RESUMEN
Chemotherapy using a nanoscaled drug delivery system is an effective cancer therapy, but its high drug concentration often causes drug resistance in cancer cells and normal cell damage. Combination therapy involving two or more different cell signaling pathways can be a powerful tool to overcome the limitations of chemotherapy. Herein, this article presents nanogel (NG)-mediated co-delivery of a chemodrug camptothecin (CPT) and mitochondria-targeting monomer (MT monomer) for efficient activation of two modes of the programmed cell death pathway (apoptosis and necroptosis) and synergistic enhancement of cancer therapy. CPT and the monomer are incorporated together into the redox-degradable polymeric NGs for release in response to the intracellular glutathione. The MT monomer is shown to undergo reactive oxygen species (ROS)-triggered disulfide polymerization inside the cancerous mitochondria in cooperation with the chemotherapeutic CPT elevating the intracellular ROS level. The CPT/monomer interconnection in cell death mechanisms for mitochondrial dysfunction and enhanced cell death is evidenced by a series of cell analyses showing ROS generation, mitochondria damage, impacts on (non)cancerous or drug-resistant cells, and cell death modes. The presented work provides beneficial insights for utilizing combination therapy to facilitate a desired cell death mechanism and developing a novel nanosystem for more efficacious cancer treatment.
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Disulfuros , Neoplasias , Polietilenglicoles , Polietileneimina , Humanos , Nanogeles , Preparaciones Farmacéuticas , Disulfuros/farmacología , Especies Reactivas de Oxígeno/metabolismo , Polimerizacion , Muerte Celular , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Camptotecina/farmacología , Camptotecina/uso terapéuticoRESUMEN
Recent emphasis on the design of drug delivery systems typically involves the effective transport of a pharmaceutical substance to the disease site with the desired therapeutic efficacy and minimal cytotoxicity. Organelle-targeted peptides have become an integral part of designing an important class of prodrug/prodrug assemblies for new supramolecular therapeutics owing to their favorable biocompatibility, synthetic ease, tunability of their aggregation behavior, and desired functionalization for site-specificity. However, it is still limited due to the low selectivity. We designed a folic acid-functionalized ß-cyclodextrin (FA-CD) as a delivery platform for specific and selective delivery of organelle-targeted (such as microtubule, lysosome, and mitochondria) peptide chemotherapeutics to the folate receptor (FR) overexpressing cancer cell lines. Low toxicity was found for the FA-CD and organelle-targeted peptide inclusion complex in FR-negative normal cells, but superior inhibition of tumor growth with no in vivo toxicity was found for the inclusion complex in the xenograft tumor model.
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Sistemas de Liberación de Medicamentos , Ácido Fólico , Péptidos , Ensayos Antitumor por Modelo de Xenoinjerto , beta-Ciclodextrinas , Ácido Fólico/química , Humanos , beta-Ciclodextrinas/química , Animales , Ratones , Sistemas de Liberación de Medicamentos/métodos , Péptidos/química , Péptidos/farmacología , Línea Celular Tumoral , Orgánulos/efectos de los fármacos , Orgánulos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Receptores de Folato Anclados a GPI/metabolismo , Profármacos/química , Profármacos/farmacología , Profármacos/administración & dosificación , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , FemeninoRESUMEN
M13 bacteriophages serve as a versatile foundation for nanobiotechnology due to their unique biological and chemical properties. The polypeptides that comprise their coat proteins, specifically pVIII, can be precisely tailored through genetic engineering. This enables the customized integration of various functional elements through specific interactions, leading to the development of innovative hybrid materials for applications such as energy storage, biosensing, and catalysis. Notably, a certain genetically engineered M13 bacteriophage variant, referred to as DSPH, features a pVIII with a repeating DSPHTELP peptide sequence. This sequence facilitates specific adhesion to single-walled carbon nanotubes (SWCNTs), primarily through π-π and hydrophobic interactions, though the exact mechanism remains unconfirmed. In this study, we synthesized the DSPHTELP peptide (an 8-mer peptide) and analyzed its interaction forces with different functional groups across various pH levels using surface forces apparatus (SFA). Our findings indicate that the 8-mer peptide binds most strongly to CH3 groups (Wad = 13.74 ± 1.04 mJ m-2 at pH 3.0), suggesting that hydrophobic interactions are indeed the predominant mechanism. These insights offer both quantitative and qualitative understanding of the molecular interaction mechanisms of the 8-mer peptide and clarify the basis of its specific interaction with SWCNTs through the DSPHTELP M13 bacteriophage.
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Bacteriófago M13 , Interacciones Hidrofóbicas e Hidrofílicas , Nanotubos de Carbono , Péptidos , Nanotubos de Carbono/química , Bacteriófago M13/química , Bacteriófago M13/genética , Bacteriófago M13/metabolismo , Péptidos/química , Péptidos/metabolismo , Concentración de Iones de Hidrógeno , Proteínas de la Cápside/química , Proteínas de la Cápside/metabolismoRESUMEN
Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.
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Apoptosis , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Lisosomas/metabolismo , Caspasas/metabolismo , Péptidos/farmacología , Péptidos/metabolismo , Línea Celular TumoralRESUMEN
Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.
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Senescencia Celular , Senoterapéuticos , Ratones , Animales , Especies Reactivas de Oxígeno , Péptidos/farmacología , IntegrinasRESUMEN
Metal-organic framework (MOF) nanoparticles have recently emerged as a promising vehicle for drug delivery with high porosity and feasibility. However, employing a MOF-based drug delivery system remains a challenge due to the difficulty in controlling interfaces of particles in a biological environment. In this paper, protein corona-blocked Zr6 -based MOF (PCN-224) nanoparticles are presented for targeted cancer therapy with high efficiency. The unmodified PCN-224 surface is precoated with glutathione transferase (GST)-fused targetable affibody (GST-Afb) proteins via simple mixing conjugations instead of chemical modifications that can induce the impairment of proteins. GST-Afb proteins are shown to stably protect the surface of PCN-224 particles in a specific orientation with GST adsorbed onto the porous surface and the GST-linked Afb posed outward, minimizing the unwanted interfacial interactions of particles with external biological proteins. The Afb-directed cell-specific targeting ability of particles and consequent induction of cell death is demonstrated both in vitro and in vivo by using two kinds of Afb, which targets the surface membrane receptor, human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR). This study provides insight into the way of regulating the protein-adhesive surface of MOF nanoparticles and designing a more effective MOF-hosted targeted delivery system.
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Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Humanos , Estructuras Metalorgánicas/metabolismo , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Proteínas de la MembranaRESUMEN
Biological nanomachines, including proteins and nucleic acids whose function is activated by conformational changes, are involved in every biological process, in which their dynamic and responsive behaviors are controlled by supramolecular recognition. The development of artificial nanomachines that mimic the biological functions for potential application as therapeutics is emerging; however, it is still limited to the lower hierarchical level of the molecular components. In this work, we report a synthetic machinery nanostructure in which actuatable molecular components are integrated into a hierarchical nanomaterial in response to external stimuli to regulate biological functions. Two nanometers core-sized gold nanoparticles are covered with ligand layers as actuatable components, whose folding/unfolding motional response to the cellular environment enables the direct penetration of the nanoparticles across the cellular membrane to disrupt intracellular organelles. Furthermore, the pH-responsive conformational movements of the molecular components can induce the apoptosis of cancer cells. This strategy based on the mechanical motion of molecular components on a hierarchical nanocluster would be useful to design biomimetic nanotoxins.
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Fenómenos Biológicos , Nanopartículas del Metal , Nanoestructuras , Membrana Celular , Oro , Nanoestructuras/toxicidadRESUMEN
A new synthetic approach for tunable mesoporous metal-organic frameworks (MeMs) is developed. In this approach, mesopores are created in the process of heat conversion of highly mosaic metal-organic framework (MOF) crystals with non-interpenetrated low-density nanocrystallites into MOF crystals with two-fold interpenetrated high-density nanocrystallites. The two-fold interpenetration reduces the volume of the nanocrystallites in the mosaic crystal, and the accompanying localized agglomeration of the nanocrystallites results in the formation of mesopores among the localized crystallite agglomerates. The pore size can be easily modulated from 7 to 90 nm by controlling the heat treatment conditions, that is, the aging temperature and aging time. Various proteins can be encapsulated in the MeM, and immobilized enzymes show catalyst activity comparable to that of the free native enzymes. Immobilized ß-galactosidase is recyclable and the enzyme activity of the immobilized catalase is maintained after exposure to high temperatures and various organic solvents.
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Enzimas Inmovilizadas , Estructuras Metalorgánicas , Catálisis , Enzimas Inmovilizadas/metabolismo , Estructuras Metalorgánicas/química , TemperaturaRESUMEN
Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.
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Antineoplásicos/farmacología , Membranas Mitocondriales/efectos de los fármacos , Compuestos de Amonio/química , Compuestos de Amonio/farmacología , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Derivados del Benceno/química , Derivados del Benceno/farmacología , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Ratones , Estructura Molecular , Células 3T3 NIH , Fosfinas/química , Fosfinas/farmacologíaRESUMEN
The development of photosensitizers for cancer photodynamic therapy has been challenging due to their low photostability and therapeutic inefficacy in hypoxic tumor microenvironments. To overcome these issues, we have developed a mitochondria-targeted photosensitizer consisting of an indocyanine moiety with triphenylphosphonium arms, which can self-assemble into spherical micelles directed to mitochondria. Self-assembly of the photosensitizer resulted in a higher photostability by preventing free rotation of the indoline ring of the indocyanine moiety. The mitochondria targeting capability of the photosensitizer allowed it to utilize intramitochondrial oxygen. We found that the mitochondria-targeted photosensitizer localized to mitochondria and induced apoptosis of cancer cells both normoxic and hypoxic conditions through generation of ROS. The micellar self-assemblies of the photosensitizer were further confirmed to selectively localize to tumor tissues in a xenograft tumor mouse model through passive targeting and showed efficient tumor growth inhibition.
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Hipoxia de la Célula/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Ratones , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The intracellular or pericellular self-assembly of amphiphilic peptides is emerging as a potent cancer therapeutic strategy. Achieving the self-assembly of amphiphilic peptides inside a cell or cellular organelle is challenging due to the complex cellular environment, which consists of many amphiphilic biomolecules that may alter the self-assembling propensity of the synthetic peptides. Herein, we show that the hydrophobic-hydrophilic balance of the amphiphilic peptides determines the self-assembling propensity, thereby controlling the fate of the cell. A series of peptides were designed to target and self-assemble inside the mitochondria of cancer cells. The hydrophobicity of the peptides was tuned by varying their N-terminus capping. The analysis showed that the largest hydrophobic peptide was self-assembled before reaching the mitochondria and showed no selectivity toward cancer cells, whereas hydrophilic peptides could not self-assemble inside the mitochondria. Optimum balance between hydrophobicity and hydrophilicity is a critical factor for achieving self-assembly inside the mitochondria, thereby providing greater selectivity against cancer cells.
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Neoplasias , Péptidos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Mitocondrias , Neoplasias/tratamiento farmacológicoRESUMEN
Here, we provide the possibility of a novel chemotherapeutic agent against gastric cancer cells, comprising the combination of 5-fluorouracil (5-FU) and a mitochondria-targeting self-assembly peptide, which is a phenylalanine dipeptide with triphenyl phosphonium (Mito-FF). The anticancer effects and mechanisms of 5-FU and Mito-FF, individually or in combination, were compared through both in vitro and in vivo models of gastric cancer. Our experiments consistently demonstrated that the 5-FU and Mito-FF combination therapy was superior to monotherapy with either, as manifested by both higher reduction of proliferation as well as an induction of apoptotic cell death. Interestingly, we found that combining 5-FU with Mito-FF leads to a significant increase of reactive oxygen species (ROS) and reduction of antioxidant enzymes in gastric cancer cells. Moreover, the inhibition of ROS abrogated the pro-apoptotic effects of combination therapy, suggesting that enhanced oxidative stress could be the principal mechanism of the action of combination therapy. We conclude that the combination of 5-FU and Mito-FF exerts potent antineoplastic activity against gastric cancer cells, primarily by promoting ROS generation and suppressing the activities of antioxidant enzymes.
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Dipéptidos/administración & dosificación , Fluorouracilo/administración & dosificación , Mitocondrias/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Animales , Catalasa/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dipéptidos/química , Dipéptidos/farmacología , Sinergismo Farmacológico , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/genética , Humanos , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Superóxido Dismutasa/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Current drug delivery systems are hampered by poor delivery to tumors, in part reflecting poor encapsulation stability of nanocarriers. Although nanocarriers such as polymeric micelles have high colloidal stability and do not aggregate or precipitate in bulk solution, nanocarriers with low encapsulation stability can lose their cargo during circulation in blood due to interactions with blood cells, cellular membranes, serum proteins, and other biomacromolecules. The resulting premature drug release from carriers limits the therapeutic efficacy at target sites. Herein, we report a simple and robust technique to improve encapsulation stability of drug delivery systems. Specifically, we show that installation of disulfide cross-linked noncovalent polymer gatekeepers onto mesoporous silica nanoparticles with a high loading capacity for hydrophobic drugs enhances in vivo therapeutic efficacy by preventing premature release of cargo. Subsequent release of drug cargos was triggered by cleavage of disulfide cross-linking by glutathione, leading to improved antitumor activity of doxoroubicin in mice. These findings provide novel insights into the development of nanocarriers with high encapsulation stability and improved in vivo therapeutic efficacy.
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Nanocápsulas/química , Animales , Antineoplásicos/administración & dosificación , Coloides/química , Reactivos de Enlaces Cruzados/química , Doxorrubicina/administración & dosificación , Femenino , Células HeLa , Humanos , Ratones , Ratones Desnudos , Micelas , Nanocápsulas/efectos adversos , Nanocápsulas/normas , Dióxido de Silicio/químicaRESUMEN
The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.
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Benzodioxoles/química , Benzodioxoles/farmacología , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/química , Mitocondrias/efectos de los fármacos , Purinas/química , Purinas/farmacología , Aminas/química , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Mitocondrias/metabolismo , Modelos Moleculares , Compuestos Organofosforados/química , Multimerización de Proteína , Estabilidad Proteica , Estructura Cuaternaria de ProteínaRESUMEN
Advances in water-insoluble drug delivery systems are limited by selective delivery, loading capacity, and colloidal and encapsulation stability. We have developed a simple and robust hydrophobic-drug delivery platform with different types of hydrophobic chemotherapeutic agents using a noncovalent gatekeeper's technique with mesoporous silica nanoparticles (MSNs). The unmodified pores offer a large volume of drug loading capacity, and the loaded drug is stably encapsulated until it enters the cancer cells owing to the noncovalently bound polymer gatekeeper. In the presence of polymer gatekeepers, the drug-loaded mesoporous silica nanoparticles showed enhanced colloidal stability. The simplicity of drug encapsulation allows any combination of small chemotherapeutics to be coencapsulated and thus produce synergetic therapeutic effects. The disulfide moiety facilitates decoration of the nanoparticles with cysteine containing ligands through thiol-disulfide chemistry under mild conditions. To show the versatility of drug targeting to cancer cells, we decorated the surface of the shell-cross-linked nanoparticles with two types of peptide ligands, SP94 and RGD. The nanocarriers reported here can release encapsulated drugs inside the reducing microenvironment of cancer cells via degradation of the polymer shell, leading to cell death.
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Antineoplásicos , Portadores de Fármacos , Nanopartículas/química , Oligopéptidos , Dióxido de Silicio/química , Antineoplásicos/química , Antineoplásicos/farmacología , Coloides , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Células Hep G2 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células KB , Oligopéptidos/química , Oligopéptidos/farmacología , PorosidadRESUMEN
Intracellular polymerization in living cells motivated chemists to generate polymeric structures with a multitude of possibilities to interact with biomacromolecules. However, out-of-control of the intracellular chemical reactions would be an obstacle restricting its application, providing the toxicity of non-targeted cells. Here, we reported intracellular thioesterase-mediated polymerization for selectively occurring polymerization using disulfide bonds in cancer cells. The acetylated monomers did not form disulfide bonds even under an oxidative environment, but they could polymerize into the polymeric structure after cleavage of acetyl groups only when encountered activity of thioesterase enzyme. Furthermore, acetylated monomers could be self-assembled with doxorubicin, providing doxorubicin loaded micelles for efficient intracellular delivery of drug and monomers. Since thioesterase enzymes were overexpressed in cancer cells specifically, the micelles were disrupted under activity of the enzyme and the polymerization could occur selectively in the cancer mitochondria. The resulting polymeric structures disrupted the mitochondrial membrane, thus activating the cellular death of cancer cells with high selectivity. This strategy selectively targets diverse cancer cells involving drug-resistant cells over normal cells. Moreover, the mitochondria targeting strategy overcomes the development of drug resistance even with repeated treatment. This approach provides a way for selective intracellular polymerization with desirable anticancer treatment.
RESUMEN
Targeted drug delivery using metal-organic frameworks (MOFs) has shown significant progress. However, the tumor microenvironment (TME) impedes efficient MOF particle transfer into tumor cells. To tackle this issue, we pre-coated nano-sized MOF-808 particles with multifunctional proteins: glutathione S-transferase (GST)-affibody (Afb) and collagenase, aiming to navigate the TME more effectively. The surface of MOF-808 particles is coated with GST-Afb-a fusion protein of GST and human epidermal growth factor receptor 2 (HER2) Afb or epidermal growth factor receptor (EGFR) Afb which has target affinity. We also added collagenase enzymes capable of breaking down collagen in the extracellular matrix (ECM) through supramolecular conjugation, all without chemical modification. By stabilizing these proteins on the surface, GST-Afb mitigate biomolecule absorption, facilitating specific tumor cell targeting. Simultaneously, collagenase degrades the ECM in the TME, enabling deep tissue penetration of MOF particles. Our resulting system, termed collagenase-GST-Afb-MOF-808 (Col-Afb-M808), minimizes undesired interactions between MOF particles and external biological proteins. It not only induces cell death through Afb-mediated cell-specific targeting, but also showcases advanced cellular internalization in 3D multicellular spheroid cancer models, with effective deep tissue penetration. The therapeutic efficacy of Col-Afb-M808 was further assessed via in vivo imaging and evaluation of tumor inhibition following injection of IR-780 loaded Col-Afb-M808 in 4T1tumor-bearing nude mice. This study offers key insights into the regulation of the multifunctional protein-adhesive surface of MOF particles, paving the way for the designing even more effective targeted drug delivery systems with nano-sized MOF particles.
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Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Humanos , Animales , Ratones , Línea Celular Tumoral , Glutatión Transferasa/metabolismo , Glutatión Transferasa/química , Colagenasas/química , Colagenasas/metabolismo , Femenino , Receptor ErbB-2/metabolismo , Receptores ErbB/metabolismo , Ratones Desnudos , Sistemas de Liberación de Medicamentos , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Ratones Endogámicos BALB CRESUMEN
Nanomedicines hold promise for the treatment of various diseases. However, treating cancer metastasis remains highly challenging. In this study, we synthesized gold nanorods (AuNRs) containing (α-GC), an immune stimulator, for the treatment of primary cancer, metastasis, and recurrence of the cancer. Therefore, the AuNR were coated with lipid bilayers loaded with α-GC (α-LA). Upon irradiation with 808 nm light, α-LA showed a temperature increase. Intra-tumoral injection of α-LA in mice and local irradiation of the 4T1 breast cancer tumor effectively eliminated tumor growth. We found that the presence of α-GC in α-LA activated dendritic cells and T cells in the spleen, which completely blocked the development of lung metastasis. In mice injected with α-LA for primary breast cancer treatment, we observed antigen-specific T cell responses and increased cytotoxicity against 4T1 cells. We conclude that α-LA is promising for the treatment of both primary breast cancer and its metastasis.
RESUMEN
Targeted drug delivery systems based on metal-organic frameworks (MOFs) have progressed tremendously since inception and are now widely applicable in diverse scientific fields. However, translating MOF agents directly to targeted drug delivery systems remains a challenge due to the biomolecular corona phenomenon. Here, we observed that supramolecular conjugation of antibodies to the surface of MOF particles (MOF-808) via electrostatic interactions and coordination bonding can reduce protein adhesion in biological environments and show stealth shields. Once antibodies are stably conjugated to particles, they were neither easily exchanged with nor covered by biomolecule proteins, which is indicative of the stealth effect. Moreover, upon conjugation of the MOF particle with specific targeted antibodies, namely, anti-CD44, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR), the resulting hybrid exhibits an augmented targeting efficacy toward cancer cells overexpressing these receptors, such as HeLa, SK-BR-3, and 4T1, as evidenced by flow cytometry. The therapeutic effectiveness of the antibody-conjugated MOF (anti-M808) was further evaluated through in vivo imaging and the assessment of tumor inhibition effects using IR-780-loaded EGFR-M808 in a 4T1 tumor xenograft model employing nude mice. This study therefore provides insight into the use of supramolecular antibody conjugation as a promising method for developing MOF-based drug delivery systems.
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Estructuras Metalorgánicas , Ratones Desnudos , Estructuras Metalorgánicas/química , Humanos , Animales , Ratones , Sistemas de Liberación de Medicamentos , Anticuerpos/química , Anticuerpos/inmunología , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Línea Celular Tumoral , Células HeLa , Ratones Endogámicos BALB C , Antineoplásicos/química , Antineoplásicos/farmacología , Receptor ErbB-2/inmunología , Receptor ErbB-2/metabolismo , FemeninoRESUMEN
Influence of Hofmeister ions has been investigated on the size and guest encapsulation stability of a polymeric nanogel. While variations in macroscopic phase transitions have been observed in response to the presence of salts, changes in the size and host-guest behavior of polymeric aggregates in the presence of salts have not been explored in any detail. We find that the size and core density of nanogel, which was prepared by self-crosslinking from a random copolymer that contains oligo(ethylene glycol) (OEG) and pyridyl disulfide (PDS) units as side-chain functionalities, can be fine-tuned through the addition of both chaotropes and kosmotropes during nanogel formation. We also demonstrate that the change in core density affects the guest encapsulation stability and stimuli-responsive character of the nanogel.