Efficient Antitumor Effect Research Articles

Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform

The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.

Metabolic regulating enhanced immunological activating nanocomposites for tumor microenvironment normalization and immunotherapy

The mitochondrial energy metabolic reprogramming of tumors leads to the hypoxic, acidic, and immunosuppressive microenvironment. To regulate the reprogrammed mitochondrial energy metabolism and the abnormal tumor microenvironment (TME) intracellularly and extracellularly, herein, we purposely constructed the metabolic regulating and immunological activating nanocomposites (NCs) formed by the manganese dioxide (MnO2) nanoparticles loaded with lactate oxidase (LOX), dichloroacetic acid (DCA) and SR-717, camouflaged by the cell membrane of tumors. After the NCs targeting to the tumors, the loaded DCA inhibited the glycolysis and triggered the produced pyruvate into mitochondria for further degradation. DCA also reduced the amount of CD39 and CD73, thereby promoting the accumulation of ATP intracellularly. The cascade of MnO2 and LOX catalyzed the lactate to pyruvate together with oxygen for the relief of the hypoxic and immunosuppressive TME. The regulation of the mitochondrial metabolism together with the degradation of lactate contributed to activating the immune cells. Meanwhile, the loaded SR-717 together with the release of Mn2+ activated the cyclic guanosine monophosphate adenosine monophosphate synthase/interferon gene stimulator signaling pathway for efficient antitumor effects and immunotherapy. Taken together, the designed multifunctional nanocomposites realized an effective tumor immunotherapy by regulating the reprogrammed mitochondrial energy metabolism intracellularly, relieving the abnormal TME and activating the innate antitumor immunological effects extracellularly. Our work established an approach to the enhanced immunotherapy by regulating the reprogrammed metabolism for efficient cancer treatment.

A Copper Silicate-Based Multifunctional Nanoplatform with Glutathione Depletion and Hypoxia Relief for Synergistic Photodynamic/Chemodynamic Therapy.

Chemodynamic therapy (CDT) alone cannot achieve sufficient therapeutic effects due to the excessive glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Developing a novel strategy to improve efficiency is urgently needed. Herein, we prepared a copper silicate nanoplatform (CSNP) derived from colloidal silica. The Cu(II) in CSNP can be reduced to Cu(I), which cascades to induce a subsequent CDT process. Additionally, benefiting from GSH depletion and oxygen (O2) generation under 660 nm laser irradiation, CSNP exhibits both Fenton-like and hypoxia-alleviating activities, contributing to the effective generation of superoxide anion radical (•O2-) and hydroxyl radical (•OH) in the TME. Furthermore, given the suitable band-gap characteristic and excellent photochemical properties, CSNP can also serve as an efficient type-I photosensitizer for photodynamic therapy (PDT). The synergistic CDT/PDT activity of CSNP presents an efficient antitumor effect and biosecurity in both in vitro and in vivo experiments. The development of an all-in-one nanoplatform that integrates Fenton-like and photosensing properties could improve ROS production within tumors. This study highlights the potential of silicate nanomaterials in cancer treatment.

Lysosome-Targeted and pH-Activatable Phototheranostics for NIR-II Fluorescence Imaging-Guided Nasopharyngeal Carcinoma Phototherapy.

Currently, clinical therapeutic strategies for nasopharyngeal carcinoma (NPC) confront insurmountable dilemmas in which surgical resection is incomplete and chemotherapy/radiotherapy has significant side effects. Phototherapy offers a maneuverable, effective, and noninvasive pattern for NPC therapy. Herein, we developed a lysosome-targeted and pH-responsive nanophototheranostic for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of NPC. A lysosome-targeted S-D-A-D-S-type NIR-II phototheranostic molecule (IRFEM) is encapsulated within the acid-sensitive amphiphilic DSPE-Hyd-PEG2k to form IRFEM@DHP nanoparticles (NPs). The prepared IRFEM@DHP exhibits a good accumulation in the acidic lysosomes for facilitating the release of IRFEM, which could disrupt lysosomal function by generating an amount of heat and ROS under laser irradiation. Moreover, the guidelines of NIR-II fluorescence enhance the accuracy of PTT/PDT for NPC and avoid damage to normal tissues. Remarkably, IRFEM@DHP enable efficient antitumor effects both in vitro and in vivo, opening up a new avenue for precise NPC theranostics.

Preparation and anti-tumor effect in hepatocellular carcinoma treatment of AS1411 aptamer-targeted polyphyllin II-loaded PLGA nanoparticles

Polyphyllin II (PPII) has been proven to have significant anti-liver cancer activity, but its application is limited by poor solubility, low bioavailability, and systemic toxicity caused by non-selectivity. To address the above problem, PPII was encapsulated into the Poly (lactic-co-glycolic acid) (PLGA) by precipitation method (PPII-NPs) for hepatocellular carcinoma treatment. Subsequently, Box–Behnken design (BBD) with three variables-three levels (33) was utilized to optimize the PPII-NPs formulation. Under optimal conditions, the drug loading of nanoparticles reached 7.29 ± 0.08% and encapsulation efficiency was 80.98 ± 1.63%. Furthermore, aptamer AS1411 was adopted to enhance the tumor-targeting ability of nanoparticles (Apt/PPII-NPs). The drug loading of Apt/PPII-NPs was 6.25 ± 0.26%, had a spherical shape with a rough surface, a particle size of 252.3 ± 3.6 nm, and showed good slow-release performance and stability. In vitro, assays showed that the targeted modified nanoparticles had significant tumor selectivity and exerted efficient anti-tumor effects by inducing tumor cell apoptosis via the mitochondrial apoptotic pathway and death‐receptor pathway. In vivo, anti-tumor evaluation further demonstrated Apt/PPII-NPs not only effectively inhibited the growth of tumors, but also reduced PPII damage to normal tissues. In summary, this report strongly illustrated the advantages of a targeted nanoparticle platform for providing a solution for the rational application of PPII and improving the therapeutic effect of hepatocellular carcinoma.

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome

BackgroundG-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored.MethodsThe mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays.ResultsPt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes’ transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy’s efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin.ConclusionThis study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.Graphical

“Four-in-One” Nanozyme for Amplified Catalytic-Photothermal Therapy

The cancer therapeutic efficacy of the peroxidase (POD)-mimicking nanozyme-based monotherapy is significantly hindered due to insufficient intratumoral hydrogen peroxide (H2O2) and glutathione (GSH) consumption effect on reactive oxygen species (ROS). In this study, we present the development of poly(o-phenylenediamine)@gold nanoparticles (AuNPs) (PoPD@Au) nanocomposites for multifunctional catalytic-photothermal therapy. These nanocomposites exhibit triple distinct nanozymatic activities, i.e., POD-like activity that catalyzes H2O2 to ROS, glucose oxidase (GOx)-like activity that supplements endogenous H2O2, and GSH depleting activity that decreases the ROS consumption efficiency. This open source and reduce expenditure strategy for ROS generation allows for the amplification of tumor oxidative stress, thereby enhancing anti-tumor efficiency. Additionally, the PoPD@Au nanocomposites demonstrate outstanding photothermal conversion efficiency, contributing to the synergistic effect between PoPD and AuNPs. Moreover, we reveal the improved photothermal performance of PoPD@Au triggered by the tumor microenvironment pH, which provides additional benefits for targeted catalytic-photothermal therapy. This “four-in-one” design of PoPD@Au enables efficient anti-tumor effects both in vitro and in vivo, making it a universal strategy for engineering catalytic-photothermal therapeutic nanoagents.

Role of damaged mitochondrial transfer in alpha-particle generator 212Pb radiation-induced bystander effect.

Rationale: 212Pb, a promising in vivo alpha-particle generator of 212Bi, has aroused much interest as a therapeutic radionuclide. For the development of targeted alpha therapy (TAT), it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated bystander cells. Currently, the critical roles of mitochondrial transfer in cellular crosstalk have garnered significant attention. However, the specific involvement of damaged mitochondrial transfer in orchestrating this alpha-particle radiation-induced bystander effect (RIBE) needs to be further explored. Methods: A novel alpha-emitting radiopharmaceutical, 212Pb-hydrogel nanoparticles (HNPs), was synthesized and subsequently evaluated its theranostics effects. The impact of irradiated cell-conditioned media (ICCM), collected at different times post-212Bi irradiation, on bystander cancer cells regarding cell viability was also investigated. Additionally, damaged mitochondria were isolated and cultured with non-irradiated bystander cells to assess their role. Results: 212Pb-HNPs exhibited efficient therapeutic antitumor effects in vitro, including increased GSH depletion, ROS accumulation, and mitochondrial damage in irradiated tumor cells. In vivo studies demonstrated its imaging potential through SPECT/CT, and RNA sequencing results indicated activation of oxidative stress-related pathways in irradiated tumors. Additionally, ICCM influenced the viability of non-irradiated bystander cells, suggesting a radiation-induced bystander effect by the alpha-particle 212Bi. Interestingly, damaged mitochondria isolated from ICCM were observed to enter co-cultured non-irradiated bystander cells. Further experiments confirmed that the transfer of damaged mitochondria results in the death of non-irradiated bystander cells. Conclusion: The present study highlights the theranostic potential of the alpha-particle generator 212Pb and, more importantly, elucidates the role of damaged mitochondrial transfer in alpha-particle RIBE. These findings provide a novel theoretical mechanism for the antitumor effects of alpha-particles and expand the clinical application prospects of TAT.

Near-Infrared Driven Gold Nanoparticles-Decorated g-C3N4/SnS2 Heterostructure through Photodynamic and Photothermal Therapy for Cancer Treatment.

Phototherapy based on photocatalytic semiconductor nanomaterials has received considerable attention for the cancer treatment. Nonetheless, intense efficacy for in vivo treatment is restricted by inadequate photocatalytic activity and visible light response. In this study, we designed a photocatalytic heterostructure using graphitic carbon nitride (g-C3N4) and tin disulfide (SnS2) to synthesize g-C3N4/SnS2 heterostructure through hydrothermal process. Furthermore, Au nanoparticles were decorated in situ deposition on the surface of the g-C3N4/SnS2 heterostructure to form g-C3N4/SnS2@Au nanoparticles. The g-C3N4/SnS2@Au nanoparticles generated intense reactive oxygen species radicals under near-infrared (NIR) laser irradiation through photodynamic therapy (PDT) pathways (Type-I and Type-II). These nanoparticles exhibited enhanced photothermal therapy (PTT) efficacy with high photothermal conversion efficiency (41%) whensubjected to 808 nm laser light, owing to the presence of Au nanoparticles. The in vitro studies have indicated that these nanoparticles can induce human liver carcinoma cancer cell (HepG2) apoptosis (approximately 80% cell death) through the synergistic therapeutic effects of PDT and PTT. The in vivo results demonstrated that these nanoparticles exhibited enhanced efficient antitumor effects based on the combined effects of PDT and PTT. The g-C3N4/SnS2@Au nanoparticles possessed enhanced photothermal properties and PDT effect, good biocompatibility and intense antitumor efficacy. Therefore, these nanoparticles could be considered promising candidates through synergistic PDT/PTT effects upon irradiation with NIR laser for cancer treatment.

Carm1 Inhibition Potentiates Irradiation-Induced Antitumor Immunity via Tumor Intrinsic STING Pathway Activation

Radiotherapy is commonly applied in multiple cancer types. Besides irradiation induced direct cell death, radiotherapy stimulated significant immune responses for tumor control. Intact and functional cGAS-STING pathway in both tumor cells and host cells is indispensable for efficient irradiation-induced anti-tumor effects. Coactivator-associated arginine methyltransferase 1 (Carm1) is emerging as an attractive therapeutic target and a biomarker for prognosis in various types of cancer. It has been reported that Carm1 inhibition could improve immunotherapy induced anti-tumor effects. However, it remains unclear how tumor cell intrinsic Carm1 affects irradiation-induced anti-tumor immunity. Carm1 deficient cell lines were established in MC38 and B16F10 murine cancer cells using the CRISPR/Cas9 technology. To verify the effects of tumor `subcutaneous tumor mouse models were established and one fraction of 15Gy was administrated when the tumor volume reached 200mm3, followed by flow cytometry assays. Transcriptome sequencing, protein mass spectrometry, single-cell sequencing, Digital Spatial Profiling (DSP), real-time qPCR, western blotting, immunofluorescence and co-immunoprecipitation were carried out to explore and verify possible molecular mechanisms. Here we found Carm1 deficiency in tumor cells dramatically enhanced irradiation-induced anti-tumor immune responses. Transcriptome sequencing of irradiated tumor cells and further experiments then validated that cGAS-STING pathway was significantly activated after irradiation in the absence of Carm1 in tumor cells, which contributed to enhance anti-tumor immunity after irradiation. Mechanistically, Carm1 deficiency in tumor cells attenuated autophagy, resulting in increased cytoplasmic mtDNA enrichment and enhanced cGAS-STING pathway activation. On the other hand, we also found that Carm1 caused asymmetric arginine methylation (ADMA) modification of TBK1 with reduced phosphorylation level, and Carm1 deficiency could activate cGAS-STING pathway by reducing AMDA modification and enhancing phosphorylation of TBK1. Finally, Carm1 inhibitor EZM2302 was applied in combination with radiotherapy in vitro, and it's indicated that combination therapy resulted in intensive anti-tumor immunity and prominent abscopal effects. In this study, we identified that Carm1 ablation in tumor cells could promote irradiation-induced antitumor immunity through tumor cell intrinsic STING pathway activation. Mechanically, Carm1 deficiency directly activated the cGAS-STING pathway by interacting with TBK1 and increased mtDNA accumulation in cytoplasm by inhibiting autophagy. These findings provided new strategies for targeting Carm1 to boost the efficacy of radiotherapy.

Remodeling the tumor microenvironment by vascular normalization and GSH-depletion for augmenting tumor immunotherapy

Remodeling tumor microenvironment (TME) is a very promising and effective strategy to enhance the effects of chemotherapy, photodynamic therapy, and immunotherapy. Normalization of tumor vasculature as well as depletion of glutathione (GSH) can improve the TME. Here, we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles (FEUQ Nps) based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer, a GSH depleting agent, and an activated fluorophore. In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment. In addition, it may deplete GSH in cancer cells, thus inducing the production of reactive oxygen species (ROS) and lipid peroxide (LPO) and promoting iron toxicity. It may also lead to endoplasmic stress and release of calmodulin, which activates the immune system. Meanwhile, quenched fluorophores are turned on in the presence of galactosidase (GLU) for tumor-specific labeling. In summary, we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.

Preclinical Assessment of ADAM9-Responsive Mesoporous Silica Nanoparticles for the Treatment of Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce off-target toxicities have been developed. In this paper, we present a preclinical evaluation of a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSNs) functionalized with a protease linker that is specifically cleaved by PDAC cells. Our previous work demonstrated that ADAM9 is a PDAC-enriched protease and that paclitaxel-loaded ADAM9-responsive MSNs effectively kill PDAC cells in vitro. Here, we show that paclitaxel-loaded ADAM9-MSNs result in off-target cytotoxicity in clinically relevant models, which spurred the development of optimized ADAM9-responsive MSNs (OPT-MSNs). We found that these OPT-MSNs still efficiently kill PDAC cells but, as opposed to free paclitaxel, do not induce death in neuronal or bone marrow cells. In line with these in vitro data, paclitaxel-loaded OPT-MSNs showed reduced organ damage and leukopenia in a preclinical PDAC xenograft model. However, no antitumor response was observed upon OPT-MSN administration in vivo. The poor in vivo antitumor activity of OPT-MSNs despite efficient antitumor effects in vitro highlights that although MSN-based tumor-targeting strategies may hold therapeutic potential, clinical translation does not seem as straightforward as anticipated.

Two-dimensional iron porphyrin nanozyme mimics cytochrome P450 activity for cancer proliferation inhibition

Two-dimensional materials have excellent performance in energy catalysis and biomedicine due to their unique advantages in surface and interfacial properties. Taking into account the unique advantages of the surface interface and catalysis of two-dimensional materials, it is a very feasible way to construct two-dimensional materials with clear atomic structure to break the redox balance in tumor cells, so as to achieve efficient anti-tumor effects. Based on this, we selected the porphyrin ligands that widely exist in nature, equipped with iron metal active centers, and constructed a two-dimensional iron porphyrin nanozyme with a clear atomic structure, which simulated the redox activity of cytochrome P450 enzymes. The experimental results show that by carrying a rotatable pyridine group on the porphyrin ring, the iron porphyrin monomers can be effectively connected and expanded into a two-dimensional iron porphyrin microstructure. Enough iron centers are exposed on the surface of two-dimensional iron porphyrins as catalytic sites. In the presence of oxidants, two-dimensional iron porphyrins can efficiently catalyze the oxidation of small organic molecules, and have good P450-like enzymatic activity. At the same time, the two-dimensional iron porphyrin nanomaterial was used for anti-tumor, and it was found that it has an efficient ability to inhibit tumor proliferation, which may be due to the catalytic oxidation of various organic small molecules in tumor cells by the high concentration of hydrogen peroxide in tumor cells. At the same time, we found that the two-dimensional iron porphyrin nanozyme may have a good drug loading capacity due to the many exposed iron sites on its surface, which provides a possible option for drug loading to achieve combined high-efficiency tumor therapy.

Spatial distribution and proximity effect-dependent multi-enzyme cascades catalysis operating in dendritic mesoporous silica nanoparticles

Enzymatic cascades catalysis engenders complex and selective intracellular transformations due to the organization of the enzymes in confined cellular environments. In this work, a biomimetic strategy is employed to develop a synthetic cell analogue for operating multi-enzymatic cascade catalysis in vitro. The glucose peroxidase (GOx) and chloroperoxidase (CPO) are co-encapsulated in the channel of dendritic mesoporous silica nanoparticles (DMSP) modified by phase-transitioned lysozyme (PTL@GOx&CPO@DMSP). The cascade efficiency is substantially enhanced compared with the diffusion mixtures of the free enzymes in bulk solution due to some nanoscale construction, such as confinement effect, proximity effect and special distribution mode of the enzymes. The high specific surface area and high concentration of mesoporous cages in DMSP is beneficial for encapsulation of enzyme. The cross-linked cavities ensure directional transfer of the intermediate from GOx to CPO, known as “substrate channel”. PTL plays multiple functions including inhibiting leaking of enzyme from DMSP, concentrating intermediate H2O2 at DMSP domains and keeping this biocomposite stable in aqueous environment by improving its dispersibility. The prepared biocomposite PTL@GOx & CPO@DMSP is very stable at harsh conditions. It can retain 42% of original catalytic activity at 90°C with incubation for 3 h while the retained activity of free enzymes is only 5% under the same conditions. Meanwhile, it can keep 92.4% of its original catalytic activity after 10 reuses. These characteristics ensure practical application of this biocatalytic material. The active HClO generated by GOx-CPO cascade has an efficient anti-tumor effect and is effectively applied to preserve fruit.

CD69 imposes tumor-specific CD8+ T-cell fate in tumor-draining lymph nodes.

Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to their cytotoxic progeny - Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLNs) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-PD-1 showed an efficient anti-tumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.

Release kinetics study of fatty acids eutectic mixture gated mesoporous carbon nanoparticles for chemo-photothermal therapy

Precise drug release in tumor sites is the key to improving the curative effect and reducing the toxic and side effects of chemotherapy. Herein, mesoporous carbon nanoparticles (MCN) and thermo-sensitive biocompatible phase change material (PCM) composed of stearic acid and lauric acid eutectic mixture were integrated for achieving the “on-demand” release of poorly soluble drug mercaptopurine (MP). MCN endowed the system with the potential of photothermal therapy (PTT) as well as high drug-loading efficiency. Fatty acids eutectic mixture with a well-designated melting point of 40 °C was used as the gatekeeper to trap MP in the mesopores of MCN. As expected, the drug was not released until PCM was melted down by the heat generated under NIR irradiation, thus inhibiting the premature release of drugs at body temperature. Notably, the release kinetic study results of inactivated MCN@MP/PCM system demonstrated the premature release of the drug was caused by diffusion, and adjusting the added PCM amounts just changed the controlled release effect of drugs without affecting release mechanisms. According to the cellular uptake, cytotoxicity and anti-tumor spheroids assays, the prominent NIR-triggered drug release property and photothermal effect of MCN@MP/PCM enhanced the antitumor activity, possessing the satisfied synergistic chemo-photothermal antitumor effect with a combination index of 0.554. This work provides a comprehending basis for designing a better-controlled release system to realize a safer and more efficient synergistic antitumor effect.

A platinum(II) complex HY1-Pt overcomes cisplatin-induced resistance and attenuates metastasis of epithelial ovarian cancer by cancer cell stemness inhibition.

Tumor recurrence, acquired resistance and metastasis have severely limited the effect of clinical treatments for epithelial ovarian cancer. Recent researches reveal that cancer stem cells play important roles in the process of cisplatin-induced resistance and cancer cell metastasis. A platinum(II) complex (HY1-Pt) owning casein kinase 2 specificity reported in our recent research was herein applied to treat cisplatin-sensitive and cisplatin-resistant epithelial ovarian cancers, respectively, anticipating to achieve high anti-tumor efficacy. HY1-Pt showed highly efficient anti-tumor effect with low toxicity for either cisplatin-sensitive or cisplatin-resistant epithelial ovarian cancer both in vitro and in vivo. Biological studies indicated that HY1-Pt as a casein kinase 2 inhibitor could effectively overcome cisplatin resistance through the signaling pathway of Wnt/β-catenin by inhibiting expression of the signature genes of cancer stemness cells in A2780/CDDP cells. Moreover, HY1-Pt could suppress tumor migration and invasion in vitro and in vivo, further proving that HY1-Pt can be a potent novel platinum(II) agent for cisplatin-resistant epithelial ovarian cancer treatment.

Copper-Coordinated Covalent Organic Framework Produced a Robust Fenton-Like Effect Inducing Immunogenic Cell Death of Tumors.

Increasing infiltration of CD8+ T cells can enhance the response rate to immune checkpoint blockade (ICB) therapies. In contrast, immunogenic cell death (ICD) induced by intracellular reactive oxygen species (ROS) is an effective strategy to increase CD8+ T cell infiltration. Cuproptosis is newly defined and reported by Tsvetkov etal. A Cu-coordinated covalent organic framework (COF) in which two valence states of copper ions are simultaneously loaded is prepared. On the one hand, Cu2+ undergoes a valence shift generating Cu+ which acts as an effective Fenton-like reagent to catalyze the production of · OH and 1 O2 from cellular overexpressed H2 O2 , causing DNA damage and lipid peroxidation (LPO), which directly produce cytotoxicity. On the other hand, residual Cu2+ can effectively deplete endogenous cellular glutathione (GSH), converting it into glutathione disulfide (GSSG), further increasing intracellular oxidative stress and reducing the scavenging of ROS, thus further enhancing the Fenton-like effect and bringing toxic effects on tumor cells. The synergy of these two functions achieves ICD, helping for transforming "cold tumor" into "hot tumor" and efficient anti-tumor effects eventually. This work provides new insights into coordinated COF and inspire the development of more versatile COF for biomedical applications.

A New Optimized Version of a Colorectal Cancer-Targeted Immunotoxin Based on a Non-Immunogenic Variant of the Ribotoxin α-Sarcin

Due to its incidence and mortality, cancer remains one of the main risks to human health and lifespans. In order to overcome this worldwide disease, immunotherapy and the therapeutic use of immunotoxins have arisen as promising approaches. However, the immunogenicity of foreign proteins limits the dose of immunotoxins administered, thereby leading to a decrease in its therapeutic benefit. In this study, we designed two different variants of non-immunogenic immunotoxins (IMTXA33αSDI and IMTXA33furαSDI) based on a deimmunized variant of the ribotoxin α-sarcin. The inclusion of a furin cleavage site in IMTXA33furαSDI would allow a more efficient release of the toxic domain to the cytosol. Both immunotoxins were produced and purified in the yeast Pichia pastoris and later functionally characterized (both in vitro and in vivo), and immunogenicity assays were carried out. The results showed that both immunotoxins were functionally active and less immunogenic than the wild-type immunotoxin. In addition, IMTXA33furαSDI showed a more efficient antitumor effect (both in vitro and in vivo) due to the inclusion of the furin linker. These results constituted a step forward in the optimization of immunotoxins with low immunogenicity and enhanced antitumor activity, which can lead to potential better outcomes in cancer treatment.

The applications of nanozymes in cancer therapy: based on regulating pyroptosis, ferroptosis and autophagy of tumor cells.

Nanozymes are nanomaterials with catalytic properties similar to those of natural enzymes, and they have recently been collectively identified as a class of innovative artificial enzymes. Nanozymes are widely used in various fields, such as biomedicine, due to their high catalytic activity and stability. Nanozymes can trigger changes in reactive oxygen species (ROS) levels in cells and the activation of inflammasomes, leading to the programmed cell death (PCD), including the pyroptosis, ferroptosis, and autophagy, of tumor cells. In addition, some nanozymes consume glucose, starving cancer cells and thus accelerating tumor cell death. In addition, the electric charge of the structure and the catalytic activity of nanozymes are sensitive to external factors such as light and electric and magnetic fields. Therefore, nanozymes can be used with different therapeutic methods, such as chemodynamic therapy (CDT), photodynamic therapy (PDT) and sonodynamic therapy (SDT), to achieve highly efficient antitumor effects. Many cancer therapies induce tumor cell death via the pyroptosis, ferroptosis, and autophagy of tumor cells mediated by nanozymes. We review the mechanisms of pyroptosis, ferroptosis, and autophagy in tumor development, as well as the potential application of nanozymes to regulate pyroptosis, ferroptosis, and autophagy in tumor cells.