RESUMO
Combining immune checkpoint blockade (ICB) therapy with chemotherapy can enhance the efficacy of ICB and expand its indications. However, the limited tumor specificity of chemotherapy drugs results in severe adverse reactions. Additionally, the low tissue penetration and immune-related adverse events associated with monoclonal antibodies restrict their widespread application. To address challenges faced by traditional combination therapies, we design a dual-responsive engineered nanoparticle based on ferritin (denoted as CMFn@OXA), achieving tumor-targeted delivery and controlled release of the anti-PD-L1 peptide CLP002 and oxaliplatin (OXA). Our results demonstrate that CMFn@OXA not only exhibits tumor-specific accumulation but also responds to matrix metalloproteinase-2/9 (MMP-2/9), facilitating the controlled release of CLP002 to block PD-1/PD-L1 interaction. Simultaneously, it ensures the precise delivery of the OXA to tumor cells and its subsequent release within the acidic environment of lysosomes, thereby fostering a synergistic therapeutic effect. Compared to traditional combination therapies, CMFn@OXA demonstrates superior performance in inhibiting tumor growth, extending the survival of tumor-bearing mice, and exhibiting excellent biocompatibility. Collectively, our results highlight CMFn@OXA as a novel and promising strategy in the field of cancer immunotherapy.
Assuntos
Nanopartículas , Neoplasias , Animais , Camundongos , Metaloproteinase 2 da Matriz , Preparações de Ação Retardada , Neoplasias/tratamento farmacológico , Oxaliplatina/farmacologia , Imunoterapia/métodos , Concentração de Íons de Hidrogênio , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.
Assuntos
Autofagia , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteólise , Proteínas Mutantes/metabolismo , Proteínas Mutantes/farmacologia , Linhagem Celular Tumoral , Peptídeos/metabolismo , Lipídeos/farmacologiaRESUMO
Immunogenic cell death (ICD) represents a promising approach for enhancing tumor therapy efficacy by inducing antitumor immune response. However, current ICD inducers often have insufficient endoplasmic reticulum (ER) enrichment and ineffectiveness in tumor immune escape caused by ER-mitochondria interaction. In this study, a kind of photoactivatable probe, THTTPy-PTSA, which enables sequential targeting of the ER and mitochondria is developed. THTTPy-PTSA incorporates p-Toluenesulfonamide (PTSA) for ER targeting, and upon light irradiation, the tetrahydropyridine group undergoes a photo oxidative dehydrogenation reaction, transforming into a pyridinium group that acts as a mitochondria-targeting moiety. The results demonstrate that THTTPy-PTSA exhibits exceptional subcellular translocation from the ER to mitochondria upon light irradiation treatment, subsequently triggers a stronger ER stress response through a cascade-amplification effect. Importantly, the augmented ER stress leads to substantial therapeutic efficacy in a 4T1 tumor model by eliciting the release of numerous damage-associated molecular patterns, thereby inducing evident and widespread ICD, consequently enhancing the antitumor immune efficacy. Collectively, the findings emphasize the pivotal role of photodynamic modulation of the ER-mitochondria network, facilitated by THTTPy-PTSA with precise spatial and temporal regulation, in effectively bolstering the antitumor immune response. This innovative approach presents a promising alternative for addressing the challenges associated with cancer immunotherapy.
Assuntos
Retículo Endoplasmático , Neoplasias , Pirenos , Humanos , Retículo Endoplasmático/metabolismo , Imunoterapia , Neoplasias/terapia , Mitocôndrias/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND: In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells. RESULTS: We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model. CONCLUSIONS: Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.
Assuntos
Cério , Nanopartículas , Neoplasias Pancreáticas , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Genes p53 , Linhagem Celular Tumoral , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genéticaRESUMO
Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-ß. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.
Assuntos
Nanopartículas , Neoplasias , Neoplasias da Próstata , Masculino , Humanos , Próstata , Morte Celular Imunogênica , Neoplasias da Próstata/tratamento farmacológico , Imunoterapia , PolietilenoglicóisRESUMO
Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85ß protein expression contributes to tamoxifen resistance, and reveal p85ß protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high performance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.
Assuntos
Neoplasias da Mama , Tamoxifeno , Feminino , Humanos , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Cobre , Chumbo , NanoestruturasRESUMO
TP53 missense mutations that express highly stabilized mutant p53 protein (mutp53) driving tumorigenesis have been witnessed in a considerable percentage of human cancers. The attempt to induce degradation of mutp53 has thus been an attractive strategy to realize precise antitumor therapy, but currently, there has been no FDA-approved medication for mutp53 cancer. Herein, we discovered a small molecule compound crizotinib, an FDA-approved antitumor drug, exhibited outstanding mutp53-degrading capability. Crizotinib induced ubiquitination-mediated proteasomal degradation of wide-spectrum mutp53 but not the wild-type p53 protein. Degradation of mutp53 by crizotinib eliminated mutp53-conferred gain-of-function (GOF), leading to reduced cell proliferation, migration, demise, and cell cycle arrest, as well as enhanced sensitivity to doxorubicin-elicited killing in mutp53 cancer. To alleviate the side effects and improve the therapeutic effect, we adopted poly(ethylene glycol)-polylactide-co-glycolide (PEG-PLGA) nanomicelles to deliver the hydrophobic drugs doxorubicin and crizotinib, demonstrating that crizotinib nanomicelles effectively enhanced doxorubicin-elicited anticancer efficacy in a p53Y220C pancreatic cancer in vitro and in vivo via mutp53 degradation induced by crizotinib, manifesting its promising application in clinical practice. Our work therefore revealed that crizotinib exerted significant synergistic chemotherapy with doxorubicin and suggested a novel combination therapeutic strategy for targeting p53 cancer in further clinical application.
Assuntos
Doxorrubicina , Proteína Supressora de Tumor p53 , Humanos , Crizotinibe/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Mutação , Linhagem Celular TumoralRESUMO
Radiotherapy (RT), through the generation of reactive oxygen species (ROS) and DNA damage to tumor cells caused by high-energy irradiation, has been a widely applied cancer treatment strategy in clinic. However, the therapeutic effect of traditional RT is restricted by the insufficient radiation energy deposition and the side effects on normal tissues. Recently, multifunctional nano-formulations and synergistic therapy has been developed as attractive strategies for used to enhancing the efficacy and safety of RT. Herein, we show that a bimetallic nanozyme (copper-modified ruthenium nanoparticles, RuCu NPs), containing the high atomic number (Z) element Ru as a novel radiosensitizer, offers an ideal solution to RT sensitization, with ultrasensitive peroxidase (POD)-like activity and catalase (CAT)-like activity. Density functional theory (DFT) calculations also clarified the optimal POD-like catalytic ratio of RuCu NPs and further revealed the mechanism of its supper catalytic activity. Under X-ray exposure, RuCu NPs coated with poly(ethylene glycol) (PEG) exhibited simultaneously improved the ROS production and relieved tumor hypoxia in the acid tumor microenvironment (TME), and demonstrated remarkable therapeutic efficacy in the MDA-MB-231 breast cancer model. Our results provide a proof-of-concept for a RT sensitization strategy, which combine the intrinsic nature of high-Z element and the advantages of nanozymes to overcome the tricky drawbacks existed in radiotherapy, and further open a new direction of exploring novel nanozyme-based strategies for tumor catalytic therapy and synergistic radiotherapy.
Assuntos
Nanopartículas , Neoplasias , Radiossensibilizantes , Humanos , Espécies Reativas de Oxigênio , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Hipóxia Tumoral , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Compared with conventional closed-shell fluorophores, radical cations provide an opportunity for development of red-to-NIR fluorophores with small sizes and easy preparation. However, most radical cations reported in the literature suffer from poor stability in water solution and are almost non-emissive. To tackle this challenge, we herein develop a deep-red-emissive and water-stable pyrrole radical cation Pâ + -DPA-Zn, which can be easily generated from P-DPA-Zn by air oxidation. The deep-red-emissive Pâ + -DPA-Zn can be used for imaging-guided mitochondria-targeted delivery of Zn2+ into cancer cells to promote mutant p53 proteins degradation and abrogate mutp53-manifested gain of function, including reduced chemotherapy resistance, inhibited cancer cell migration, decreased tumor cell colony and sphere formation. The water-stable and deep-red emissive pyrrole radical cation is thus promising for cancer theranostic applications.
Assuntos
Neoplasias , Água , Humanos , Água/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Mutantes/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Cátions/metabolismo , PirróisRESUMO
Point mutations within the DNA-binding domain of the TP53 gene occur in a significant percentage of human cancer, leading to cellular accumulation of highly stabilized mutant p53 proteins (mutp53) with tumor-promoting properties. Depletion of mutp53, through inducing either autophagic or proteasomal degradation, is an attractive strategy for the therapy of p53-mutated cancer, but the currently-known degradation inducers, almost exclusively small molecules, are inadequate. Here we show that pH-responsive zeolitic imidazolate framework-8 (ZIF-8) offers a novel solution to mutp53 degradation. ZIF-8 facilitated ubiquitination-mediated and glutathionylation-dependent proteasomal degradation of all of the nine mutp53 we tested, including six hot-spot mutp53, but not the wild-type p53 protein. Sustained elevation of intracellular Zn++ level, resulted from decomposition of the internalized ZIF-8 in the acidic endosomes, decreased the intracellular reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and was essential for mutp53 glutathionylation and degradation. ZIF-8 modified with an Z1-RGD peptide, exhibiting enhanced cellular internalization and improved decomposition behavior, preferentially killed mutp53-expressing cancer cells and demonstrated remarkable therapeutic efficacy in a p53 S241F ES-2 ovarian cancer model as well as in a p53 Y220C patient-derived xenograft (PDX) breast cancer model. The ability to induce wide-spectrum mutp53 degradation gives ZIF-8 a clear advantage over other degradation-inducers, and engineered nanomaterials may be promising alternatives to small molecules for the development of mutp53-targeting drugs.
Assuntos
Proteína Supressora de Tumor p53 , Zeolitas , Linhagem Celular Tumoral , Genes p53 , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Proteína Supressora de Tumor p53/genéticaRESUMO
Phage therapy holds great promise for resolving the ever-worsening crisis of antibiotic resistance, but it also faces many challenges. One of the issues hampering phage therapy is the short blood residence time of bacteriophages. We have previously identified, through in vivo phage display, a blood circulation-prolonging peptide (BCP1) that was capable of significantly prolonging the blood retention time of a doxorubicin-loaded human ferritin nanocage, leading to enhanced therapeutic efficacy against tumors. Herein, we aimed to extend the application of BCP1 to anti-bacterial phage therapy. Methods: A genetically engineered M13 phage, BCP1-BGL, that displayed the BCP-1 peptide and expressed the restriction endonuclease Bgl II, was constructed. Taking advantage of the fact that BCP1 harbors an RGD motif (a three amino-acid sequence Arg-Gly-Asp with the ability to bind to integrins) and exerts its circulation-prolonging activity primarily through interaction with platelets, we further designed and fabricated a biomimetic phage-platelet hybrid nanoparticle (PPHN) via the physical binding of the BCP1-BGL phage to the platelet membrane nanoparticles derived via a repeated freeze-thaw procedure. A series of experiments in vitro and in vivo were conducted to reveal the long circulation and anti-bacterial capacities of BCP1-BGL phages and PPHNs. Results: The resulting PPHNs possessed a hydrodynamic size of 368 nm in deionized water, with each spherical membranous nanoparticle harboring approximately 12 rod-shaped phage particles stably bound to its surface. PPHNs, which were superior to the BCP1-BGL phages that displayed significantly prolonged anti-bacterial action in vivo against Escherichia coli infection, exhibited further extended blood retention time and optimal anti-bacterial performance in both the prophylactic and treatment approaches. Conclusion: Our work demonstrated a novel strategy in engineering biomimetic phage-based nanoparticles with improved blood retention and anti-bacterial performance and may have implications in phage therapy.
Assuntos
Antibacterianos/farmacologia , Bacteriófago M13/genética , Plaquetas/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Nanopartículas/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Animais , Infecções por Escherichia coli/microbiologia , Engenharia Genética , Masculino , Microrganismos Geneticamente Modificados/genética , Nanopartículas/química , Ratos , Ratos Sprague-DawleyRESUMO
Autophagy plays a critical role in intracellular metabolism and maintaining cellular homeostasis. Certain tumor cells present a higher basal autophagy rate and autophagy inhibition can lead to impaired metabolic dysfunction in autophagy-dependent tumor cells. Autophagy status in immune cells dictates their fate and response to antigen; however, autophagy in immune cells may be beneficial or detrimental depending on the developmental stage of the cell and more specifically its degree of differentiation. Autophagy-deficient hosts present variations in many metabolites, proteins and enzymes that may have tumor-promoting or -inhibiting effects. The centrality of autophagy in the metabolism of some cancers and immune cells poses as a critical target whose mechanisms must be further unraveled to optimize patient response and prevent tumor recurrence.
Assuntos
Autofagia , Imunoterapia/métodos , Neoplasias/terapia , Microambiente Tumoral/imunologia , Animais , Homeostase , Humanos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Sustaining blood retention for theranostic nanoparticles is a big challenge. Various approaches have been attempted and have demonstrated some success but limitations remain. We hypothesized that peptides capable of increasing blood residence time for M13 bacteriophage, a rod-shaped nanoparticle self-assembled from proteins and nucleic acids, should also prolong blood circulation for engineered nanoparticles. Here we demonstrate the feasibility of this approach by identifying a series of blood circulation-prolonging (BCP) peptides through in vivo screening of an M13 peptide phage display library. Intriguingly, the majority of the identified BCP peptides contained an arginine-glycine-aspartic acid (RGD) motif, which was necessary but insufficient for the circulation-prolonging activity. We further demonstrated that the RGD-mediated specific binding to platelets was primarily responsible for the enhanced blood retention of BCP1. The utility of the BCP1 peptide was demonstrated by fusion of the peptide to human heavy-chain ferritin (HFn), leading to significantly improved pharmacokinetic profile, enhanced tumor cell uptake and optimum anticancer efficacy for doxorubicin encapsulated in the HFn nanocage. Our results provided a proof-of-concept for an innovative yet simple strategy, which utilizes phage display to discover novel peptides with the capability of substantially prolonging blood circulation for engineered theranostic nanoparticles.