ABSTRACT
Tumor metastasis and recurrence are closely related to immune escape and hypoxia. Chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) can induce immunogenic cell death (ICD), and their combination with immune checkpoint agents is a promising therapeutic strategy. Iron based nanomaterials have received more and more attention, but their low Fenton reaction efficiency has hindered their clinical application. In this study, Fe3O4-carbon dots complex (Fe3O4-CDs) was synthesized, which was modified with ferrocenedicarboxylic acid by amide bond, and crosslinked into Fe3O4-CDs@Fc nano complex. The CDs catalyzed the Fenton reaction activity of Fe3O4 by helping to improve the electron transfer efficiency, extended the reaction pH condition to 7.4. The Fe3O4-CDs@Fc exhibit exceptional optical activity, achieving a thermal conversion efficiency of 56.43 % under 808 nm light and a photosensitive single-line state oxygen quantum yield of 33 % under 660 nm light. Fe3O4-CDs@Fc improved intracellular oxygen level and inhibited hypoxia-inducing factor (HIF-1α) by in-situ oxygen production based on Fenton reaction. The multimodal combination of Fe3O4-CDs@Fc (CDT/PDT/PTT) strongly induced immune cell death (ICD). The expression of immune-related protein and HIF-1α was investigated by immunofluorescence method. In vivo, Fe3O4-CDs@Fc combined with immune checkpoint blocker (antibody PD-L1, αPD-L1) effectively ablated primary tumors and inhibited distal tumor growth. Fe3O4-CDs@Fc is a promising immune-antitumor drug.
Subject(s)
Carbon , Oxygen , Quantum Dots , Mice , Animals , Quantum Dots/chemistry , Carbon/chemistry , Humans , Catalysis , Oxygen/chemistry , Immunotherapy , Particle Size , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Photochemotherapy , Mice, Inbred BALB C , Cell Line, Tumor , Iron/chemistry , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/pharmacology , Surface Properties , Cell Survival/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , FemaleABSTRACT
The metastasis and recurrence of cancer are related to immunosuppression and hypoxia in the tumor microenvironment. Activating immune activity and improving the hypoxic environment face essential challenges. This paper reports on a multifunctional nanomaterial, HSCCMBC, that induces immunogenic cell death through powerful photodynamic therapy/chemodynamic therapy synergistic antitumor effects. The tumor microenvironment changed from the immunosuppressive type to immune type, activated the immune activity of the system, decomposed hydrogen peroxide to generate oxygen based on Fenton-like reaction, and effectively increased the level of intracellular O2 with the assistance of 3-bromopyruvate, a cell respiratory inhibitor. The structure and composition of HSCCMBC were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, infrared spectroscopy, etc. Oxygen probe RDPP was used to investigate the oxygen level inside and outside the cell, and hydroxyl radical probe tetramethylbenzidine was used to investigate the Fenton-like reaction ability. The immunofluorescence method investigated the expression of various immune markers and hypoxia-inducing factors in vitro and in vivo after treatment. In vitro and in vivo experiments indicate that HSCCMBC is an excellent antitumor agent and is expected to be a candidate drug for antitumor immunotherapy.
Subject(s)
Nanoparticles , Neoplasms , Humans , Silicon Dioxide/pharmacology , Copper/chemistry , Carbon/pharmacology , Immunogenic Cell Death , Neoplasms/drug therapy , Oxygen/chemistry , Hypoxia , Cell Line, Tumor , Hydrogen Peroxide/chemistry , Tumor Microenvironment , Nanoparticles/chemistryABSTRACT
Cancer metastasis and recurrence are closely associated with immunosuppression and a hypoxic tumor microenvironment. Chemodynamic therapy (CDT) and photothermodynamic therapy (PTT) have been shown to induce immunogenic cell death (ICD), effectively inhibiting cancer metastasis and recurrence when combined with immune adjuvants. However, the limited efficacy of Fenton's reaction and suboptimal photothermal effect present significant challenges for successfully inducing ICD through CDT and PTT. This paper described the synthesis and immunoantitumor activity of the novel iron-copper-doped folic acid carbon dots (CFCFB). Copper-doped folic acid carbon dots (Cu-FACDs) were initially synthesized via a hydrothermal method, using folic acid and copper gluconate as precursors. Subsequently, the nanoparticles CFCFB were obtained through cross-linking and self-assembly of Cu-FACDs with ferrocene dicarboxylic acid (FeDA) and 3-bromopyruvic acid (3BP). The catalytic effect of carbon dots in CFCFB enhanced the activity of the Fenton reaction, thereby promoting CDT-induced ICD and increasing the intracellular oxygen concentration. Additionally, 3BP inhibited cellular respiration, further amplifying the oxygen concentration. The photothermal conversion efficiency of CFCFB reached 55.8%, which significantly enhanced its antitumor efficacy through photothermal therapy. Immunofluorescence assay revealed that treatment with CFCFB led to an increased expression of ICD markers, including calreticulin (CRT) and ATP, as well as extracellular release of HMGB-1, indicating the induction of ICD by CFCFB. Moreover, the observed downregulation of ARG1 expression indicates a transition in the tumor microenvironment from an immunosuppressive state to an antitumor state following treatment with CFCFB. The upregulation of IL-2 and CD8 expression facilitated the differentiation of effector T cells, resulting in an augmented population of CD8+ T cells, thereby indicating the activation of systemic immune response.
Subject(s)
Nanoparticles , Neoplasms , Humans , Copper/pharmacology , CD8-Positive T-Lymphocytes , Iron/pharmacology , Carbon/pharmacology , Folic Acid/pharmacology , Neoplasms/drug therapy , Oxygen/pharmacology , Cell Line, Tumor , Tumor Microenvironment , Hydrogen PeroxideABSTRACT
Cancer metastasis and invasion are closely related to tumor cell immunosuppression and intracellular hypoxia. Activation of immunogenicity and intracellular oxygenation are effective strategies for cancer treatment. In this study, multifunctional nanomicelle hyaluronic acid and cinnamaldehyde is self-assembled into nanomicelles (HPCNPs) were constructed for immunotherapy and tumor cell oxygenation. The Schiff base was constructed of HPCNPs with pyropheophorbide a-Cu (PPa-Cu). HPCNPs are concentrated in tumor sites under the guidance of CD44 proteins, and under the stimulation of tumor environment (weakly acidic), the Schiff base is destroyed to release free PPa. HPCNPs with photodynamic therapeutic functions and chemokinetic therapeutic functions produce a large number of reactive oxygen species (1O2 and â¢OH) under exogenous (laser) and endogenous (H2O2) stimulations, causing cell damage, and then inducing immunogenic cell death (ICD). ICD markers (CRT and ATP) and immunoactivity markers (IL-2 and CD8) were characterized by immunofluorescence. Downregulation of Arg1 protein proved that the tumor microenvironment changed from immunosuppressive type (M2) to antitumor type (M1). The oxidation of glutathione by HPCNP cascades to amplify the concentration of reactive oxygen species. In situ oxygenation by HPCNPs based on a Fenton-like reaction improves the intracellular oxygen level. In vitro and in vivo experiments demonstrated that HPCNPs combined with an immune checkpoint blocker (α-PD-L1) effectively ablated primary tumors, effectively inhibited the growth of distal tumors, and increased the oxygen level in tumor cells.
Subject(s)
Hyaluronic Acid , Hydrogen Peroxide , Hyaluronic Acid/pharmacology , Reactive Oxygen Species , Schiff Bases , Oxygen , Hydrogen-Ion ConcentrationABSTRACT
As an emerging cancer treatment strategy, ferroptosis is distinguished by the perturbation of lipid metabolism equilibrium and the accumulation of lipid peroxidation. However, the efficacy is consistently hindered by excessive GSH in the tumor microenvironment (TME). Here, this work designed and prepared multifunctional tumor-targeting carbon dots (FG-CDs@Cu) for ferroptosis and immunotherapy. Cu2+ in FG-CDs@Cu rapidly depletes high concentrations of GSH and inhibits glutathione peroxidase 4 (GPX4) expression in an acidic TME. Meanwhile, the generated Cu+ produced reactive oxygen species (ROS) through Fenton-like reaction. Due to the high efficiency of ROS production and GSH depletion, ferroptosis mediated by oxidative stress is significantly enhanced by FG-CDs@Cu in vivo, which can induce immunogenic cell death and promote CD8+ T cell infiltration. Meanwhile, the generated O2 effectively improves the hypoxic environment of the cells and leads to the reduction of hypoxia factor-1α (HIF-1α) expression, which activates the transformation of tumor-promoting M2-type tumor-associated macrophages (TAMs) to tumor-inhibiting M1-type TAMs, further enhancing the immune response and ferroptosis. The in vivo tests suggested that FG-CDs@Cu could efficiently suppress tumor growth in the mouse model and did not cause obvious toxicity. The combination with antiprogrammed death-ligand 1 (αPD-L1) synergy immune therapy could effectively restrain the growth of distal tumors, suggesting the significant potential of FG-CDs@Cu in augmenting ferroptosis and immunotherapy for efficacious cancer treatment.
ABSTRACT
Photodynamic therapy (PDT) and chemodynamic therapy (CDT) can activate immunogenicity, so PDT and CDT combined immunotherapy is a promising treatment strategy. However, insufficient hydrogen peroxide activity, hypoxia, and overexpressed glutathione in the tumor microenvironment (TME) significantly impaired the ability to activate immunogenicity. Thus, in this paper, self-reinforcing conjugates Cu2+-Pyropheophorbide-a-Cysteine (CuPPaCC), combined synergetic NIR and pH triggered PDT/CDT with glutathione depletion ability was constructed. CuPPaCC was encapsulated in mesoporous silica, and spherical HSCuPPaCC nanoparticles were prepared by Hyaluronic acid (HA) on the silica surface by Schiff base modification. HSCuPPaCC has tumor-specific targeting via HA mediated. In acidic solution, the Schiff base of HSCuPPaCC is destroyed and CuPPaCC is released (>70%), with excellent pH response release function. The results of the MTT analysis showed that the PDT/CDT synergistic anti-tumor effect was significant. HSCuPPaCC was activated in TME, catalyzing the decomposition of hydrogen peroxide to generate hydroxyl radicals and oxygen, alleviating TME hypoxia, replenishing oxygen to PDT, and significantly down regulating hypoxia factor HIF-1α expression. HSCuPPaCC has an excellent dual ROS mechanism and a dual depleting GSH mechanism resulting in a surge in intracellular ROS levels to efficiently kill cancer cells, enhance the ability to induce immunogenicity, and make tumors more sensitive to checkpoint PD-L1 blockade therapy. With the CT26 mouse model, not only the primary tumor was eradicated, but also the distal tumor at the end of treatment was completely suppressed by HSCuPPaCC combined with anti-PD-L1 immune checkpoint blockade therapy.
Subject(s)
Nanoparticles , Neoplasms , Photochemotherapy , Animals , Mice , Cystine , Hydrogen Peroxide , Reactive Oxygen Species , Schiff Bases , Immunotherapy , Glutathione , Hyaluronic Acid , Cell Line, Tumor , Tumor Microenvironment , Neoplasms/drug therapyABSTRACT
Immune checkpoint blockade (ICB) is a kind of promising anti-tumor immunotherapy that can block the negative immune regulatory pathways using a particular antibody. Weak immunogenicity in most patients is a key obstacle to ICB therapy. Photodynamic therapy (PDT) is a non-invasive treatment that can enhance the immunogenicity of the host and realize systemic anti-tumor immunotherapy; yet tumor microenvironment hypoxia and glutathione overexpression severely restrict the PDT effect. To overcome the above issues, we design a combination therapy based on PDT and ICB. We prepared red carbon dot (RCD)-doped Cu-metal-organic framework nanoparticles (Cu-MOF@RCD) as smart nano-reactors because their tumor microenvironment and near-infrared light responsive property can decompose tumor endogenous H2O2 through Fenton-like reactions. Cu-MOF@RCD also shows clear near-infrared photothermal therapy (PTT) effect and has an ability to deplete glutathione (DG), which together enhances decomposition of cellular H2O2 and amplifies reactive oxygen species (ROS) levels in cells, thus leading to enhanced PDT and chemodynamic therapy (CDT) effect. Moreover, programmed cell death-ligand 1 antibody (anti-PD-L1) is used together to enable combination therapy, as Cu-MOF@RCD can significantly enhance host immunogenicity. In summary, the combination of Cu-MOF@RCD with anti-PD-L1 antibody exerts a synergistic PDT/PTT/CDT/DG/ICB therapy and can be used to eradicate the primary tumors and inhibit the growth of untreated distant tumors and tumor metastasis.
Subject(s)
Neoplasms , Photochemotherapy , Humans , Immune Checkpoint Inhibitors/pharmacology , Carbon/pharmacology , Hydrogen Peroxide/pharmacology , Neoplasms/drug therapy , Glutathione/pharmacology , Tumor MicroenvironmentABSTRACT
Carbon dots (CDs) have great potential for cancer diagnosis and treatment. Photodynamic therapy and chemodynamic therapy are promising treatments mediated by reactive oxygen species (ROS), which have the advantages of being minimally invasive, having no multi-drug resistance, and having no systemic toxic side effects. However, the tumor microenvironment (TME) and poor targetability often reduce the therapeutic effect. In this work, we have successfully prepared folate-based carbon dots (FCP-CDs) from folic acid (FA), citric acid (CA), and polyethyleneimine (PEI) for tumor-targeting. The surface of FCP-CDs was modified using organic disulfide, 3,3'-dithiodipropionic acid (DTPA), and a photosensitizer (PS) pyropheophorbide-a (PPa) to form a tumor microenvironment-responsive nanoplatform, FCP-CDs@DTPA@PPa (named FCPPD), for synergistic cancer therapy. The results showed that FCPPD effectively preserved the tumor target specificity of folic acid and the photodynamic therapeutic (PDT) activity of PPa, and could provide additional chemodynamic therapeutic (CDT) function by reacting with hydrogen peroxide (H2O2) to generate ËOH. The introduction of DTPA, which contains disulfide bonds, endows FCPPD with an excellent ability to deplete glutathione (GSH) in tumors via intracellular redox reactions, amplifying intracellular oxidative strain and enhancing ROS-based therapeutic effects. Systematic in vitro and in vivo studies under various conditions have shown that the obtained FCPPD nanoparticles have good biocompatibility and could be a promising therapeutic agent for imaging-guided PDT/CDT combination therapy.
Subject(s)
Nanoparticles , Neoplasms , Photochemotherapy , Humans , Hydrogen Peroxide , Reactive Oxygen Species , Neoplasms/drug therapy , Carbon , Disulfides , Folic Acid , Glutathione , Pentetic Acid , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for drug development. In an effort to identify what conformation could be accounting for the bioactive disparity of natural and synthetic cyclic peptides, some structurally-constrained analogs of cyclopeptide Axinastatin 3 were prepared by photo-induced single electron transfer (SET) reaction. Detailed stereochemistry study was performed by experimental electronic circular dichroism combined with theoretical calculations. Our study suggested that the cyclopeptide 1 with ßI-turn presented stronger antitumor activity comparing with those without such secondary structures. Moreover, a rare 'π helix unit' (compound 3) was realized because of the constrained cyclic structure, which could be considered an important research object for future study of unique helix secondary structures.
Subject(s)
Peptides, Cyclic/pharmacology , Animals , Antineoplastic Agents , Cell Line , Cell Proliferation/drug effects , Density Functional Theory , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Electron Transport , Fibroblasts/drug effects , Humans , Mice , Models, Molecular , Molecular Conformation , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Photochemical Processes , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A cyclic analog of natural peptide Yunnanin A was synthesized via photoinduced single electron transfer reaction (SET) in the paper. The resulting compound exhibited potent bioactivity (with IC50 values 29.25 µg mL-1 against HepG-2 cell lines and 65.01 µg mL-1 against HeLa cell lines), but almost have no toxicity to normal cells (with IC50 values 203.25 µg mL-1 against L929 cell lines), which may be served as a potential antitumor drug for medical treatment. The spatial structure was examined by experimental electronic circular dichroism (ECD) and quantum chemistry calculations. Moreover, the theoretical study suggested that special intramolecular hydrogen bonds and γ, ß-turn secondary structures may be possible sources affecting cyclic peptide's bioactivity.