RESUMO
The high level of lactate in tumor microenvironment not only promotes tumor development and metastasis, but also induces immune escape, which often leads to failures of various tumor therapy strategies. We here report a sono-triggered cascade lactate depletion strategy by using semiconducting polymer nanoreactors (SPNLCu) for cancer cuproptosis-immunotherapy. The SPNLCu mainly contain a semiconducting polymer as sonosensitizer, lactate oxidase (LOx) conjugated via a reactive oxygen species (ROS)-cleavable linker and chelated Cu2+. Upon ultrasound (US) irradiation, the semiconducting polymer generates singlet oxygen (1O2) to cut ROS-cleavable linker to allow the release of LOx that catalyzes lactate depletion to produce hydrogen peroxide (H2O2). The Cu2+ will be reduced to Cu+ in tumor microenvironment, which reacts with the produced H2O2 to obtain hydroxyl radical (â OH) that further improves LOx release via destroying ROS-cleavable linkers. As such, sono-triggered cascade release of LOx achieves effective lactate depletion, thus relieving immunosuppressive roles of lactate. Moreover, the toxic Cu+ induces cuproptosis to cause immunogenic cell death (ICD) for activating antitumor immunological effect. SPNLCu are used to treat both subcutaneous and deep-tissue orthotopic pancreatic cancer with observably enhanced efficacy in restricting the tumor growths. This study thus provides a precise and effective lactate depletion tactic for cancer therapy.
Assuntos
Cobre , Imunoterapia , Ácido Láctico , Neoplasias Pancreáticas , Polímeros , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/terapia , Ácido Láctico/química , Ácido Láctico/metabolismo , Polímeros/química , Polímeros/farmacologia , Cobre/química , Humanos , Animais , Camundongos , Semicondutores , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/química , Oxigenases de Função Mista/metabolismo , Oxigenases de Função Mista/química , Ondas Ultrassônicas , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.
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Matriz Extracelular/metabolismo , Imunoterapia , Proteínas de Membrana , Nanopartículas , Fototerapia , Animais , Feminino , Proteínas de Membrana/agonistas , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/metabolismo , Processos FotoquímicosRESUMO
Malignant glioma remains incurable largely due to the aggressive and infiltrative nature, as well as the existence of blood-brain-barrier (BBB). Precise diagnosis of glioma, which aims to accurately delineate the tumor boundary for guiding surgical resection and provide reliable feedback of the therapeutic outcomes, is the critical step for successful treatment. Numerous imaging modalities have been developed for the efficient diagnosis of tumors from structural or functional aspects. However, the presence of BBB largely hampers the entrance of contrast agents (Cas) or probes into the brain, rendering the imaging performance highly compromised. The development of nanomaterials provides promising strategies for constructing nano-sized Cas or probes for accurate imaging of glioma owing to the BBB crossing ability and other unique advantages of nanomaterials, such as high loading capacity and stimuli-responsive properties. In this review, the recent progress of nanomaterials applied in single modal imaging modality and multimodal imaging for a comprehensive diagnosis is thoroughly summarized. Finally, the prospects and challenges are offered with the hope for its better development.
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Meios de Contraste , Diagnóstico por Imagem/métodos , Glioma/diagnóstico por imagem , Nanoestruturas , Animais , Barreira Hematoencefálica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Tomografia Computadorizada de Feixe Cônico , Meios de Contraste/química , Glioma/patologia , Imageamento por Ressonância Magnética , Nanoestruturas/química , Imagem Óptica/métodosRESUMO
Gas therapy (GT) has attracted increasing attention in recent years as a new cancer treatment method with favorable therapeutic efficacy and reduced side effects. Several gas molecules, such as nitric oxide (NO), carbon monoxide (CO), hydrogen (H2), hydrogen sulfide (H2S) and sulfur dioxide (SO2), have been employed to treat cancers by directly killing tumor cells, enhancing drug accumulation in tumors or sensitizing tumor cells to chemotherapy, photodynamic therapy or radiotherapy. Despite the great progress of gas therapy, most gas molecules are prone to nonspecific distribution when administered systemically, resulting in strong toxicity to normal tissues. Therefore, how to deliver and release gas molecules to targeted tissues on demand is the main issue to be considered before clinical applications of gas therapy. As a specific and noninvasive stimulus with deep penetration, near-infrared (NIR) light has been widely used to trigger the cleavage and release of gas from nano-prodrugs via photothermal or photodynamic effects, achieving the on-demand release of gas molecules with high controllability. In this review, we will summarize the recent progress in cancer gas therapy triggered by NIR light. Furthermore, the prospects and challenges in this field are presented, with the hope for ongoing development.
Assuntos
Gases/uso terapêutico , Raios Infravermelhos , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Animais , Gases/química , Gases/metabolismo , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/uso terapêutico , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Óxido Nítrico/uso terapêutico , Terapia Fototérmica/métodos , Pró-Fármacos/químicaRESUMO
Hyperglycemia-induced proximal tubule injury plays a critical role in the pathogenesis of diabetic nephropathy (DN). Attenuating high glucose (HG)-induced oxidative damage in renal tubular epithelial cells has been documented to ameliorate DN. Obacunone (OB), a natural bioactive compound isolated from the Rutaceae family, has been demonstrated to possess various pharmacological effects with low toxicity. However, the role of OB in DN has not yet been investigated. To explore the influence of OB on oxidative damage that is induced by HG and its potential mechanisms of action, we set up a high glucose model and induced oxidative damage in NRK-52E cells. OB could protect the NRK-52E cells from the HG-induced decrease of cell viability and the accumulation of ROS. The protective effects of OB were associated with its ability to increase the levels of antioxidants (SOD, GSH and CAT), inhibit the production of ROS, and stabilize the mitochondrial membrane potential. In addition, OB significantly downregulated the activity of GSK-3ß, enhanced the nuclear translocation of Nrf2 and increased the mRNA expression of the Nrf2-driven genes NQO-1 and HO-1 in HG-treated cells. OB also decreased the release of cytochrome c from the mitochondria to the cytosol and inhibited the activation of caspase-3 in HG-treated cells. Pretreatment with a GSK-3ß activator blocked the protective effects of OB, while pretreatment with a GSK-3ß inhibitor yielded opposite results. These findings indicate that the renoprotective effects of OB against HG-induced oxidative damage in NRK-52E cells may be mediated by its ability to inhibit oxidative stress and mitochondrial dysfunction through the GSK-3ß signaling pathway.
Assuntos
Antioxidantes/farmacologia , Benzoxepinas/farmacologia , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Limoninas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , RatosRESUMO
BACKGROUND: Our previous studies (Int J Nanomed 10:22, 2015) have indicated that a single large dose of mesoporous silica nanoparticles (MSNs) can induce severe and selective nephrotoxicity, which is closely related to inflammation mediated by the NF-κB pathway. However, the effect of MSNs on other organs and the interactions of nanomaterials with biological systems remain rudimentary. OBJECTIVE: This study aimed to clarify the biological behaviour and influence of MSNs on macrophages. METHODS: The mice received a single intraperitoneal injection of a suspension of 150, 300 of 600 mg/kg MSNs, and RAW 264.7 cells were treated with MSNs at various concentrations and times. Cell viability was determined by MTT assay and LDH release assay. The NF-κB pathway and the target proinflammatory cytokines IL-1ß and TNF-α were determined by western blotting or ELISA. Autophagy is considered as an emerging mechanism of nanomaterials. So the autophagic ultrastructural analysis, the determination of Beclin-1 and LC3 expression, and the calculation of LC3II dots were employed to verify autophagy activation. In addition, RNA interference, autophagy agonist and inhibitor were used to explore the role of autophagy in inflammation. RESULTS: The results indicated that MSNs are internalized into macrophages and induce cytotoxicity in a dose- and time-dependent manner. The NF-κB pathway, IL-1ß and TNF-α were induced and released by MSNs. The levels of Beclin-1 and LC3II dots were obviously up-regulated by MSNs, which indicated that autophagy was induced in the MSN-treated cells. Moreover, the enhanced autophagy can attenuate the inflammation mediated by the NF-κB pathway, whereas the inhibition of autophagy can contribute to inflammation. CONCLUSIONS: In summary, our results suggest that autophagy may be a possible protective factor in inflammation induced by MSNs in macrophages.
Assuntos
Autofagia/imunologia , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Interleucina-1beta/imunologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/ultraestrutura , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Porosidade , Fator de Necrose Tumoral alfa/imunologia , Regulação para CimaRESUMO
A novel rod-containing block copolymer is constructed by supramacromolecular self-assembly of α-cyclodextrin and a triblock copolymer with methoxy polyethylene glycol as the flanking chains and the midterm block alternately connected by 2,2-dimethylolbutyric acid and isophorone diisocyanate. The assembled rod-containing block copolymer shows an exciting phenomenon of concentration- and pH-dependent morphological switching of well-defined nanostructures. In the solutions at pH 9.2, spherical micelles, rod-like micelles, and hydrogel are observed successively with an increase of the concentration. Notably, the rod-like micelles are composed of spherical segments due to the combination of the crystalline cores of the spherical micelles. In addition, 1D nanostructures with different curvatures from linear rod-like micelles (pH 9.2) to ring-shaped micelles (pH 7.5) can be obtained by controlling the pH values of the assembled systems.
Assuntos
Micelas , Nanoestruturas/química , Nanotubos/química , Polímeros/química , CristalizaçãoRESUMO
Nanoscale drug delivery systems (nDDS) have been employed widely in enhancing the therapeutic efficacy of drugs against diseases with reduced side effects. Although several nDDS have been successfully approved for clinical use up to now, biological barriers between the administration site and the target site hinder the wider clinical adoption of nDDS in disease treatment. Polyethylene glycol (PEG)-modification (or PEGylation) has been regarded as the gold standard for stabilising nDDS in complex biological environment. However, the accelerated blood clearance (ABC) of PEGylated nDDS after repeated injections becomes great challenges for their clinical applications. Zwitterionic polymer, a novel family of anti-fouling materials, have evolved as an alternative to PEG due to their super-hydrophilicity and biocompatibility. Zwitterionic nDDS could avoid the generation of ABC phenomenon and exhibit longer blood circulation time than the PEGylated analogues. More impressively, zwitterionic nDDS have recently been shown to overcome multiple biological barriers such as nonspecific organ distribution, pressure gradients, impermeable cell membranes and lysosomal degradation without the need of any complex chemical modifications. The realization of overcoming multiple biological barriers by zwitterionic nDDS may simplify the current overly complex design of nDDS, which could facilitate their better clinical translation. Herein, we summarise the recent progress of zwitterionic nDDS at overcoming various biological barriers and analyse their underlying mechanisms. Finally, prospects and challenges are introduced to guide the rational design of zwitterionic nDDS for disease treatment.
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Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.
Assuntos
Glioma , Imageamento por Ressonância Magnética , Compostos de Manganês , Nanomedicina Teranóstica , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/terapia , Glioma/patologia , Animais , Camundongos , Humanos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Vacinas Anticâncer/química , Imunoterapia , Óxidos/química , Óxidos/farmacologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Barreira Hematoencefálica/metabolismo , Nanogéis/química , Imiquimode/química , Imiquimode/farmacologia , NanovacinasRESUMO
With only limited clinical patient benefit, focusing on new immune checkpoint pathways could be an important complement to current immune checkpoint drugs. In addition, not only does T cell-mediated adaptive immunity play an important role, but also macrophage-mediated innate immunity, due to its abundant presence in solid tumors. Here, we developed an engineered M1-like macrophage exosome, OX40L M1-exos. OX40L M1-exos can activate the adaptive immunity by activating the OX40/OX40L pathway and can reprogram M2-like tumor-associated macrophages into M1-like macrophages, thereby restoring and enhancing macrophage-mediated innate immunity. Our OX40L M1-exos achieved an effective synergistic effect of innate and adaptive immunity and achieved a potent therapeutic effect in a mouse breast cancer model, effectively inhibiting tumor growth and metastasis. These results suggest that OX40L M1-exos are an attractive therapeutic strategy and may be an important complement to current cancer immunotherapies.
Assuntos
Exossomos , Neoplasias , Humanos , Camundongos , Animais , Macrófagos , Imunoterapia/métodos , Imunidade Inata , Neoplasias/terapiaRESUMO
Enzymes provide a class of potential options to treat cancer, while the precise regulation of enzyme activities for effective and safe therapeutic actions has been poorly reported. Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared (NIR-II) photoactivatable ferroptosis-immunotherapy are reported in this study. Such nanoagents (termed SPHGA) consist of hemoglobin (Hb)-based semiconducting polymer (SP@Hb), adenosine deaminase (ADA) and glucose oxidase (GOx) with loadings in a thermal-responsive nanoparticle shell. NIR-II photoactivation of SPHGA results in the generation of heat to trigger on-demand releases of two enzymes (ADA and GOx) via destroying the thermal-responsive nanoparticle shells. In the tumor microenvironment, GOx oxidizes glucose to form hydrogen peroxide (H2O2), which promotes the Fenton reaction of iron in SP@Hb, resulting in an enhanced ferroptosis effect and immunogenic cell death (ICD). In addition, ADA degrades high-level adenosine to reverse the immunosuppressive microenvironment, thus amplifying antitumor immune responses. Via NIR-II photoactivatable ferroptosis-immunotherapy, SPHGA shows an improved effect to absolutely remove bilateral tumors and effectively suppress tumor metastases in subcutaneous 4T1 breast cancer models. This study presents a dual-enzyme-based nanoagent with controllable therapeutic actions for effective and precise cancer therapy.
Assuntos
Ferroptose , Imunoterapia , Raios Infravermelhos , Nanopartículas , Polímeros , Semicondutores , Ferroptose/efeitos dos fármacos , Animais , Imunoterapia/métodos , Camundongos , Polímeros/química , Polímeros/uso terapêutico , Feminino , Nanopartículas/uso terapêutico , Nanopartículas/química , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Glucose Oxidase/metabolismo , Glucose Oxidase/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Hemoglobinas/farmacologia , Hemoglobinas/metabolismoRESUMO
In this work, a promising treatment strategy for triggering robust antitumor immune responses in transarterial chemoembolization of hepatocellular carcinoma (HCC) is presented. The zeolitic imidazolate framework nanoparticles loaded with hypoxia-activated prodrug tirapazamine and immune adjuvant resiquimod facilitated in situ generation of nanovaccine via a facile approach. The nanovaccine can strengthen the ability of killing the liver cancer cells under hypoxic environment, while was capable of improving immunogenic tumor microenvironment and triggering strong antitumor immune responses by increasing the primary and distant intratumoral infiltration of immune cells such as cytotoxic T cells. Moreover, a porous microcarrier, approved by FDA as pharmaceutical excipient, was designed to achieve safe and effective delivery of the nanovaccine via transarterial therapy in rabbit orthotopic VX2 liver cancer model. The microcarrier exhibited the characteristics of excellent drug loading and occlusion of peripheral artery. The collaborative delivery of the microcarrier and nanovaccine demonstrated an exciting inhibitory effect on solid tumors and tumor metastases, which provided a great potential as novel combination therapy for HCC interventional therapy.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Animais , Coelhos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/patologia , Nanovacinas , Hipóxia/tratamento farmacológico , Microambiente TumoralRESUMO
Developing effective nanomedicines to cross the blood-brain barrier (BBB) for efficient glioma theranostics is still considered to be a challenging task. Here, we describe the development of macrophage membrane (MM)-coated nanoclusters (NCs) of ultrasmall iron oxide nanoparticles (USIO NPs) with dual pH- and reactive oxygen species (ROS)-responsivenesses for magnetic resonance (MR) imaging and chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Surface citrate-stabilized USIO NPs were solvothermally synthesized, sequentially modified with ethylenediamine and phenylboronic acid, and cross-linked with gossypol to form gossypol-USIO NCs (G-USIO NCs), which were further coated with MMs. The prepared MM-coated G-USIO NCs (G-USIO@MM NCs) with a mean size of 99.9 nm display tumor microenvironment (TME)-responsive gossypol and Fe release to promote intracellular ROS production and glutathione consumption. With the MM-mediated BBB crossing and glioma targeting, the G-USIO@MM NCs can specifically inhibit orthotopic glioma in vivo through the gossypol-mediated chemotherapy and Fe-mediated CDT. Meanwhile, USIO NPs can be dissociated from the NCs under the TME, thus allowing for effective T1-weighted glioma MR imaging. The developed G-USIO@MM NCs with simple components and drug as a crosslinker are promising for glioma theranostics, and may be extended to tackle other cancer types.
Assuntos
Glioma , Macrófagos , Nanomedicina Teranóstica , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/química , Imageamento por Ressonância Magnética , Humanos , Linhagem Celular Tumoral , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Espécies Reativas de Oxigênio/metabolismo , Membrana Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacosRESUMO
The heterogeneity of triple-negative breast cancers (TNBC) remains challenging for various treatments. Ferroptosis, a recently identified form of cell death resulting from the unrestrained peroxidation of phospholipids, represents a potential vulnerability in TNBC. In this study, a high intensity focused ultrasound (HIFU)-driven nanomotor is developed for effective therapy of TNBC through induction of ferroptosis. Through bioinformatics analysis of typical ferroptosis-associated genes in the FUSCCTNBC dataset, gambogic acid is identified as a promising ferroptosis drug and loaded it into the nanomotor. It is found that the rapid motion of nanomotors propelled by HIFU significantly enhanced tumor accumulation and penetration. More importantly, HIFU not only actuated nanomotors to trigger effective ferroptosis of TNBC cells, but also drove nanomotors to activate ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, resulting in effective tumor regression and prevention of metastases. Overall, HIFU-driven nanomotors show great potential for ferroptosis-immunotherapy of TNBC.
Assuntos
Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/terapia , Imunoterapia , Morte Celular , Biologia ComputacionalRESUMO
Nowadays, the photothermal therapy (PTT) has received widespread attention and research by rapidly killing tumors with local high temperature. However, due to the irregular edges of tumor and the blurred boundary between normal and necrotic tissues, the desirable treatment cannot be achieved by the single PTT, and excessive heat will cause serious inflammation in local tissues. Herein, an injectable composite hydrogel is prepared by the oxidized hyaluronic acid (OHA) and hydroxypropyl chitosan (HPCS) via the imine bonds, which is employed as the delivery substrate for functional substances. In the gel medium, the mesoporous polydopamine (MPDA) nanoparticles are incorporated as the high efficiency photothermal agent and a reservoir of DOX, which can achieve the good photothermal conversion performance and pulsed drug release. Besides, the addition of the curcumin-cyclodextrin host-guest inclusion complex (CUR@NH2-CD) in the composite hydrogel could reduce the inflammation caused by PTT. The composite hydrogel shows favorable the Hepa1-6 tumor inhibition in vivo by virtue of the comprehensive effect of the admired photothermal efficacy of MPDA, chemotherapy of DOX and anti-inflammatory of CUR. It can be predicted that the composite hydrogel has a broad prospect in the field of comprehensive therapy for tumor.
Assuntos
Quitosana , Nanopartículas , Neoplasias , Humanos , Quitosana/uso terapêutico , Terapia Fototérmica , Ácido Hialurônico/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Nanogéis/uso terapêutico , Fototerapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nanopartículas/química , Inflamação/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Hidrogéis/químicaRESUMO
The cutaneous wound in diabetic patients frequently encounters intractable pathogenic infections due to the hyperglycemia micromilieu which is conducive to bacterial growth and multiplication. Despite the extensive clinical use of antibiotics to treat bacterial infections, the emergence of drug-resistant and super pathogens as well as the potential side effects of antibiotics have elicited alarming challenges to public health. To address this daunting concern, we devise and develop a photo-activated cascade bio-heterojunctions (C-bio-HJs) for rapid sterilization and diabetic cutaneous regeneration. In the designed C-bio-HJs, photo-generated electron-hole pairs of graphite-phase carbon nitride (g-C3N4) are effectively separated with the marriage of molybdenum disulfide (MoS2), which achieves the augmented photodynamic antibacterial effect. Moreover, glucose oxidase (GOx) tethered on the bio-HJs catalyzes glucose into hydrogen peroxide (H2O2) in diabetic wounds for starvation therapy. Furthermore, Mo4+ enables the catalysis of H2O2 into a highly effective hydroxyl radical (·OH) for chemodynamic-photothermal combined antibacterial therapy. Both in vitro and in vivo results authenticate the cascading antibacterial properties and skin regeneration-promoting effects of the C-bio-HJs, which provide a facile strategy to combat diabetic wound healing through the synergistic GOx-primed dynamic therapies.
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Ischemic stroke (IS) refers to local brain tissue necrosis which is caused by impaired blood supply to the carotid artery or vertebrobasilar artery system. As the second leading cause of death in the world, IS has a high incidence and brings a heavy economic burden to all countries and regions because of its high disability rate. In order to effectively treat IS, a large number of drugs have been designed and developed. However, most drugs with good therapeutic effects confirmed in preclinical experiments have not been successfully applied to clinical treatment due to the low accumulation efficiency of drugs in IS areas after systematic administration. As an emerging strategy for the treatment of IS, stimuli-responsive nanomedicines have made great progress by precisely delivering drugs to the local site of IS. By response to the specific signals, stimuli-responsive nanomedicines change their particle size, shape, surface charge or structural integrity, which enables the enhanced drug delivery and controlled drug release within the IS tissue. This breakthrough approach not only enhances therapeutic efficiency but also mitigates the side effects commonly associated with thrombolytic and neuroprotective drugs. This review aims to comprehensively summarize the recent progress of stimuli-responsive nanomedicines for the treatment of IS. Furthermore, prospect is provided to look forward for the better development of this field.
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The past decades have witnessed great progress in cancer immunotherapy, which has profoundly revolutionized oncology, whereas low patient response rates and potential immune-related adverse events remain major clinical challenges. With the advantages of controlled delivery and modular flexibility, cancer nanomedicine has offered opportunities to strengthen antitumor immune responses and to sensitize tumor to immunotherapy. Furthermore, tumor-microenvironment (TME)-responsive nanomedicine has been demonstrated to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, increasing patient response rates to immunotherapy and reducing the immune-related side effects simultaneously. Here, the recent progress of TME-responsive nanomedicine for cancer immunotherapy is summarized, which responds to the signals in the TME, such as weak acidity, reductive environment, high-level reactive oxygen species, hypoxia, overexpressed enzymes, and high-level adenosine triphosphate. Moreover, the potential to combine nanomedicine-based therapy and immunotherapeutic strategies to overcome each step of the cancer-immunity cycle and to enhance antitumor effects is discussed. Finally, existing challenges and further perspectives in this rising field with the hope for improved development of clinical applications are discussed.
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Imunoterapia/métodos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Humanos , Imunidade/imunologia , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêuticoRESUMO
Cancer photo-immunotherapy (CPIT) as an ideal strategy can rapidly release hostile signals by appropriate dosage of focal laser irradiation to unmask primary tumor immunogenicity and can activate adaptive immunity to control distant metastases. However, many factors, including disordered immunometabolism, poor penetration of photothermal agents and immuno-regulators, inadequate laser penetration into the deep tumor region, restrict the therapeutic outcomes of CPIT. Here, a second near-infrared window (NIR-II) photo-immunometabolic cancer therapy (PICT) by a programmed raspberry-structured nanoadjuvant (PRNMT ) is presented that can potentiates efficient immunogenic cell death (ICD) in deep tumor tissue and alleviates immunometabolic disorder. The PRNMT is architected through self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor modified small-sized CuS nanoparticles (CuS5 ) and tumor microenvironment (TME) responsive cationized polymeric matrix. The TME can trigger the splitting and surface cationization of PRNMT into small cationized CuS5 that feature high transcytosis potential and TME immunometabolic regulation. Upon NIR-II irradiation, CuS5 induce homogeneous ICD and release immunometabolic regulator in deep tumor tissues, which ameliorates IDO-1 mediated immunometabolic disorder and further suppresses regulatory T cells infiltration. PRNMT mediated PICT effectively delays the primary murine mammary carcinoma 4T1 tumor growth and inhibits the lethal pulmonary metastasis in combination with programmed cell death protein 1 (PD1) blockade.
Assuntos
Neoplasias , Camundongos , Animais , Neoplasias/terapia , Cobre , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase , Transcitose , Microambiente TumoralRESUMO
INTRODUCTION: Red blood cell (or erythrocyte) membrane-camouflaged nanoparticles (RBC-NPs) not only have a superior circulation life and do not induce accelerated blood clearance but also possess special functions, which offers great potential in cancer therapy. AREAS COVERED: This review focuses on the recent advances of RBC-NPs for delivering various agents to treat cancers in light of their vital role in improving drug delivery. Meanwhile, the construction and in vivo behavior of RBC-NPs are discussed to provide an in-depth understanding of the basis of RBC-NPs for improved cancer drug delivery. EXPERT OPINION: Although RBC-NPs are quite prospective in delivering anti-cancer therapeutics, they are still in their infancy stage and many challenges need to be overcome for successful translation into the clinic. The preparation and modification of RBC membranes, the optimization of coating methods, the scale-up production and the quality control of RBC-NPs, and the drug loading and release should be carefully considered in the clinical translation of RBC-NPs for cancer therapy.