RESUMEN
The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.
Asunto(s)
Proteínas de Ciclo Celular , Nanopartículas , Proteolisis , Factores de Transcripción , Humanos , Proteolisis/efectos de los fármacos , Animales , Nanopartículas/química , Línea Celular Tumoral , Ratones , Factores de Transcripción/metabolismo , Femenino , Proteínas de Ciclo Celular/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Profármacos/farmacología , Profármacos/química , Fotoquimioterapia/métodos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente Tumoral/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteínas Nucleares/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Proteínas que Contienen BromodominioRESUMEN
Heterogeneous dual-site electrocatalysts are emerging cutting-edge materials for efficient electrochemical water splitting. However, the corresponding oxygen evolution reaction (OER) mechanism on these materials is still unclear. Herein, based on a series of in-situ spectroscopy experiments and density function theory (DFT) calculations, a new heterogeneous dual-site O-O bridging mechanism (DSBM) is proposed. This mechanism is to elucidate the sequential appearance of dual active sites through in-situ construction (hybrid ions undergo reconstruction initially), determine the crucial role of hybrid dual sites in this mechanism (with Ni sites preferentially adsorbing hydroxyls for catalysis followed by proton removal at Fe sites), assess the impact of O-O bond formation on the activation state of water (inducing orderliness of activated water), and investigate the universality (with Co doping in Ni(P4O11)). Under the guidance of this mechanism, with Fe-Ni(P4O11) as pre-catalyst, the in-situ formed Fe-Ni(OH)2 electrocatalyst has reached a record-low overpotential of 156.4 mV at current density of 18.0 mA cm-2. Successfully constructed Fe-Ni(P4O11)/Ti uplifting the overall efficacy of the phosphate from moderate to superior, positioning it as an innovative and highly proficient electrocatalyst for OER.
RESUMEN
mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence-known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen-presenting cells (APCs) can synthesize mutant neo-antigens and multi-antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T-cell receptor (TCR), CD134, and immune-modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large-scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA-based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA-based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA-based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA-based cancer immunotherapy are also discussed.
RESUMEN
Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.
Asunto(s)
Nanopartículas , Profármacos , Proteolisis , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Humanos , Animales , Proteolisis/efectos de los fármacos , Nanopartículas/química , Línea Celular Tumoral , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/metabolismo , Ratones , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/metabolismo , Factores de Transcripción/metabolismo , Ratones Desnudos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos , Proteínas que Contienen Bromodominio , Ubiquitina-Proteína LigasasRESUMEN
Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, the crucial role of bromodomain-containing protein 4 (BRD4)-RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC is revealed. A versatile nanosensitizer (RPB7H) is thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO2) nanoparticles to downregulate BRD4-RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulate at the tumor tissue and internalize into tumor cells by recognizing neuropilin-1 overexpressed in the tumor mass. HfO2 nanoparticles enhance RT effectiveness by amplifying X-ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT-induced H2O2 secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT-induced DNA damage repair. This versatile nanosensitizer, combined with X-ray irradiation, effectively regresses HNSCC tumor growth in a mouse model. The findings introduce a PROTAC prodrug-based radiosensitization strategy by targeting the BRD4-RAD51AP1 axis, may offer a promising avenue to augment RT and more effective HNSCC therapy.
Asunto(s)
Nanopartículas , Profármacos , Fármacos Sensibilizantes a Radiaciones , Factores de Transcripción , Profármacos/química , Profármacos/farmacología , Animales , Humanos , Línea Celular Tumoral , Ratones , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Factores de Transcripción/metabolismo , Nanopartículas/química , Proteínas de Ciclo Celular/metabolismo , Proteolisis/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Daño del ADN/efectos de los fármacos , Neuropilina-1/metabolismo , Proteínas que Contienen BromodominioRESUMEN
The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator may provide a novel avenue for enhanced PDAC immunotherapy.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Evasión Inmune , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Fibrosis , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Controllable activation of the innate immune adapter protein - stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential "on-target off-tumor" toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.
RESUMEN
The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-ß (TGF-ß) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-ß inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.
Asunto(s)
Neoplasias , Femenino , Animales , Ratones , Neoplasias/terapia , Fármacos Fotosensibilizantes/farmacología , Linfocitos Infiltrantes de Tumor , Inmunoterapia , Factor de Crecimiento Transformador beta/farmacología , Microambiente Tumoral , Línea Celular TumoralRESUMEN
The real-time detection of nitric oxide (NO) in living cells is essential to reveal its physiological processes. However, the popular electrochemical detection strategy is limited to the utilization of noble metals. The development of new detection candidates without noble metal species still maintaining excellent catalytic performance has become a big challenge. Herein, we propose a spinel oxide doped with heteroatom-Cu-doped Co3O4 (Cu-Co3O4) for the sensitive and selective detection of NO release from the living cells. The material is strategically designed with Cu occupying the tetrahedral (Td) center of Co3O4 through the formation of a Cu-O bond. The introduced Cu regulates the local coordination environment and optimizes the electronic structure of Co3O4, hybridizing with the N 2p orbital to enhance charge transfer. The CuTd site can well inhibit the current response to nitrite (NO2-), resulting in a high improvement in the electrochemical oxidation of NO. The selectivity of Cu-Co3O4 can be markedly improved by the pore size of the molecular sieve and the negative charge on the surface. The rapid transmission of electrons is due to the fact that Cu-Co3O4 can be uniformly and densely in situ grown on Ti foil. The rationally designed Cu-Co3O4 sensor displays excellent catalytic activity toward NO oxidation with a low limit of detection of 2.0 nM (S/N = 3) and high sensitivity of 1.9 µA nM-1 cm-2 in cell culture medium. The Cu-Co3O4 sensor also shows good biocompatibility to monitor the real-time NO release from living cells (human umbilical vein endothelial cells: HUVECs; macrophage: RAW 264.7 cells). It was found that a remarkable response to NO was obtained in different living cells when stimulated by l-arginine (l-Arg). Moreover, the developed biosensor could be used for real-time monitoring of NO released from macrophages polarized to a M1/M2 phenotype. This cheap and convenient doping strategy shows universality and can be used for sensor design of other Cu-doped transition metal materials. The Cu-Co3O4 sensor presents an excellent example through the design of proper materials to implement unique sensing requirements and sheds light on the promising strategy for electrochemical sensor fabrication.
Asunto(s)
Óxido Nítrico , Óxidos , Humanos , Óxidos/química , Células Endoteliales de la Vena Umbilical HumanaRESUMEN
The proteolysis targeting chimeras (PROTACs) approach has attracted extensive attention in the past decade, which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors. PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest (POI) via ubiquitin-proteasome system in a cycle-catalytic manner. The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable, which enormously extends the space of drug development. Furthermore, PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI. Nevertheless, PROTACs display high-efficiency and always-on properties to degrade POI, they may cause severe side effects due to an "on-target but off-tissue" protein degradation profile at the undesirable tissues and cells. Given that, the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets, which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation. Herein, we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs. We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells.
Asunto(s)
Neoplasias , Profármacos , Humanos , Proteolisis , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas/metabolismo , Neoplasias/tratamiento farmacológicoRESUMEN
As a "star molecule", nitric oxide (NO) either promotes or inhibits many physiological processes depending on its concentration. The in situ generation and monitoring of therapeutic gas molecules has been a problem that many researchers have been working to address due to the stochastic nature of gas molecule movement. There are still relatively few studies using short peptides as NO storage systems, and there are still challenges in monitoring NO release in situ with real-time imaging over long periods of time. In this work, a morphologically transformable NO release, diagnosis and treatment integrated multifunctional nanoplatform was fabricated. A new NO-activated probe (DPBTD) with emission in the first near infrared (NIR-I) region was encapsulated into the hydrophobic domains of Ac-KLVFFAL-NH2 peptide derivatives as a biosensor for NO release. Peptide scaffolds were endowed with the capacity of controlled NO release by the introduction of NO donor (organic nitrates). Interestingly, morphology of the nanoplatform could be transformed from one-dimensional (1D) nanowires to two-dimensional (2D) nanosheets via nanorods transition state under tip sonication, which was allowed for better cell uptake. Eventually, this nanocarrier was used for stimuli-responsive NO release, real-time imaging and treatment in tumor tissues of 4T1 tumor-bearing mice. This strategy expands the application potential of peptide-based nanomaterials and provides ideas for monitoring the progress of gas-mediated cancer therapy.
Asunto(s)
Técnicas Biosensibles , Nanopartículas , Neoplasias , Fotoquimioterapia , Ratones , Animales , Óxido Nítrico , Fotoquimioterapia/métodos , Péptidos , Nanopartículas/química , Línea Celular TumoralRESUMEN
The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8+ cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.
Asunto(s)
Vacunas contra el Cáncer , Melanoma Experimental , Animales , Humanos , Ratones , Recurrencia Local de Neoplasia , Inmunoterapia , Células Presentadoras de Antígenos , Vacunación , Interferones , Ratones Endogámicos C57BLRESUMEN
Electrochemical activation strategy is very effective to improve the intrinsic catalytic activity of metal phosphate toward the sluggish oxygen evolution reaction (OER) for water electrolysis. However, it is still challenging to operando trace the activated reconstruction and corresponding electrocatalytic dynamic mechanisms. Herein, a constant voltage activation strategy is adopted to in situ activate Ni2 P4 O12 , in which the break of NiONi bond and dissolution of PO4 3- groups could optimize the lattice oxygen, thus reconstructing an irreversible amorphous Ni(OH)2 layer with a thickness of 1.5-3.5 nm on the surface of Ni2 P4 O12 . The heterostructure electrocatalyst can afford an excellent OER activity in alkaline media with an overpotential of 216.5 mV at 27.0 mA cm-2 . Operando X-ray absorption fine structure spectroscopy analysis and density functional theory simulations indicate that the heterostructure follows a nonconcerted proton-electron transfer mechanism for OER. This activation strategy demonstrates universality and can be used to the surface reconstruction of other metal phosphates.
RESUMEN
Chemoradiotherapy is the standard of care for the clinical treatment of locally advanced head and neck cancers. However, the combination of ion radiation with free chemotherapeutics yields unsatisfactory therapeutic output and severe side effects due to the nonspecific biodistribution of the anticancer drugs. Herein, a self-cooperative prodrug nanovesicle is reported for highly tumor-specific chemoradiotherapy. The nanovesicles integrating a prodrug of oxaliplatin (OXA) can passively accumulate at the tumor site and penetrate deep into the tumor mass via matrix metalloproteinase 2-mediated cleavage of the polyethylene glycol corona. The OXA prodrug can be restored inside the tumor cells with endogenous glutathione to trigger immunogenic cell death (ICD) of the tumor cells and sensitize the tumor to ion radiation. The nanovesicles can be further loaded with the JAK inhibitor ruxolitinib to abolish chemoradiotherapy-induced programmed death ligand 1 (PD-L1) upregulation on the surface of the tumor cells, thereby prompting chemoradiotherapy-induced immunotherapy by blocking the interferon gamma-Janus kinase-signal transducer and activator of transcription axis. The prodrug nanoplatform reported herein might present a novel strategy to cooperatively enhance chemoradiotherapy of head and cancer and overcome PD-L1-dependent immune evasion.
Asunto(s)
Neoplasias de Cabeza y Cuello , Profármacos , Humanos , Antígeno B7-H1/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Evasión Inmune , Distribución Tisular , Neoplasias de Cabeza y Cuello/terapia , Oxaliplatino , QuimioradioterapiaRESUMEN
Clear elucidation of the changes in Alzheimer's disease (AD)-related methylglyoxal (MGO) levels in vivo is significant yet highly challenging. Fluorescence imaging in the second near-infrared region (NIR-II, 1000-1700 nm) has gained increasing attention as an observation method in living organisms, but an MGO-activatable fluorescent probe that emits in this region for in vivo brain imaging is lacking because of the existence of the blood-brain barrier (BBB). Herein, a biocompatible Fe3O4 nanoparticle (IONP)-conjugated MGO-activatable NIR-II fluorescent probe (MAM) modified with the peptide T7 (HAIYPRH) (named TM-IONP) is reported for the in situ detection of MGO in a transgenic AD mouse model. In this system, the T7 peptide enhances BBB crossing and brain accumulation by specifically targeting transferrin receptors on the BBB. Due to the MAM probe, TM-IONPs emit fluorescence in the NIR-II region and display high selectivity with an MGO detection limit of 72 nM and a 10-fold increase in the fluorescence signal. After intravenous administration, the TM-IONPs are easily delivered to the brain and pass through the BBB without intervention, and as a result, the brains of AD mice can be noninvasively imaged for the first time by the in situ detection of MGO with a 24.2-fold enhancement in NIR-II fluorescence intensity compared with wild-type mice. Thus, this MGO-activated NIR-II-emitting nanoprobe is potentially useful for early AD diagnosis in clinic.
RESUMEN
Glioblastoma (GBM) therapy is severely impaired by the blood-brain barrier (BBB) and invasive tumor growth in the central nervous system. To improve GBM therapy, we herein presented a dual-targeting nanotheranostic for second near-infrared (NIR-II) fluorescence imaging-guided photo-immunotherapy. Firstly, a NIR-â ¡ fluorophore MRP bearing donor-acceptor-donor (D-A-D) backbone was synthesized. Then, the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1 (JPC) and T7 ligand-modified PEG5k-DSPE. T7 can cross the BBB for tumor-targeted delivery of JPC and MRP. JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells. MRP could generate NIR-II fluorescence to navigate 808 nm laser, induce a photothermal effect to trigger in-situ antigen release at the tumor site, and ultimately elicit antitumor immunogenicity. Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo. The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.
RESUMEN
PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.
Asunto(s)
Nanopartículas , Neoplasias , Animales , Humanos , Ratones , Proteínas de Ciclo Celular/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteolisis , Factores de Transcripción/metabolismo , Microambiente TumoralRESUMEN
Electrochemical water decomposition to produce hydrogen is a promising approach for renewable energy storage. It is vital to develop a catalyst with low overpotential, low cost and high stability for hydrogen evolution reaction (HER) under alkaline conditions. Herein, we used a simple hydrothermal method to obtain a AgCo(CO)4 precursor on the surface of carbon fiber paper (CFP). After thermal phosphorization, the self-supporting catalyst AgCoPO4/CFP was obtained, which greatly improved the HER catalytic performance under alkaline conditions. At 10 mA cm-2, it showed an overpotential of 32 mV. The Tafel slope was 34.4 mV dec-1. The high catalytic performance of AgCoPO4/CFP may be due to the hydrophilic surface promoting effective contact with the electrolyte and the synergistic effect of the two metals, which accelerated electron transfer and thus promoted hydrogen evolution reaction. In addition, it showed an outstanding urea oxidation reaction (UOR) activity. After adding 0.5 M urea, the over-potential of the AgCoPO4/CFP assembled electrolytic cell was only 1.45 V when the current density reached 10 mA cm-2, which was much lower than that required for overall water splitting. This work provides a new method for the design and synthesis of efficient HER electrocatalysts.
RESUMEN
Fluorescence imaging in the near-infrared (NIR) window has great potential for clinical diagnosis and treatment because of its deep penetration and high contrast. Here, a NIR hemicyanine-based probe (CyP) was synthesized for selective detection and imaging of Hg2+ in living cells and animals. Using the rigid xanthene structure as the electron donor, trimethylindolenine as the electron acceptor and diphenylphosphinothioic chloride as the recognition element, the probe CyP could specifically respond to Hg2+ and transform into an activated donor-π-acceptor (D-π-A) motif with a NIR emission maximum at 710 nm. Cell and animal imaging experiments showed that the probe CyP could be activated by Hg2+ and had good concentration dependence in imaging. Meanwhile, animal imaging experiments showed that the activated CyP probe exhibited a higher tissue penetration depth and spatiotemporal resolution. Thus, the probe CyP could be a useful tool for monitoring and visually evaluating Hg2+ in living systems.