodides (CPIs) nanoenzymes were designed for infrared thermal (IR) and computed tomography (CT) imaging-guided synergistic chemodynamic-photothermal therapy (CDT and PTT) of tumor. CPIs act as peroxidase (POD)-like enzymes to catalyze the generation of hydroxyl radicals (OH) from endogenous H2O2, and also reduce the excess glutathione (GSH) in the TME to relieve tumor antioxidant ability, which enhance the effect of CDT. More importantly, due to the promoted non-radiative recombination of carries, the CPIs shift the light absorption range to the near-infrared region and confer higher photothermal conversion efficiency (47.72%), which improves the photothermal therapeutic effect and accelerate the generation rate of OH. Furthermore, the CT images exhibited by CPIs can help guide synergistic CDT/PTT treatment due to the high X-ray attenuation coefficient of the I-element. Finally, based on the dual oxidation of Cu(Ⅰ) and I(Ⅰ), the CPIs can be degraded to avoid long-term toxicity after inhibiting tumor growth. All in all, this nanotherapeutic platform constructed by iodides provide a possibility to simultaneously meet the biodegradability and imaging-guided synergistic chemodynamic-photothermal therapy.

Synergistic Apoptosis-Ferroptosis: Oxaliplatin loaded amorphous iron oxide nanoparticles for High-efficiency therapy of orthotopic pancreatic cancer and CA19-9 levels decrease

Pancreatic cancer is a highly malignant tumor with early metastasis, poor prognosis, and resistant to existing chemotherapy drugs such as oxaliplatin (Oxp). Therefore, a nanodrug of amorphous iron oxide packaged Oxp (AIOoxp) was proposed to achieve a more efficient treatment of orthotopic pancreatic cancer than that of free Oxp. The obtained AIOoxp increased the accumulation of Pt at tumor sites and effectively reduced Oxp-induced systemic toxicity. In addition, the Fe2+/Fe3+ ions released by AIOoxp react with H2O2 through Fenton’s reaction and produce a large amount of reactive oxygen species (ROS), which further induce ferroptosis, thus promoting Oxp-induced apoptosis and achieve synergistic tumor therapy. Furthermore, AIOoxp nanoplatforms can significantly reduce the levels of carbohydrate antigen 19–9 (CA19-9), which is the most important biomarker and promoter of pancreatic cancer, suggesting favorable therapeutic effects and prognosis. Overall, this study provides new insights and solutions for the clinical treatment of pancreatic cancer.

Enzyme functionalized PEOz modified magnetic polydopamine with enhanced penetration for cascade-augmented synergistic tumor therapy

In recent years, reactive oxygen species (ROS)-mediated cancer therapies have been widely recognized for their high selectivity and good biological safety. However, due to the difficulties of endogenous tumor microenvironment (TME), penetration of tumor tissues and integration of multimodal tumor ablation, the treatment with traditional therapies could not achieve satisfactory tumor inhibition effects. Here, a doxorubicin (DOX)-glucose oxidase (GOx) dual-loaded and poly (2-ethyl-2-oxazoline) (PEOz) decorated magnetic polydopamine nanoparticles (Fe3O4-DOX@PDA-GOx@PEOz, FDPGP) were constructed for tumor ablation. GOx-mediated cascade enzyme reactions could amplify oxidative stress damage and further synergistically inhibit breast cancer. Its pH-responsive charge reversal, drug-controlled release, photothermal, and cascade reactions were evaluated through extracellular experiments. Cellular uptake, cell cytotoxicity, tumor penetration and therapeutic efficacy of FDPGP were investigated through intracellular experiments. Finally, in vivo distribution, photothermal, synergistic antitumor therapeutic effect and biosafety were evaluated comprehensively by in vivo experiments. Excitingly, outstanding tumor enrichment and penetration, superior anticancer effects and biosafety were achieved by the combination of photothermal therapy (PTT)/starvation therapy (ST)/chemodynamic therapy (CDT)/chemotherapy (CT). As such, the FDPGP nanoplatform provides a new insight into the development of collaboratively multimodal enhanced tumor therapy.

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy.

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.

Tumor microenvironment-responsive artesunate loaded Z-scheme heterostructures for synergistic photo-chemodynamic therapy of hypoxic tumor

Tumor microenvironment (TME) with the particular features of severe hypoxia, insufficient endogenous H2O2, and overexpression of glutathione (GSH) markedly reduced the antitumor efficacy of monotherapy. Herein, a TME-responsive multifunctional nanoplatform (Bi2S3@Bi@PDA-HA/Art NRs) was presented for synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and photodynamic therapy (PDT) to achieve better therapeutic outcomes. The Z-scheme heterostructured bismuth sulfide@bismuth nanorods (Bi2S3@Bi NRs) guaranteed excellent photothermal performance of the nanoplatform. Moreover, its ability to produce O2 and reactive oxygen species (ROS) synchronously could relieve tumor hypoxia and improve PDT outcomes. The densely coated polydopamine/ammonium bicarbonate (PDA/ABC) and hyaluronic acid (HA) layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ “bomb-like” release of Art. The CDT treatment was achieved by activating the released Art through intracellular Fe2+ ions in an H2O2-independent manner. Furthermore, decreasing the glutathione peroxidase 4 (GPX4) levels by Art could also increase the PDT efficiency of Bi2S3@Bi NRs. Owing to the synergistic effect, this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo. Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.

Hollow Nanoporous Prussian Blue Nanocubes Enriched with Cu2+ and Loaded with Quercetin for Synergistic Tumor Therapy

Combination therapy based on Prussian blue nanoparticles (PB NPs) is particularly effective in cancer because of their outstanding photothermal properties and excellent biocompatibility. However, the application of PB in tumor therapy is hindered by their poor reactive oxygen species (ROS) production capacity, and low drug loading rate. More importantly, PB NPs could activate heat shock proteins (HSPs) in photothermal therapy, which induces the self-protection of tumor cells. Structural and functional modulation improved antitumor efficacy by enhancing reactive oxygen species (ROS) production and inhibiting heat shock protein expression. In this work, we synthesized Cu2+-enriched hollow nanoporous PB nanocubes (Cu-HNPB NCs) that enhanced the •OH generating capability of PB as Cu hybridization increases the oxidation potential of PB. Moreover, in the tumor milieu, Cu2+ release depletes glutathione (GSH) and converts to Cu+, further improving ROS levels. Excess ROS amplifies cellular oxidative stress and destroys the heat-induced formation of HSPs, thus breaking the self-protection mechanism of tumor cells. To enhance the therapeutic efficiency, quercetin (QUE) was loaded in Cu-HNPB NCs (Cu-HNPB@QUE NCs). Surprisingly, the large specific surface area (127.79 m2 g–1) endowed Cu-HNPB NCs with ultrahigh loading capacity (57.25%). As the nanoplatform enhances synergistic therapeutic effects, this study provides a new approach for designing multimodal combination nanomedicine.

Novel nanocarrier for promoting tumor synergistic therapy by down-regulation of heat shock proteins and increased Fe3+ supply

Novel nanocarrier for promoting tumor synergistic therapy by down-regulation of heat shock proteins and increased Fe3+ supply

Fe(III)-Naphthazarin Metal-Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis-Apoptosis Combined Cancer Therapy.

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H2 O2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one-step strategy for the construction of Fe3+ -naphthazarin metal-phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH2 -PEG-NH2 , is developed. The carrier-free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe3+ , which is further reduced to Fe2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)-triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe2+ as a T1 -weighted contrast agent endows the FNP MPNs with magneticresonanceimaging(MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.

A sequential delivery system based on MoS2 nanoflower doped chitosan/oxidized dextran hydrogels for colon cancer treatment

A sequential delivery system based on MoS2 nanoflower (MoS2 NF) doped chitosan (CS)/oxidized dextran (OD) hydrogels is developed for the treatment of colon cancer. 5-Fluorouracil (5-FU) is combined with polyethylenimine (PEI) decorated MoS2 NF via electrostatic attraction and hydrogen bonding, and the obtained 5-FU/PEI/MoS2 is encapsulated by 1-tetradecanol (TD), a commonly used phase transition material. The resultant TD/5-FU/PEI/MoS2 (TFPM) is then co-encapsulated with methotrexate (MTX) in the CS/OD hydrogels generated via Schiff base reaction and electrostatic attraction. Because the electrostatic attraction between CS and OD is pH-sensitive, MTX and TD/5-FU/PEI/MoS2 can be easily released from the hydrogels at pH 7.4. MoS2 is an outstanding photothermal agent, and the generated hyperthermia under near infrared (NIR) irradiation can lead to the melting of TD and the consequent release of 5-FU encapsulated. More importantly, the generated hyperthermia under NIR irradiation can realize the chemo-photothermal synergistic tumor therapy. Finally, the practicability of the developed sequential delivery system is demonstrated by cytotoxicity test.

Photoactive Oligomer with an Acceptor–Donor–Acceptor-Conjugated Structure for Single Near-Infrared Light-Triggered Photothermal/Photodynamic Synergistic Therapy of Tumors

Phototherapy is attracting increasing attention as a noninvasive, safe, and effective therapeutic modality for tumors. Especially, it is expected to achieve better therapeutic efficacy, fewer side effect, and deeper tissue penetration by the combination of photothermal (PTT) and photodynamic (PDT) under single near-infrared (NIR) light irradiation. For this purpose, herein, we develop a photoactive acceptor (A)–donor (D)–acceptor (A)-type conjugated oligomer (UF-TTOEH-2Cl). A NIR light-responsive nanoplatform (UTNPs) was fabricated based on UF-TTOEH-2Cl, and a folic acid-functionalized amphiphilic block copolymer (FA-PEG-PBLA10) was prepared as the polymer matrix through a nanoprecipitation method, which showed a high photothermal conversion efficiency (42%) and singlet oxygen (1O2) quantum yield (ΦΔ = 17.2%) under 880 nm laser irradiation. Furthermore, efficient UTNPs-based PDT/PTT synergistic therapy of tumors was demonstrated utilizing HeLa and SiHa cells as the models in vitro.

A biodegradable covalent organic framework for synergistic tumor therapy.

Stimulus-responsive biodegradable nanocarriers with tumor-selective targeted drug delivery are critical for cancer therapy. Herein, we report for the first time a redox-responsive disulfide-linked porphyrin covalent organic framework (COF) that can be nanocrystallized by glutathione (GSH)-triggered biodegradation. After loading 5-fluorouracil (5-Fu), the generated nanoscale COF-based multifunctional nanoagent can be further effectively dissociated by endogenous GSH in tumor cells, releasing 5-Fu efficiently to achieve selective chemotherapy on tumor cells. Together with the GSH depletion-enhanced photodynamic therapy (PDT), an ideal synergistic tumor therapy for MCF-7 breast cancer via ferroptosis is achieved. In this research, the therapeutic efficacy was significantly improved in terms of enhanced combined anti-tumor efficiency and reduced side effects by responding to significant abnormalities such as high concentrations of GSH in the tumor microenvironment (TME).

Photo-/piezo-activated ultrathin molybdenum disulfide nanomedicine for synergistic tumor therapy.

Molybdenum disulfide (MoS2), as a transition metal dichalcogenide, has attracted tremendous attention owing to its remarkable electronic, physical, and chemical properties. In this study, based on the energy-converting nanomedicine, we report multifunctional two-dimensional (2D) MoS2 nanosheets with inherent plasmonic property and piezocatalytic activity for imaging-guided synergistic tumor therapy. MoS2 nanosheets display strong plasmon resonances in the near-infrared (NIR) region, especially in the second NIR biological window, possessing a notable light energy to heat effect under 1064 nm laser irradiation, which not only serves as a robust photothermal agent for cancer cell ablation but also acts as a contrast-enhanced agent for thermal imaging and photoacoustic imaging. Meanwhile, MoS2 nanosheets feature a remarkable piezotronic effect, exhibiting mechanical vibration energy to electricity under the stimulation of ultrasound-mediated microscopic pressure for reactive oxygen species generation to further kill cancer cells. The new function for old materials may open up the in-depth exploration of MoS2-based functional biomaterials in the future clinical application of imaging-guided photothermal and piezocatalytic synergetic treatment.

Nucleus-selective self-augmenting cascade nanoassemblies for targeted synergistic photo-chemo therapy of tumors.

A nucleus-targeted enzyme prodrug nanocomposite, assembled from β-cyclodextrin-lysine (CL), catalase (CAT), Pt(IV) and chlorin e6 (Ce6), was developed for self-augmenting cascade photo-chemo therapy of tumors. It can effectively transport through the cytoplasm and accumulate in the nucleus, thereby significantly inhibiting tumor growth and lung metastasis.

Light-initiated aggregation of gold nanoparticles for synergistic chemo-photothermal tumor therapy.

The combination of chemotherapy with photothermal therapy (PTT) has attracted extensive attention due to its excellent synergetic effect attributing to the fact that hyperthermia can effectively promote the tumor uptake of chemotherapeutic drugs. Herein, we propose a light-initiated gold nanoparticle (AuNP) aggregation boosting the uptake of chemotherapeutic drugs for enhanced chemo-photothermal tumor therapy. Novel light-responsive AuNPs (tm-AuNPs) were rationally designed and fabricated by conjugating both 2,5-diphenyltetrazole (Tz) and methacrylic acid (Ma) onto the surface of AuNPs with small size (∼20 nm). Upon the irradiation of 405 nm laser, AuNPs could be initiated to form aggregates specifically within tumors through the covalent cycloaddition reaction between Tz and Ma. Taking advantage of the controllable photothermal effect of Au aggregates under NIR excitation, improved enrichment of doxorubicin (DOX) in tumor tissues was realized, combined with PTT, resulting in outstanding synergetic anti-tumor efficacy in living mice. We thus believe that this light-initiated AuNP aggregation approach would offer a valuable and powerful tool for precisely synergistic chemo-photothermal tumor therapy.

Calcination-controlled performance optimization of iron-vanadium bimetallic oxide nanoparticles for synergistic tumor therapy.

Calcination has been widely demonstrated as a favorable protocol for producing various inorganic nanomaterials for tumor therapy. However, little attention has been paid to its effect on the biotherapeutic efficacy of inorganic nanomaterials. Herein, we compare the effects of different calcination atmospheres on the therapeutic efficacy of Fe-V-O (FVO) nanomaterials. We find that compared with FVO nanomaterials synthesized by calcination in air, those prepared by argon calcination have a lower metallic valence state and a higher near-infrared light absorption capacity, hence resulting in significantly better biosafety and higher chemodynamic therapy (CDT)/photothermal therapy (PTT) efficacy. This study demonstrates that the therapeutic efficacy of inorganic nanomaterials can be optimized by employing different thermal treatment atmospheres, which provides new insights into the development of efficient anti-tumor agents.

Dual enzyme-like Co-FeSe2 nanoflowers with GSH degradation capability for NIR II-enhanced catalytic tumor therapy.

Nanozymes mediated catalytic therapy can produce toxic reactive oxygen species (ROS) and destroy the metabolic balance of tumor cells, providing a new direction for cancer treatment. However, the catalytic efficiency of a single nanozyme is limited by the complexity of the tumor microenvironment (hypoxia, GSH overexpression, etc.). In order to overcome these problems, we designed flower-like Co-doped FeSe2 (Co-FeSe2) nanozymes by a simple wet chemistry method. Co-FeSe2 nanozymes not only exhibit high POD and OXD-mimicking activities for facile kinetics, but also effectively consume over-expressed glutathione (GSH), inhibiting the consumption of generated ROS and destroying the metabolic balance of the tumor microenvironment. These catalytic reactions trigger cell death through apoptosis and ferroptosis dual pathways. More importantly, under the NIR II laser irradiation, the catalytic activities of Co-FeSe2 nanozymes are boosted, confirming the photothermal and catalytic synergistic tumor therapy. This study takes advantage of self-cascading engineering that offers new ideas for designing efficient redox nanozymes and promoting their clinical translation.

Cascade biomimetic intelligent nanotheranostic agents for imaging-guided tumor synergistic therapy.

Aim: Achieving drug-targeting delivery and environment-responsive releasing to realize imaging-guided precise tumor therapy. Materials & methods: Graphene oxide (GO) was used as the drug-delivery system to load indocyanine green (ICG) and doxorubicin (DOX) to form a GO/ICG&DOX nanoplatform, inwhich GOcan quench the fluorescence of ICG and DOX. MnO2 and folate acid-functionalized erythrocyte membrane were further coated into the surface of GO/ICG&DOX to obtain an FA-EM@MnO2-GO/ICG&DOX nanoplatform. Results: The FA-EM@MnO2-GO/ICG&DOX nanoplatform has longer blood circulation time, precise targeting delivery to tumor tissues and catalase-like activity. Both in vitro and in vivo results demonstrated that the FA-EM@MnO2-GO/ICG&DOX nanoplatform has better therapeutic efficacy. Conclusion: The authors successfully fabricated a glutathione-responsive FA-EM@MnO2-GO/ICG&DOX nanoplatform, which can achieve drug-targeting delivery and precise drug release.