RESUMEN
Cancer immunotherapy suffers from inefficient antigen presentation owing to the limited endocytosis of antigen by dendritic cells (DCs) and dysfunction of DCs in the immunosuppressive tumor microenvironment (ITME). Here, we revealed that cinnamaldehyde-grafted polyethylenimine (PC) held the potential to serve as a neoadjuvant to modulate the above processes and thus potentiate immune responses. The PC neoadjuvant could capture the tumor antigen generated during chemotherapy to enhance the crosstalk between the antigen and DCs. Then, it depleted the intracellular glutathione by the in situ Michael addition reaction, which not only activated the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) pathway to promote DCs maturation but also triggered the antigen release. As a result, it significantly augmented antigen presentation with a 46% ratio of DCs maturation and a 53% ratio of CD8+ T cell infiltration in low immunogenic murine breast cancer.
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Pathophysiological barriers in "cold" tumors seriously limit the clinical outcomes of chemoimmunotherapy. These barriers distribute in a spatial order in tumors, including immunosuppressive microenvironment, overexpressed chemokine receptors, and dense tumor mesenchyme, which require a sequential elimination in therapeutics. Herein, we reported a "dominolike" barriers elimination strategy by an intratumoral ATP supersensitive nanogel (denoted as BBLZ-945@PAC-PTX) for enhanced chemoimmunotherapy. Once it has reached the tumor site, BBLZ-945@PAC-PTX nanogel undergoes supersensitive collapse triggered by adenosine triphosphate (ATP) in perivascular regions and releases BLZ-945 conjugated albumin (BBLZ-945) to deplete tumor-associated macrophages (TAMs). Deeper spatial penetration of shrunk nanogel (PAC-PTX) could not only block CXCR4 on the cell membrane to decrease immunosuppressive cell recruitment but also internalize into tumor cells for tumor-killing and T cell priming. The strategy of "dominolike" barriers elimination in tumors enables immune cell infiltration for a potentiated immune response and offers a high-responsive treatment opinion for chemoimmunotherapy.
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Neoplasias , Humanos , Nanogeles , Neoplasias/tratamiento farmacológico , Inmunoterapia , Adenosina Trifosfato , Adenosina , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
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Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy. Here, we developed an immunomodulatory nano-formulation (FEM@PFC) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the FEM@PFC nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.
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Neoplasias , Linfocitos T Reguladores , Animales , Ratones , Terapia de Inmunosupresión , Tolerancia Inmunológica , Inmunoterapia , Oxígeno , Microambiente TumoralRESUMEN
Natural killer (NK) cell therapies, primarily based on chimeric antigen receptor NK cells (CAR-NK), have been developed and applied clinically for therapeutic treatment of patients with mid-to-late-stage tumors. However, NK cell therapy has limited efficacy due to insufficient antigen expression on the tumor cell surface. Here, a universal "illuminate tumor homogenization antigen properties" (ITHAP) strategy to achieve stable and controlled antigen expression on the surface of tumor cells using nanomedicine, thus significantly enhancing the immune recognizability of tumor cells, is described. The ITHAP strategy is used to generate bio-liposomes (Pt@PL-IgG) composed of intermingled platelet membranes and liposomes with NK-activatable target antigen (IgG antibodies) and cisplatin pre-drug. It is demonstrated that Pt@PL-IgG successfully targets tumor cells using the autonomous drive of platelet membranes and achieves IgG implantation on tumor cells by utilizing membrane fusion properties. Moreover, it is shown that the Pt-DNA complex combined with NK cell-induced pyroptosis causes substantial interferon (IFN) secretion, thus providing a synthase-stimulator of interferon genes (STING)-IFN-mediated positive immune microenvironment to further potentiate NK therapy. These results show that anchoring cancer cells with NK-activatable target antigens is a promising translational strategy for addressing therapeutic challenges in tumor heterogeneity.
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Células Asesinas Naturales , Neoplasias , Liposomas/química , Células Asesinas Naturales/química , Células Asesinas Naturales/inmunología , Neoplasias/química , Neoplasias/inmunología , Antígenos de Neoplasias/química , Antígenos de Neoplasias/inmunología , Platino (Metal)/química , Humanos , Animales , Ratones , Línea Celular TumoralRESUMEN
Directly delivering therapeutic proteins to their intracellular targets remains a great challenge. Here, we apply CD8+ T cells to form pores on the tumor cells' plasma membranes, enabling perfusion of ribonuclease A (RNase A) and granzyme B into cells, therefore effectively inducing tumor apoptosis and pyroptosis by activating caspase 3 and gasdermin E pathways to potentiate the CD8+ T cell-mediated immunotherapy. Then, RNase A, programmed cell death ligand 1 antibody, and a photothermal agent were further loaded into an injectable hydrogel to treat the low immunogenic murine breast cancer. Notably, three courses of laser irradiation induced efficient cell apoptosis and immune activation, resulting in a notable therapeutic efficacy that 75% of the tumors were ablated without relapse.
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Linfocitos T CD8-positivos , Neoplasias , Ratones , Animales , Ribonucleasa Pancreática , Piroptosis/fisiología , Inmunoterapia , Apoptosis , Neoplasias/terapiaRESUMEN
Tumor metastasis contributes to high cancer mortality. Tumor cells in lymph nodes (LNs) are difficult to eliminate but underlie uncontrollable systemic metastasis. The CC chemokine receptor 7 (CCR7) is overexpressed in tumor cells and interacts with CC chemokine ligand 21 (CCL21) secreted from LNs, potentiating their lymphatic migration. Here, a site-specific polyplex is developed to block the CCR7-CCL21 signal and kill tumor cells toward LNs, greatly limiting their lymphatic infiltration. A CCR7-targeting small interfering RNA (siCCR7) is condensed by mPEG-poly-(lysine) with chlorin e6 (Ce6) modification (PPLC) to form PPLC/siCCR7. The knockdown of CCR7 by siCCR7 in tumor cells significantly reduced their response on CCL21 and LN tropism. Additionally, photodynamic therapy-mediated immune activation precisely targets and kills tumor cells released from the primary foci before they reaches the LNs, reducing the number of tumor cells entering the LNs. Consequently, the PPLC/siCCR7 polyplexes inhibited up to 92% of lung metastasis in 4T1 tumor bearing mice and reduced tumor cell migration to LNs by up to 80%. This site-specific strategy optimized anti-metastasis efficacy and promotes the clinical translational development of anti-metastatic therapy.
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Quimiocina CCL21 , Linfocitos T , Ratones , Animales , Receptores CCR7/genética , Receptores CCR7/metabolismo , Metástasis Linfática , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Regulación hacia Abajo , Linfocitos T/metabolismo , Movimiento Celular , Línea Celular TumoralRESUMEN
Most ofin vivotissue cells reside in 3D extracellular matrix (ECM) with fluid flow. To better study cell physiology and pathophysiology, there has been an increasing need in the development of methods for culturing cells inin vivolike microenvironments with a number of strategies currently being investigated including hydrogels, spheroids, tissue scaffolds and very promising microfluidic systems. In this paper, a 'sandwich' structure-liked microfluidic device integrated with a 3D printing scaffold is proposed for three-dimensional and dynamic cell culture. The device consists of three layers, i.e. upper layer, scaffold layer and bottom layer. The upper layer is used for introducing cells and fixing scaffold, the scaffold layer mimicking ECM is used for providing 3D attachment areas, and the bottom layer mimicking blood vessels is used for supplying dynamic medium for cells. Thermally assisted electrohydrodynamic jet (TAEJ) printing technology and microfabrication technology are combined to fabricate the device. The flow field in the chamber of device is evaluated by numerical simulation and particle tracking technology to investigate the effects of scaffold on fluid microenvironment. The cell culturing processes are presented by the flow behaviors of inks with different colors. The densities and viabilities of HeLa cells are evaluated and compared after 72 h of culturing in the microfluidic devices and 48-well plate. The dose-dependent cell responses to doxorubicin hydrochloride (DOX) are observed after 24 h treatment at different concentrations. These experimental results, including the evaluation of cell proliferation andin vitrocytotoxicity assessment of DOX in the devices and plate, demonstrate that the presented microfluidic device has good biocompatibility and feasibility, which have great potential in providing native microenvironments forin vitrocell studies, tissue engineering and drug screening for tumor therapy.
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Dispositivos Laboratorio en un Chip , Impresión Tridimensional , Células HeLa , Humanos , Ingeniería de Tejidos/métodos , Andamios del TejidoRESUMEN
The growth and rapid proliferation of tumor cells depend on both glycolysis and glutamine metabolism, leading to metabolic compensation. Here, dual inhibition on the metabolic plasticity by Glucose oxidase and Telaglenastat loaded liposome (Lip@GOx&Tel) were studied for intervening metabolic pathway on energy and material against breast cancer. Lip@GOx&Tel targeting inhibited the two nutrient supply mechanisms employed by tumor cells, reducing the supply of ATP production and biosynthesis precursors essential necessary for tumor, thereby eliciting anti-tumor and anti-metastasis effect. Meanwhile, Lip@GOx&Tel ingeniously amplify the therapeutic effect by up-regulating ROS and down-regulating GSH to disrupt redox homeostasis, thus resulting in inspiring 82% tumor suppression rate on 4 T1 tumor model. Moreover, our study solved the limitation of combination between protein drugs and small molecule drugs in vivo by using liposome nanoparticles with clinical translation value. In short, this work provides a unique perspective of nanomedicine for treating diseases from metabolic intervention.
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Neoplasias de la Mama , Glutamina , Adenosina Trifosfato , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Glucosa Oxidasa , Glutamina/metabolismo , Humanos , Liposomas , Especies Reactivas de OxígenoRESUMEN
Despite the great progress in the control of primary tumor growth, metastasis remains the major challenge of breast cancer therapy in clinics, which is highly related to the upregulation of reactive oxygen species (ROS) and overexpression of its relevant pro-survival miR-155 gene. Therefore, we fabricated a poly-antioxidant (FTP) to deliver anti-miR-155 for synergistic treatment of metastatic breast cancer by ROS scavenging and miR-155 inhibition. FTP was synthesized by the polymerization of fluorated-polyethyleneimine (FPEI) and antioxidants (TEMPOL), using a glutathione (GSH) responsive linker for controlled drug release. Notably, the poly-drug strategy could not only promote the tumoral accumulation of small molecular antioxidants but also enhance the transfection efficiency of anti-miR-155 owing to the hydrophobic property of TEMPOL. After synergistic treatment, the NF-κB pathway was significantly blocked, thereby generating strong anti-metastatic ability both in vitro and in vivo. The poly-antioxidant could be a new type of nanoplatform for highly efficient and safe miRNA delivery, which also provides a promising strategy for the synergistic treatment of metastatic breast cancer.
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Neoplasias de la Mama , MicroARNs , Antagomirs/uso terapéutico , Antioxidantes/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Glutatión/metabolismo , Humanos , MicroARNs/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The abundant M1 macrophages in the joint synovium were the main factors that exacerbate rheumatoid arthritis (RA) by secreting various types of inflammatory cytokines. Here, we note that cGAS-STING, an important pro-inflammatory pathway, was significantly up-regulated in RA, enabling it be the potential target for RA therapy. Therefore, in this work, we developed M1 macrophages targeted micelles capable of cGAS-STING pathway inhibition for the smart treatment of RA. The folic acid (FA) and lauric acid (LA) were modified on dextran to obtain an amphiphilic polymer (FDL). Then, FDL was subsequently applied to encapsulate triptolide (TP) to form FDL@TP nanomicelles. The FDL@TP could target the joint and enhance the cell uptake of TP by M1 macrophages (overexpressing folate receptor-ß), which also reduced the side effects of TP on normal tissues. In M1 macrophages, the released TP, acted as an anti-inflammatory and immunosuppressant, obviously down-regulated the expressions of cGAS and STING protein, and thus reduced the secretion of TNF-α, IL-1ß and IL-6. Importantly, compared with the same dose of free TP, FDL@TP could significantly enhance the anti-inflammatory effect. Therefore, FDL@TP nanomicelles were believed to be superior candidates for the clinical treatment of RA.
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Artritis Reumatoide , Micelas , Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Citocinas/metabolismo , Dextranos/metabolismo , Dextranos/uso terapéutico , Diterpenos , Compuestos Epoxi , Ácido Fólico/metabolismo , Humanos , Inmunosupresores/metabolismo , Inmunosupresores/uso terapéutico , Interleucina-6/metabolismo , Macrófagos/metabolismo , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/uso terapéutico , Fenantrenos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The abundant glutathione (GSH) in "cold" tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid-like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch "ON", but also led to the depletion of intracellular GSH. Ferroptosis was significantly enhanced after combination with sorafenib (SRF) and elicited a robust immune response inâ vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration.
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Ferroptosis , Neoplasias , Animales , Linfocitos T CD8-positivos , Línea Celular Tumoral , Glutatión , Inmunoterapia , Ratones , Neoplasias/tratamiento farmacológico , Sorafenib/farmacología , Sorafenib/uso terapéuticoRESUMEN
Protein drugs hold tremendous promise for therapeutic applications due to their direct and superior pharmacological effects. However, protein drugs can be degraded in blood stream and unable to cross many physical barriers to exert therapeutic effect. Degradable synthetic crosslinking is a versatile strategy to enhance the stability of the nanoparticle in a complex physiological medium and is helpful to get through physical barriers. Herein, crosslinked polypeptide (PABP) composed of poly-amino acids including cystine, tyrosine, lysine, ketal bridge, and polyethylene glycol (PEG) is modularly explored and synthesized for protein delivery. Notably, plasma membrane V-ATPase is the particular pathway which induces the macropinocytosis of the inner peptide analogous core (PAB/protein) after the outer PEG shell disassociation at tumor intercellular sites. In addition, PABP/protein achieves proteins' activity shielding in systemic circulation and recovery in tumor cytoplasm precisely. In application, PABP/RNase-A shows satisfying tumor accumulation and antineoplastic efficacy. More importantly, PABP/Cas9 + small guide RNA displays obvious gene editing efficiency. The crosslinked protein delivery strategy not only makes the accurate protein transport and activity regulation possible but also is promising in paving the way for clinical translation of protein drugs.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Edición Génica , Humanos , Micelas , Neoplasias/tratamiento farmacológico , Péptidos/farmacología , Polietilenglicoles/químicaRESUMEN
Metastasis is refractory systemic disease resulting in low survival rate of breast cancer patients, especially in the late stage. The processes of metastasis are mainly initiated by strong "attractive force" from distant organs and deteriorated by weak "adhesion force" in primary tumor. Here, we reported "attractive/adhesion force" dual-regulatory nanogels (CQ-HF/PTX) for the precise treatment of both primary and metastasis of metastatic breast cancer. Hydroxychloroquine (HCQ) and hydrophobic Fmoc were grafted on hydrophilic hydroxyethyl starch (HES) to obtain amphiphilic CQ-HF polymer, which was assembly with chemotherapy drug paclitaxel (PTX) to form the nanogels for anti-primary tumor. Meanwhile, CQ-HF/PTX nanogels play two roles in anti-metastasis: i) For reducing the "attractive force", it could block the CXCR4/SDF-1 pathway, preventing tumor cells metastasis to the lung; ii) For reinforcing "adhesion force", it could inhibit the excessive autophagy for hindering the degradation of paxillin and enhancing the cell adhesion. As a result, dual-regulatory CQ-HF/PTX nanogels dramatically inhibited tumor and the lung metastasis of mouse breast cancer. Therefore, the fabricating of synergetic dual-regulatory nanogels uncovered the explicit mechanism and provided an efficient strategy for combating malignant metastatic tumors.
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Neoplasias de la Mama , Animales , Autofagia , Neoplasias de la Mama/patología , Adhesión Celular , Femenino , Humanos , Ratones , Nanogeles , Paclitaxel , Receptores CXCR4RESUMEN
BACKGROUND: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death. PURPOSE: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor ß (TGFß) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFß silencing and CXCR4 Inhibition, respectively, to treat CCl4-induced liver fibrosis in a mouse model. METHODS: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFß silencing of PEI-Cyclam polyplex was authenticated by Western blotting. RESULTS: The 1H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFß polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFß polyplex significantly downregulated α-smooth muscle actin, TGFß, and collagen type III. CONCLUSION: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFß siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl4-induced liver fibrosis.
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Tetracloruro de Carbono/efectos adversos , Compuestos Heterocíclicos/química , Cirrosis Hepática/genética , Polietileneimina/química , ARN Interferente Pequeño/genética , Factor de Crecimiento Transformador beta/genética , Animales , Apoptosis/efectos de los fármacos , Portadores de Fármacos/química , Silenciador del Gen , Humanos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Ratones , Tamaño de la Partícula , ARN Interferente Pequeño/química , Receptores CXCR4/genética , Factor de Crecimiento Transformador beta/deficienciaRESUMEN
Self-assembled nanofibers hold tremendous promise for cancer theranostics owing to their in situ assembly, spatiotemporal responsiveness, and diverse bioactivity. Herein, this review summarizes the recent advances of self-assembled peptide nanofibers and their applications in biological systems, focusing on the dynamic process of capturing cancer cells from the outside-in. (1) In situ self-assembly in response to pathological or physiological changes. (2) Diverse functions at different locations of tumors, such as forming thrombus in tumor vasculature, constructing a barrier on the cancer cell membrane, and disrupting the cancer organelles. Of note, with the assembly/aggregation induced residence (AIR) effect, the nanofibers could form a drug depot in situ for sustained release of chemotherapeutic drugs to increase their local concentration and prolong the residence time. Finally, perspectives toward future directions and challenges are presented to further understand and expand this exciting field.
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Nanofibras , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Péptidos , Medicina de PrecisiónRESUMEN
Gasdermin D (GSDMD) plays a causal role in NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis eruption, which has been regarded as a potential therapeutic target for pyroptosis-related diseases including acute gouty arthritis. In the present study, the synthesized PEI-Chol (cholesterol grafted polyethylenimine) was assembled with GSDMD small interfering RNA (siRNA) to form PEI-Chol/siGSDMD polyplexes, which provided high transfection efficiency for siRNA-mediated GSDMD knockdown. Then we evaluated the effect of GSDMD siRNA-loaded PEI-Chol on inflammatory cascades in bone-marrow-derived macrophages (BMDMs) and acute gouty arthritis animal models under MSU exposure. When accompanied by pyroptosis blockade and decreased release of interleukin-1 beta (IL-1ß), NLRP3 inflammasome activation was also suppressed by GSDMD knockdown in vivo and in vitro. Moreover, in MSU-induced acute gouty arthritis mice, blocking GSDMD with siRNA significantly improved ankle swelling and inflammatory infiltration observed in histopathological analysis. Furthermore, investigation using a mouse air pouch model verified the effect of siGSDMD-loaded PEI-Chol on pyroptosis of recruited macrophages and related signaling pathways in response to MSU. These novel findings exhibited that GSDMD knockdown relieved acute gouty arthritis through inhibiting pyroptosis, providing a possible therapeutic approach for MSU-induced acute gouty arthritis molecular therapy using PEI-Chol as a nucleic acid delivery carrier.
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Artritis Gotosa/tratamiento farmacológico , Portadores de Fármacos/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas de Unión a Fosfato/antagonistas & inhibidores , Piroptosis/efectos de los fármacos , ARN Interferente Pequeño/administración & dosificación , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Gotosa/inducido químicamente , Artritis Gotosa/inmunología , Artritis Gotosa/patología , Células Cultivadas , Colesterol , Técnicas de Silenciamiento del Gen/métodos , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo , Polietileneimina/química , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Ácido Úrico/administración & dosificación , Ácido Úrico/toxicidadRESUMEN
The high redox level of tumor microenvironment inhibits the oxidation treatment and the immune response. Here, we innovatively develop maleimide liposome (ML) adjuvants to promote immunogenic cell death (ICD) induction and dendritic cells (DCs) maturation by glutathione (GSH) depletion for augmenting the photothermal immunotherapy of breast cancer. The ML effectively depletes the intracellular GSH and up-regulates reactive oxygen species (ROS) in both tumor cells and DCs. In tumor cells, the ROS boosted the ABTS·+ production to activate photothermal-induced ICD. In DCs, it relieved the immunosuppression, promoting DC maturation (57%) and antigen presenting. As a result of the ML assistant, the therapeutic systems improved the infiltration of CD8+ T cells to 53% in tumor tissues, eliciting strong abscopal effect and antimetastasis effect. The MLs were believed to be a superior candidate of adjuvants for enhancing immune response and cancer therapeutic efficacy.
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Neoplasias de la Mama , Liposomas , Neoplasias de la Mama/terapia , Linfocitos T CD8-positivos , Línea Celular Tumoral , Femenino , Glutatión , Humanos , Inmunoterapia , Especies Reactivas de Oxígeno , Microambiente TumoralRESUMEN
Protein drugs own a large share in the market and hold great prospects for the treatment of many diseases. However, the available protein drugs are limited to the extracellular target, owing to the inefficient transduction and activity modulation of proteins targeting intracellular environment. In this study, we constructed ATP-charged platforms to overcome the above-mentioned barriers for cancer theranostics. The phenylboronic acid-modified polycations (PCD) were synthesized to assemble with enzymes and shield its activity in the blood circulation. When the PCD nanoclusters reached tumor site, they effectively transported the enzymes into the cells, followed by recovering its catalytic activity after being charged with ATP. Importantly, the cascaded enzyme systems (GOx&HRPA) selectively induced starvation therapy as well as photoacoustic imaging of tumor. Our results revealed that the intelligent nanoclusters were broadly applicable for protein transduction and enzyme activity modulation, which could accelerate the clinical translation of protein drugs toward intracellular target.
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Chemotherapy plays an important role in cancer treatment, yet its clinical application is inhibited by side effects. Chemotherapeutic agents accumulate at nonspecific sites and induce oxidative stress damage in noncancer tissues. A selective approach would be ideal, which would not only enhance anticancer efficacy in the tumor sites but also reduce chemotherapy-induced adverse effects on normal tissues. Therefore, we reported an adenosine-5'-triphosphate (ATP)-responsive oxidative stress nanoregulator (DePQu-DOX) to achieve the tissue-specific therapy. The DePQu-DOX NPs coloading doxorubicin (DOX) and quercetin (Qu) enhanced oxidative stress in murine breast cancer cells and scavenged DOX-induced oxygen free radicals in normal cardiac myocytes and podocytes. The released Qu could accelerate free radical scavenging more efficiently in oxygen-rich myocardium than in hypoxic tumors. Additionally, the ATP-specific responsiveness of nanocarriers enable cargos to selectively accumulate at tumor sites and decline the accumulation amount at normal tissues, resulting in lower system toxicity and improved anticancer effects. In vitro and in vivo experiments showed that this oxidative stress nanoregulator could efficiently protect normal tissues and significantly inhibit tumor growth. This study suggests that nanomedicine-mediated oxidative stress regulation could provide selective tumor therapeutics and reduce anthracycline-induced system toxicity.