RESUMEN
Accurate diagnosis and effective treatment of tumors remain significant clinical challenges. While fluorescence imaging is essential for tumor detection, it has limitations in terms of specificity, penetration depth, and emission wavelength. Here, we report a novel glutathione (GSH)-responsive peptide self-assembly excimer probe (pSE) that optimizes two-photon tumor imaging and self-assisted counteraction of the cisplatin resistance in cancer cells. The GSH-responsive self-assembly of pSE induces a monomer-excimer transition of coumarin, promoting a near-infrared redshift of fluorescence emission under two-photon excitation. This process enhances penetration depth and minimizes interference from biological autofluorescence. Moreover, the intracellular self-assembly of pSE impacts GSH homeostasis, modulates relevant signaling pathways, and significantly reduces GSTP1 expression, resulting in decreased cisplatin efflux in cisplatin-resistant cancer cells. The proposed self-assembled excimer probe not only distinguishes cancer cells from normal cells but also enhances the efficacy of cisplatin chemotherapy, offering significant potential in tumor diagnosis and overcoming cisplatin-resistant tumors.
Asunto(s)
Antineoplásicos , Cisplatino , Resistencia a Antineoplásicos , Glutatión , Péptidos , Cisplatino/farmacología , Cisplatino/química , Humanos , Péptidos/química , Péptidos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Glutatión/metabolismo , Glutatión/química , Fotones , Imagen Óptica , Colorantes Fluorescentes/química , Cumarinas/química , Cumarinas/farmacología , Línea Celular TumoralRESUMEN
Tumor immunotherapy has become a research hotspot in cancer treatment, with macrophages playing a crucial role in tumor development. However, the tumor microenvironment restricts macrophage functionality, limiting their therapeutic potential. Therefore, modulating macrophage function and polarization is essential for enhancing tumor immunotherapy outcomes. Here, a supramolecular peptide amphiphile drug-delivery system (SPADS) is utilized to reprogram macrophages and reshape the tumor immune microenvironment (TIM) for immune-based therapies. The approach involved designing highly specific SPADS that selectively targets surface receptors of M2-type macrophages (M2-Mφ). These targeted peptides induced M2-Mφ repolarization into M1-type macrophages by dual inhibition of endoplasmic reticulum and oxidative stresses, resulting in improved macrophagic antitumor activity and immunoregulatory function. Additionally, TIM reshaping disrupted the immune evasion mechanisms employed by tumor cells, leading to increased infiltration, and activation of immune cells. Furthermore, the synergistic effect of macrophage reshaping and anti-PD-1 antibody (aPD-1) therapy significantly improved the immune system's ability to recognize and eliminate tumor cells, thereby enhancing tumor immunotherapy efficacy. SPADS utilization also induced lung metastasis suppression. Overall, this study demonstrates the potential of SPADS to drive macrophage reprogramming and reshape TIM, providing new insights, and directions for developing more effective immunotherapeutic approaches in cancer treatment.
Asunto(s)
Neoplasias de la Mama , Inmunoterapia , Nanosferas , Péptidos , Microambiente Tumoral , Macrófagos Asociados a Tumores , Microambiente Tumoral/efectos de los fármacos , Inmunoterapia/métodos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Animales , Nanosferas/química , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Péptidos/química , Péptidos/farmacología , Femenino , Ratones , Línea Celular Tumoral , Humanos , Ratones Endogámicos BALB CRESUMEN
Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.
Asunto(s)
Antígeno CD24 , Antígeno CD47 , Macrófagos , Péptidos , Fagocitosis , Transducción de Señal , Antígeno CD47/metabolismo , Antígeno CD47/inmunología , Animales , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones , Fagocitosis/efectos de los fármacos , Antígeno CD24/metabolismo , Antígeno CD24/inmunología , Femenino , Humanos , Línea Celular Tumoral , Péptidos/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Ratones Endogámicos BALB C , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Inmunoterapia/métodos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Anticuerpos/inmunología , Anticuerpos/farmacología , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidoresRESUMEN
Microvascular dysfunction following myocardial infarction exacerbates coronary flow obstruction and impairs the preservation of ventricular function. The apelinergic system, known for its pleiotropic effects on improving vascular function and repairing ischemic myocardium, has emerged as a promising therapeutic target for myocardial infarction. Despite its potential, the natural apelin peptide has an extremely short circulating half-life. Current apelin analogs have limited receptor binding efficacy and poor targeting, which restricts their clinical applications. In this study, we utilized an enzyme-responsive peptide self-assembly technique to develop an enzyme-responsive small molecule peptide that adapts to the expression levels of matrix metalloproteinases in myocardial infarction lesions. This peptide is engineered to respond to the high concentration of matrix metalloproteinases in the lesion area, allowing for precise and abundant presentation of the apelin motif. The changes in hydrophobicity allow the apelin motif to self-assemble into a supramolecular multivalent peptide ligand-SAMP. This self-assembly behavior not only prolongs the residence time of apelin in the myocardial infarction lesion but also enhances the receptor-ligand interaction through increased receptor binding affinity due to multivalency. Studies have demonstrated that SAMP significantly promotes angiogenesis after ischemia, reduces cardiomyocyte apoptosis, and improves cardiac function. This novel therapeutic strategy offers a new approach to restoring coronary microvascular function and improving damaged myocardium after myocardial infarction.
Asunto(s)
Apelina , Infarto del Miocardio , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Animales , Apelina/administración & dosificación , Apelina/metabolismo , Ligandos , Masculino , Ratones Endogámicos C57BL , Humanos , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence.