RESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.
Asunto(s)
Antineoplásicos , Compuestos de Bifenilo , Resistencia a Antineoplásicos , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ligando Inductor de Apoptosis Relacionado con TNF , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/uso terapéutico , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/química , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Especies Reactivas de Oxígeno/metabolismo , Distribución Tisular , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Ligando Inductor de Apoptosis Relacionado con TNF/farmacologíaRESUMEN
Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-ß (CSF1R/CCR2/TGF-ß Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.
Asunto(s)
Monocitos , Receptor de Factor Estimulante de Colonias de Macrófagos , Receptores CCR2 , Microambiente Tumoral , Humanos , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inhibidores , Monocitos/metabolismo , Monocitos/inmunología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Femenino , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Ratones , Movimiento Celular/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/patologíaRESUMEN
Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.
Asunto(s)
Carbonato de Calcio , Carboplatino , Glioma , Hidrogeles , Ratones Endogámicos C57BL , Animales , Glioma/patología , Glioma/tratamiento farmacológico , Glioma/radioterapia , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carboplatino/farmacología , Hidrogeles/química , Línea Celular Tumoral , Carbonato de Calcio/química , Ratones , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapiaRESUMEN
The residual bone tumor and defects which is caused by surgical therapy of bone tumor is a major and important problem in clinicals. And the sequential treatment for irradiating residual tumor and repairing bone defects has wildly prospects. In this study, we developed a general modification strategy by gallic acid (GA)-assisted coordination chemistry to prepare black calcium-based materials, which combines the sequential photothermal therapy of bone tumor and bone defects. The GA modification endows the materials remarkable photothermal properties. Under the near-infrared (NIR) irradiation with different power densities, the black GA-modified bone matrix (GBM) did not merely display an excellent performance in eliminating bone tumor with high temperature, but showed a facile effect of the mild-heat stimulation to accelerate bone regeneration. GBM can efficiently regulate the microenvironments of bone regeneration in a spatial-temporal manner, including inflammation/immune response, vascularization and osteogenic differentiation. Meanwhile, the integrin/PI3K/Akt signaling pathway of bone marrow mesenchymal stem cells (BMSCs) was revealed to be involved in the effect of osteogenesis induced by the mild-heat stimulation. The outcome of this study not only provides a serial of new multifunctional biomaterials, but also demonstrates a general strategy for designing novel blacked calcium-based biomaterials with great potential for clinical use.
Asunto(s)
Neoplasias Óseas , Regeneración Ósea , Calcio , Ácido Gálico , Células Madre Mesenquimatosas , Ácido Gálico/química , Regeneración Ósea/efectos de los fármacos , Animales , Calcio/metabolismo , Neoplasias Óseas/terapia , Neoplasias Óseas/tratamiento farmacológico , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Terapia Fototérmica/métodos , Osteogénesis/efectos de los fármacos , Ratones , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Línea Celular TumoralRESUMEN
Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Microambiente Tumoral , Fotoquimioterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Animales , Nanopartículas/química , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Humanos , Ratones , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Transferencia de Energía , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ratones Endogámicos BALB C , Luz , Ratones Desnudos , Óxido Nítrico/metabolismoRESUMEN
Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.
Asunto(s)
Inmunoterapia , Nanomedicina , Animales , Inmunoterapia/métodos , Nanomedicina/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Terapia Fototérmica/métodos , Ratones , Humanos , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Proteínas/química , Femenino , Neoplasias/terapia , Neoplasias/inmunología , Adhesivos/química , Ratones Endogámicos C57BL , Adyuvantes Inmunológicos/farmacologíaRESUMEN
The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.
Asunto(s)
Cobre , Hidrogeles , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Activación de Linfocitos , Triterpenos Pentacíclicos , Especies Reactivas de Oxígeno , Linfocitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacología , Hidrogeles/química , Animales , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Activación de Linfocitos/efectos de los fármacos , Cobre/química , Microambiente Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/química , Femenino , Triterpenos/farmacología , Triterpenos/químicaRESUMEN
Copper-catalyzed click chemistry offers creative strategies for activation of therapeutics without disrupting biological processes. Despite tremendous efforts, current copper catalysts face fundamental challenges in achieving high efficiency, atom economy, and tissue-specific selectivity. Herein, we develop a facile "mix-and-match synthetic strategy" to fabricate a biomimetic single-site copper-bipyridine-based cerium metal-organic framework (Cu/Ce-MOF@M) for efficient and tumor cell-specific bioorthogonal catalysis. This elegant methodology achieves isolated single-Cu-site within the MOF architecture, resulting in exceptionally high catalytic performance. Cu/Ce-MOF@M favors a 32.1-fold higher catalytic activity than the widely used MOF-supported copper nanoparticles at single-particle level, as first evidenced by single-molecule fluorescence microscopy. Furthermore, with cancer cell-membrane camouflage, Cu/Ce-MOF@M demonstrates preferential tropism for its parent cells. Simultaneously, the single-site CuII species within Cu/Ce-MOF@M are reduced by upregulated glutathione in cancerous cells to CuI for catalyzing the click reaction, enabling homotypic cancer cell-activated in situ drug synthesis. Additionally, Cu/Ce-MOF@M exhibits oxidase and peroxidase mimicking activities, further enhancing catalytic cancer therapy. This study guides the reasonable design of highly active heterogeneous transition-metal catalysts for targeted bioorthogonal reactions.
Asunto(s)
Materiales Biomiméticos , Cobre , Humanos , Cobre/química , Materiales Biomiméticos/química , Catálisis , Estructuras Metalorgánicas/química , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Cerio/química , Línea Celular Tumoral , Animales , Química Clic/métodos , Biomimética/métodos , RatonesRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.
Asunto(s)
Neoplasias Colorrectales , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico , Oxaliplatino , Especies Reactivas de Oxígeno , Saponinas , Triterpenos , Animales , Humanos , Masculino , Ratones , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células HCT116 , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Oxaliplatino/farmacología , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Triterpenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.
Asunto(s)
Nanopartículas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Receptor Toll-Like 7/agonistas , Femenino , Nanopartículas/química , Ratones , Receptor Toll-Like 8/agonistas , Inmunomodulación/efectos de los fármacos , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Ratones Endogámicos BALB C , Micelas , HumanosRESUMEN
The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.
Asunto(s)
Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Proteínas de la Membrana , Mitoxantrona , Nucleotidiltransferasas , Factor de Transcripción STAT3 , Mitoxantrona/farmacología , Mitoxantrona/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Humanos , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Factor de Transcripción STAT3/metabolismo , Ratones , Inmunoterapia/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Benzofuranos , NaftoquinonasRESUMEN
Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.
Asunto(s)
Cobre , Nanomedicina , Células Madre Neoplásicas , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Animales , Femenino , Nanomedicina/métodos , Cobre/química , Cobre/farmacología , Línea Celular Tumoral , Ratones , Nanopartículas/química , Ratones Endogámicos BALB C , Terapia Fototérmica/métodos , Humanos , Polímeros/química , Indoles/farmacologíaRESUMEN
Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo, we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation.
Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Animales , Humanos , Distribución Tisular , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Oxazoles/química , Ratones , Propiedades de Superficie , Línea Celular Tumoral , Ratones Endogámicos C57BL , FemeninoRESUMEN
The notorious tumor microenvironment (TME) usually becomes more deteriorative during phototherapeutic progress that hampers the antitumor efficacy. To overcome this issue, we herein report the ameliorative and adaptive nanoparticles (TPASIC-PFH@PLGA NPs) that simultaneously reverse hypoxia TME and switch photoactivities from photothermal-dominated state to photodynamic-dominated state to maximize phototherapeutic effect. TPASIC-PFH@PLGA NPs are designed by incorporating oxygen-rich liquid perfluorohexane (PFH) into the intraparticle microenvironment to regulate the intramolecular motions of AIE photosensitizer TPASIC. TPASIC exhibits a unique aggregation-enhanced reactive oxygen species (ROS) generation feature. PFH incorporation affords TPASIC the initially dispersed state, thus promoting active intramolecular motions and photothermal conversion efficiency. While PFH volatilization leads to nanoparticle collapse and the formation of tight TPASIC aggregates with largely enhanced ROS generation efficiency. As a consequence, PFH incorporation not only currently promotes both photothermal and photodynamic efficacies of TPASIC and increases the intratumoral oxygen level, but also enables the smart photothermal-to-photodynamic switch to maximize the phototherapeutic performance. The integration of PFH and AIE photosensitizer eventually delivers more excellent antitumor effect over conventional phototherapeutic agents with fixed photothermal and photodynamic efficacies. This study proposes a new nanoengineering strategy to ameliorate TME and adapt the treatment modality to fit the changed TME for advanced antitumor applications.
Asunto(s)
Fluorocarburos , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Especies Reactivas de Oxígeno , Microambiente Tumoral , Nanopartículas/química , Microambiente Tumoral/efectos de los fármacos , Animales , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Fluorocarburos/química , Fluorocarburos/farmacología , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Humanos , Ratones , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ratones Endogámicos BALB C , Terapia Fototérmica/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fototerapia/métodos , FemeninoRESUMEN
Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (â¢OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.
Asunto(s)
Clorofilidas , Indoles , Platino (Metal) , Polímeros , Porfirinas , Neoplasias de la Tiroides , Microambiente Tumoral , Terapia por Ultrasonido , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Indoles/química , Terapia por Ultrasonido/métodos , Porfirinas/química , Porfirinas/farmacología , Polímeros/química , Animales , Platino (Metal)/química , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Ratones , Quinolinas/farmacología , Quinolinas/química , Ratones Desnudos , Portadores de Fármacos/químicaRESUMEN
Telomere length plays a crucial role in cellular aging and the risk of diseases. Unlike normal cells, cancer cells can extend their own survival by maintaining telomere stability through telomere maintenance mechanism. Therefore, regulating the lengths of telomeres have emerged as a promising approach for anti-cancer treatment. In this study, we introduce a nanoscale octopus-like structure designed to induce physical entangling of telomere, thereby efficiently triggering telomere dysfunction. The nanoscale octopus, composed of eight-armed PEG (8-arm-PEG), are functionalized with cell penetrating peptide (TAT) to facilitate nuclear entry and are covalently bound to N-Methyl Mesoporphyrin IX (NMM) to target G-quadruplexes (G4s) present in telomeres. The multi-armed configuration of the nanoscale octopus enables targeted binding to multiple G4s, physically disrupting and entangling numerous telomeres, thereby triggering telomere dysfunction. Both in vitro and in vivo experiments indicate that the nanoscale octopus significantly inhibits cancer cell proliferation, induces apoptosis through telomere entanglement, and ultimately suppresses tumor growth. This research offers a novel perspective for the development of innovative anti-cancer interventions and provides potential therapeutic options for targeting telomeres.
Asunto(s)
Apoptosis , Telómero , Telómero/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Animales , Línea Celular Tumoral , Ratones , G-Cuádruplex/efectos de los fármacos , Ratones Desnudos , Polietilenglicoles/química , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Femenino , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Nanoestructuras/químicaRESUMEN
The accumulation of photosensitizers (PSs) in lesion sites but not in other organs is an important challenge for efficient image guiding in photodynamic therapy. Cancer cells are known to express a significant number of albumin-binding proteins that take up albumin as a nutrient source. Here, we converted albumin to a novel BODIPY-like PS by generating a tetrahedral boron environment via a flick reaction. The formed albumin PS has almost the same 3-dimensional structural feature as free albumin because binding occurs at Sudlow Site 1, which is located in the interior space of albumin. An i.v. injection experiment in tumor-bearing mice demonstrated that the human serum albumin PS effectively accumulated in cancer tissue and, more surprisingly, albumin PS accumulated much more in the cancer tissue than in the liver and kidneys. The albumin PS was effective at killing tumor cells through the generation of reactive oxygen species under light irradiation. The crystal structure of the albumin PS was fully elucidated by X-ray crystallography; thus, further tuning of the structure will lead to novel physicochemical properties of the albumin PS, suggesting its potential in biological and clinical applications.
Asunto(s)
Compuestos de Boro , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fotoquimioterapia/métodos , Animales , Compuestos de Boro/química , Humanos , Ratones , Línea Celular Tumoral , Ratones Endogámicos BALB C , Especies Reactivas de Oxígeno/metabolismo , Ratones Desnudos , Albúminas/química , Albúminas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismoRESUMEN
Numerous nanoparticles have been utilized to deliver Fe2+ for tumor ferroptosis therapy, which can be readily converted to Fe3+via Fenton reactions to generate hydroxyl radical (â¢OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe3+ to Fe2+via Fenton reactions. Herein, a strategy of intratumor Fe3+/2+ cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe3+, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O2 can be catalyzed into superoxide anion (O2â¢-) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O2â¢-. The O2â¢- can react with Fe3+ to generate Fe2+, and raise H2O2 level via the superoxide dismutase. The generated Fe2+ and H2O2 can be fast converted into Fe3+ and â¢OH via Fenton reactions. The cyclic catalysis of intratumor Fe3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.
Asunto(s)
Ferroptosis , Hierro , Ferroptosis/efectos de los fármacos , Animales , Catálisis , Humanos , Hierro/química , Línea Celular Tumoral , Nanopartículas/química , Porosidad , Ratones , Cisplatino/química , Cisplatino/uso terapéutico , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Ratones Endogámicos BALB C , Peróxido de Hidrógeno/química , Microambiente Tumoral/efectos de los fármacos , Ratones Desnudos , FemeninoRESUMEN
Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.
Asunto(s)
Neoplasias de la Mama , Senescencia Celular , Resistencia a Antineoplásicos , Células Madre Neoplásicas , Humanos , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Senescencia Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ingeniería Genética/métodos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Nanopartículas/química , Anticuerpos de Cadena Única/química , Escape del Tumor/efectos de los fármacos , Antígeno B7-H1/metabolismo , Apoptosis/efectos de los fármacos , Biomimética/métodos , Antígenos B7RESUMEN
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.