RESUMEN
BACKGROUND: Cancer stem-like cells (CSCs) play an important role in initiation and progression of aggressive cancers, including esophageal cancer. Natural killer (NK) cells are key effector lymphocytes of innate immunity that directly attack a wide variety of cancer cells. NK cell-based therapy may provide a new treatment option for targeting CSCs. In this study, we aimed to investigate the sensitivity of human esophageal CSCs to NK cell-mediated cytotoxicity. METHODS: CSCs were enriched from human esophageal squamous cell carcinoma cell lines via sphere formation culture. Human NK cells were selectively expanded from the peripheral blood of healthy donors. qRT-PCR, flow cytometry and ELISA assays were performed to examine RNA expression and protein levels, respectively. CFSE-labeled target cells were co-cultured with human activated NK cells to detect the cytotoxicity of NK cells by flow cytometry. RESULTS: We observed that esophageal CSCs were more resistant to NK cell-mediated cytotoxicity compared with adherent counterparts. Consistently, esophageal CSCs showed down-regulated expression of ULBP-1, a ligand for NK cells stimulatory receptor NKG2D. Knockdown of ULBP-1 resulted in significant inhibition of NK cell cytotoxicity against esophageal CSCs, whereas ULBP-1 overexpression led to the opposite effect. Finally, the pro-differentiation agent all-trans retinoic acid was found to enhance the sensitivity of esophageal CSCs to NK cell cytotoxicity. CONCLUSIONS: This study reveals that esophageal CSCs are more resistant to NK cells through down-regulation of ULBP-1 and provides a promising approach to promote the activity of NK cells targeting esophageal CSCs.
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Citotoxicidad Inmunológica , Regulación hacia Abajo , Neoplasias Esofágicas , Células Asesinas Naturales , Células Madre Neoplásicas , Humanos , Células Asesinas Naturales/inmunología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Regulación hacia Abajo/efectos de los fármacos , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos , Proteínas Ligadas a GPI/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.
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Nanopartículas , Neoplasias , Humanos , Inmunoterapia , Lípidos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/farmacología , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
Immune stimulating complexes (ISCOMs) are safe and effective saponin-based adjuvants formed by the self-assembly of saponin, cholesterol, and phospholipids in water to form cage-like 30-40 nm diameter particles. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) in ISCOM particles yields a promising next-generation adjuvant termed Saponin-MPLA NanoParticles (SMNP). In this work, we detail protocols to produce ISCOMs or SMNP via a tangential flow filtration (TFF) process suitable for scalable synthesis and Good Manufacturing Practice (GMP) production of clinical-grade adjuvants. SMNP or ISCOM components were solubilized in micelles of the surfactant MEGA-10, then diluted below the critical micelle concentration (CMC) of the surfactant to drive ISCOM self-assembly. Assembly of ISCOM/SMNP particles using the purified saponin QS-21 used in clinical-grade saponin adjuvants was found to require controlled stepwise dilution of the initial micellar solution, to prevent formation of undesirable kinetically-trapped aggregate species. An optimized protocol gave yields of ~77% based on the initial feed of QS-21 and the final SMNP particle composition mirrored the feed ratios of the components. Further, samples were highly homogeneous with comparable quality to that of material prepared at lab scale by dialysis and purified via size-exclusion chromatography. This protocol may be useful for clinical preparation of ISCOM-based vaccine adjuvants and therapeutics.
RESUMEN
Chimeric antigen receptor (CAR) T cells remain unsatisfactory in treating solid tumors. The frequency of tumor-infiltrating T cells is closely related to the good prognosis of patients. Augmenting T cell accumulation in the tumor microenvironment is essential for tumor clearance. To overcome insufficient immune cell infiltration, innovative CAR designs need to be developed immediately. CXCL9 plays a pivotal role in regulating T cell migration and inhibiting tumor angiogenesis. Therefore, we engineered CAR T cells expressing CXCL9 (CART-CXCL9). The addition of CXCL9 enhanced cytokine secretion and cytotoxicity of CAR T cells and endowed CAR T cells with the ability to recruit activated T cells and antiangiogenic effect. In tumor-bearing mice, CART-CXCL9 cells attracted more T cell trafficking to the tumor site and inhibited angiogenesis than conventional CAR T cells. Additionally, CART-CXCL9 cell therapy slowed tumor growth and prolonged mouse survival, displaying superior antitumor activity. Briefly, modifying CAR T cells to express CXCL9 could effectively improve CAR T cell efficacy against solid tumors.
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Neoplasias , Receptores Quiméricos de Antígenos , Animales , Línea Celular Tumoral , Citocinas , Inmunoterapia Adoptiva , Ratones , Neoplasias/terapia , Receptores Quiméricos de Antígenos/genética , Linfocitos T , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe3O4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.
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Antineoplásicos/química , Ferroptosis/efectos de los fármacos , Hierro/química , Nanopartículas del Metal/química , Animales , Antineoplásicos/farmacocinética , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Inmunoterapia , Hierro/farmacocinética , Riñón , Ratones , Terapia Molecular Dirigida , Especies Reactivas de Oxígeno/metabolismo , Especificidad por Sustrato , Microambiente TumoralRESUMEN
Zinc-phthalocyanine (ZnPc) photosensitizers (PSs) have shown great potential in photodynamic therapy (PDT) owing to their strong absorption at long wavelengths (650-750 nm), high triplet quantum yields, and biocompatibility. However, the clinical utility of ZnPc PSs is limited by their poor solubility and tendency to aggregate in aqueous environments. Here we report the design of a new nanoscale metal-organic layer (nMOL) assembly, ZnOPPc@nMOL, with ZnOPPc [ZnOPPc = zinc(II)-2,3,9,10,16,17,23,24-octa(4-carboxyphenyl)phthalocyanine] PSs supported on the secondary building units (SBUs) of a Hf12 nMOL for PDT. Upon irradiation, SBU-bound ZnOPPc PSs absorb 700 nm light and efficiently sensitize the formation of singlet oxygen by preventing aggregation-induced self-quenching of ZnOPPc excited states. With intrinsic mitochondria-targeting capability, ZnOPPc@nMOL showed exceptional PDT efficacy with >99% tumor growth inhibition and 40-60% cure rates on two mouse models of colon cancer.
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Indoles/química , Indoles/farmacología , Mitocondrias/efectos de los fármacos , Nanomedicina , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Animales , Línea Celular Tumoral , Indoles/uso terapéutico , Isoindoles , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Compuestos Organometálicos/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Oxígeno Singlete/metabolismo , Solubilidad , Compuestos de ZincRESUMEN
Tandem catalytic reactions improve atom- and step-economy over traditional synthesis but are limited by the incompatibility of the required catalysts. Herein, we report the design of bifunctional metal-organic layers (MOLs), HfOTf-Fe and HfOTf-Mn, consisting of triflate (OTf)-capped Hf6 secondary building units (SBUs) as strong Lewis acidic centers and metalated TPY ligands as metal active sites for tandem catalytic transformations using O2 and CO2 as coreactants. HfOTf-Fe effectively transforms hydrocarbons into cyanohydrins via tandem oxidation with O2 and silylcyanation whereas HfOTf-Mn converts styrenes into styrene carbonates via tandem epoxidation and CO2 insertion. Density functional theory calculations revealed the involvement of a high-spin FeIV (S = 2) center in the challenging oxidation of the sp3 C-H bond. This work highlights the potential of MOLs as a tunable platform to incorporate multiple catalysts for tandem transformations.
RESUMEN
Cancer immunotherapy, particularly checkpoint blockade immunotherapy (CBI), has revolutionized the treatment of some cancers by reactivating the antitumor immunity of hosts with durable response and manageable toxicity. However, many cancer patients with low tumor antigen exposure and immunosuppressive tumor microenvironments do not respond to CBI. A variety of methods have been investigated to reverse immunosuppressive tumor microenvironments and turn "cold" tumors "hot" with the goal of extending the therapeutic benefits of CBI to a broader population of cancer patients. Immunostimulatory adjuvant treatments, such as cancer vaccines, photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT), promote antigen presentation and T cell priming and, when used in combination with CBI, reactivate and sustain systemic antitumor immunity. Cancer vaccines directly provide tumor antigens, while immunoadjuvant therapies such as PDT, RT, RT-RDT, and CDT kill cancer cells in an immunogenic fashion to release tumor antigens in situ. Direct administration of tumor antigens or indirect intratumoral immunoadjuvant therapies as in situ cancer vaccines initiate the immuno-oncology cycle for antitumor immune response.With the rapid growth of cancer nanotechnology in the past two decades, a large number of nanoparticle platforms have been studied, and some nanomedicines have been translated into clinical trials. Nanomedicine provides a promising strategy to enhance the efficacy of immunoadjuvant therapies to potentiate cancer immunotherapy. Among these nanoparticle platforms, nanoscale metal-organic frameworks (nMOFs) have emerged as a unique class of porous hybrid nanomaterials with metal cluster secondary building units and organic linkers. With molecular modularity, structural tunability, intrinsic porosity, tunable stability, and biocompatibility, nMOFs are ideally suited for biomedical applications, particularly cancer treatments.In this Account, we present recent breakthroughs in the design of nMOFs as nanocarriers for cancer vaccine delivery and as nanosensitizers for PDT, CDT, RT, and RT-RDT. The versatility of nMOFs allows them to be fine-tuned to effectively load tumor antigens and immunoadjuvants as cancer vaccines and significantly enhance the local antitumor efficacy of PDT, RT, RT-RDT, and CDT via generation of reactive oxygen species (ROS) for in situ cancer vaccination. These nMOF-based treatments are further combined with cancer immunotherapies to elicit systemic antitumor immunity. We discuss novel strategies to enhance light tissue penetration and overcome tumor hypoxia in PDT, to increase energy deposition and ROS diffusion in RT, to combine the advantages of PDT and RT to enable RT-RDT, and to trigger CDT by hijacking aberrant metabolic processes in tumors. Loading nMOFs with small-molecule drugs such as an indoleamine 2,3-dioxygenase inhibitor, the toll-like receptor agonist imiquimod, and biomacromolecules such as CpG oligodeoxynucleotides and anti-CD47 antibody synergizes with nMOF-based radical therapies to enhance their immunotherapeutic effects. Further combination with immune checkpoint inhibitors activates systemic antitumor immune responses and elicits abscopal effects. With structural and compositional tunability, nMOFs are poised to provide a new clinically deployable nanotechnology platform to promote immunostimulatory tumor microenvironments by delivering cancer vaccines, mediating PDT, enhancing RT, enabling RT-RDT, and catalyzing CDT and potentiate cancer immunotherapy.
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Inmunoterapia , Estructuras Metalorgánicas/química , Neoplasias/terapia , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Materiales Biocompatibles/química , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/uso terapéutico , Humanos , Activación de Linfocitos , Ratones , Nanoestructuras/química , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Porosidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy-radiodynamic therapy (RT-RDT). Herein, we report surface modification of a Hf-DBP nMOF for the co-delivery of a hydrophobic small-molecule toll-like receptor 7 agonist, imiquimod (IMD), and a hydrophilic macromolecule, anti-CD47 antibody (αCD47), for macrophage modulation and reversal of immunosuppression in tumors. IMD repolarizes immunosuppressive M2 macrophages to immunostimulatory M1 macrophages, while αCD47 blocks CD47 tumor cell surface marker to promote phagocytosis. Upon X-ray irradiation, IMD@Hf-DBP/αCD47 effectively modulates the immunosuppressive tumor microenvironment and activates innate immunity to orchestrate adaptive immunity when synergized with an anti-PD-L1 immune checkpoint inhibitor, leading to complete eradication of both primary and distant tumors on a bilateral colorectal tumor model. nMOFs thus provide a unique platform to co-deliver multiple immunoadjuvants for macrophage therapy to induce systematic immune responses and superb antitumor efficacy.
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Anticuerpos/farmacología , Antígeno CD47/antagonistas & inhibidores , Neoplasias Colorrectales/terapia , Imiquimod/farmacología , Inmunoterapia , Estructuras Metalorgánicas/química , Receptor Toll-Like 7/agonistas , Animales , Antígeno CD47/inmunología , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Nanoestructuras/química , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Receptor Toll-Like 7/inmunologíaRESUMEN
Herein we report the design of a bacteriochlorin-based nanoscale metal-organic framework, Zr-TBB, for highly effective photodynamic therapy via both type I and type II mechanisms. The framework of Zr-TBB stabilizes 5,10,15,20-tetra(p-benzoato)bacteriochlorin (TBB) ligands toward oxygen and light via geometrical constraint. Upon 740 nm light irradiation, Zr-TBB efficiently generates various reactive oxygen species, including singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radicals, to afford superb antitumor efficacy on mouse models of breast and colon cancers, with cure rates of 40% and 60%, respectively.
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Estructuras Metalorgánicas/efectos de la radiación , Nanomedicina/métodos , Fotoquimioterapia/métodos , Porfirinas/químicaRESUMEN
Cerium-based materials such as ceria are increasingly used in catalytic reactions. We report here the synthesis of the first Ce-based metal-organic layer (MOL), Ce6-BTB, comprising Ce6 secondary building units (SBUs) and 1,3,5-benzenetribenzoate (BTB) linkers, and its functionalization for photocatalytic hydrogen evolution reaction (HER). Ce6-BTB was postsynthetically modified with photosensitizing [(MBA)Ir(ppy)2]Cl or [(MBA)Ru(bpy)2]Cl2 (MBA = 2-(5'-methyl-[2,2'-bipyridin]-5-yl)acetate, ppy = 2-phenylpyridine, bpy = 2,2'-bipyridine) to afford Ce6-BTB-Ir or Ce6-BTB-Ru MOLs, respectively. The proximity of photosensitizing ligands and Ce6 SBUs in the MOLs facilitates electron transfer to drive photocatalytic HER under visible light with turnover numbers of 1357 and 484 for Ce6-BTB-Ir and Ce6-BTB-Ru, respectively. Photophysical and electrochemical studies revealed a novel dual photoexcitation pathway whereby the excited photosensitizers in the MOL are reductively quenched and then transfer electrons to Ce6 SBUs to generate CeIII centers, which are further photoexcited to CeIII* species for HER.
RESUMEN
Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale metal-organic framework, W-TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear WVI secondary building units and photosensitizing 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) ligands, cationic W-TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.
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Presentación de Antígeno/inmunología , Inmunoterapia/métodos , Estructuras Metalorgánicas/química , Oligodesoxirribonucleótidos/química , Fotoquimioterapia/métodos , HumanosRESUMEN
With tunability and porosity, nanoscale metal-organic frameworks (nMOFs) can incorporate multiple components to realize complex functions for biomedical applications. Here we report the synthesis of W18@Hf12-DBB-Ir, a new nMOF assembly hierarchically incorporating three high-Z components-Hf-based metal-oxo clusters, Ir-based bridging ligands, and W-based polyoxometalates (POMs)-as a multifarious radioenhancer. Cationic Hf12-DBB-Ir was built from Hf12 secondary building units (SBUs) and [Ir(bpy)2(ppy)]+ (bpy = 2,2'-bipyridine, ppy = 2-phenylpyridine) derived dicarboxylate ligands (DBB-Ir) and then loaded with Wells-Dawson-type [P2W18O62]6- (W18) POMs to afford W18@Hf12-DBB-Ir. Upon X-ray irradiation, W18@Hf12-DBB-Ir significantly enhances hydroxyl radical generation from Hf12 SBUs, singlet oxygen generation from DBB-Ir ligands, and superoxide generation from W18 POMs, respectively. Through synergistic cell killing by these distinct reactive oxygen species, W18@Hf12-DBB-Ir elicited superb anticancer efficacy with >98% tumor regression at a low X-ray dose of 5 × 1 Gy.
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Antineoplásicos/uso terapéutico , Estructuras Metalorgánicas/uso terapéutico , Nanoestructuras/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Radical Hidroxilo/metabolismo , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/efectos de la radiación , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanoestructuras/química , Nanoestructuras/efectos de la radiación , Fotoquimioterapia , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Oxígeno Singlete/metabolismo , Rayos XRESUMEN
As a monolayered version of nanoscale metal-organic frameworks (nMOFs), nanoscale metal-organic layers (nMOLs) represent an emerging class of highly tunable two-dimensional materials for hierarchical functionalization and with facile access to analytes. Here we report the design of the first nMOL-based biosensor for ratiometric pH and oxygen sensing in mitochondria. Cationic Hf12-Ru nMOL was solvothermally synthesized by laterally connecting Hf12 secondary building units (SBUs) with oxygen-sensitive Ru(bpy)32+-derived DBB-Ru ligands (bpy = 2,2'-bipyridine). The Hf12-Ru nMOL was then covalently functionalized with pH-sensitive fluorescein isothiocyanate and pH/oxygen-independent Rhodamine-B isothiocyanate through thiourea linkages to afford Hf12-Ru-F/R as a mitochondria-targeted ratiometric sensor for pH and O2 in live cells. High-resolution confocal microscope imaging with Hf12-Ru-F/R revealed a positive correlation between pH and local O2 concentration in mitochondria. Our work shows the potential of nMOL-based ratiometric biosensors in sensing and imaging of biologically important analytes in live cells.
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Técnicas Biosensibles/métodos , Estructuras Metalorgánicas/química , Nanoestructuras/química , Oxígeno/análisis , Línea Celular , Humanos , Concentración de Iones de Hidrógeno , Mitocondrias/química , Nanoestructuras/ultraestructuraRESUMEN
Nanoscale metal-organic frameworks (nMOFs) have shown great potential as nanophotosensitizers for photodynamic therapy (PDT) owing to their high photosensitizer loadings, facile diffusion of reactive oxygen species (ROSs) through their porous structures, and intrinsic biodegradability. The exploration of nMOFs in PDT, however, remains limited to an oxygen-dependent type II mechanism. Here we report the design of a new nMOF, Ti-TBP, composed of Ti-oxo chain secondary building units (SBUs) and photosensitizing 5,10,15,20-tetra( p-benzoato)porphyrin (TBP) ligands, for hypoxia-tolerant type I PDT. Upon light irradiation, Ti-TBP not only sensitizes singlet oxygen production, but also transfers electrons from excited TBP* species to Ti4+-based SBUs to afford TBPâ¢+ ligands and Ti3+ centers, thus propagating the generation of superoxide, hydrogen peroxide, and hydroxyl radicals. By generating four distinct ROSs, Ti-TBP-mediated PDT elicits superb anticancer efficacy with >98% tumor regression and 60% cure rate.
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Antineoplásicos/uso terapéutico , Estructuras Metalorgánicas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/uso terapéutico , Animales , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Luz , Estructuras Metalorgánicas/efectos de la radiación , Ratones Endogámicos BALB C , Nanoestructuras/efectos de la radiación , Nanoestructuras/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/efectos de la radiación , Porfirinas/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Titanio/química , Titanio/efectos de la radiaciónRESUMEN
Phototherapy involves the irradiation of tissues with light, and is commonly implemented in the forms of photodynamic therapy (PDT) and photothermal therapy (PTT). Photosensitizers (PSs) are often needed to improve the efficacy and selectivity of phototherapy via enhanced singlet oxygen generation in PDT and photothermal responses in PTT. In both cases, efficient and selective delivery of PSs to the diseased tissues is of paramount importance. Nanoscale metal-organic frameworks (nMOFs), a new class of hybrid materials built from metal connecting points and bridging ligands, have been examined as nanocarriers for drug delivery due to their compositional and structural tunability, highly porous structures, and good biocompatibility. This review summarizes recent advances on using nMOFs as nanoparticle PSs for applications in PDT and PTT.
RESUMEN
Nanoscale metal-organic layers (nMOLs) are an emerging class of 2D crystalline materials formed by reducing the dimensionality of nanoscale metal-organic frameworks (nMOFs). nMOLs hold significant potential in biomedical applications by combining the structural and compositional tunability of nMOFs and anisotropic properties of 2D nanomaterials. Here we report two novel nMOLs, Hf12-Ir and Hf6-Ir, based on Hf12 and Hf6 secondary building units (SBUs) and photosensitizing Ir(bpy)[dF(CF3)ppy]2+ derived ligands [bpy = 2,2'-bipyridine; dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine] for radiotherapy (RT) and radiodynamic therapy (RDT). Upon X-ray irradiation, the Hf12 or Hf6 SBUs in the nMOLs efficiently absorb X-rays to enhance RT by producing hydroxyl radicals and to elicit RDT through the excitation of Ir(bpy)[dF(CF3)ppy]2+ derived ligands to generate singlet oxygen and superoxide anions. Hf12-Ir and Hf6-Ir promoted effective cell instant death through RDT and cell reproductive death through RT to elicit superb anticancer efficacy, resulting in >99% tumor regression at low X-ray doses of 0.5 × 5 Gy.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Estructuras Metalorgánicas/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , ADN/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Radical Hidroxilo/metabolismo , Iridio/química , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/efectos de la radiación , Ratones Endogámicos C57BL , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Radioterapia/métodos , Oxígeno Singlete/metabolismo , Superóxidos/metabolismo , Rayos XRESUMEN
Immunotherapy has become a promising cancer therapy, but only works for a subset of cancer patients. Immunogenic photodynamic therapy (PDT) can prime cancer immunotherapy to increase the response rates, but its efficacy is severely limited by tumor hypoxia. Here we report a nanoscale metal-organic framework, Fe-TBP, as a novel nanophotosensitizer to overcome tumor hypoxia and sensitize effective PDT, priming non-inflamed tumors for cancer immunotherapy. Fe-TBP was built from iron-oxo clusters and porphyrin ligands and sensitized PDT under both normoxic and hypoxic conditions. Fe-TBP mediated PDT significantly improved the efficacy of anti-programmed death-ligand 1 (α-PD-L1) treatment and elicited abscopal effects in a mouse model of colorectal cancer, resulting in >90% regression of tumors. Mechanistic studies revealed that Fe-TBP mediated PDT induced significant tumor infiltration of cytotoxic T cells.
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Neoplasias Colorrectales/tratamiento farmacológico , Hipoxia/tratamiento farmacológico , Inmunoterapia , Estructuras Metalorgánicas/uso terapéutico , Nanoestructuras/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Hipoxia/metabolismo , Estructuras Metalorgánicas/química , Ratones , Fármacos Fotosensibilizantes/químicaRESUMEN
We report the rational design of metal-organic layers (MOLs) that are built from [Hf6 O4 (OH)4 (HCO2 )6 ] secondary building units (SBUs) and Ir[bpy(ppy)2 ]+ - or [Ru(bpy)3 ]2+ -derived tricarboxylate ligands (Hf-BPY-Ir or Hf-BPY-Ru; bpy=2,2'-bipyridine, ppy=2-phenylpyridine) and their applications in X-ray-induced photodynamic therapy (X-PDT) of colon cancer. Heavy Hf atoms in the SBUs efficiently absorb X-rays and transfer energy to Ir[bpy(ppy)2 ]+ or [Ru(bpy)3 ]2+ moieties to induce PDT by generating reactive oxygen species (ROS). The ability of X-rays to penetrate deeply into tissue and efficient ROS diffusion through ultrathin 2D MOLs (ca. 1.2â nm) enable highly effective X-PDT to afford superb anticancer efficacy.