RESUMEN
Chemotherapy is the main treatment method for osteosarcoma in the clinic. However, drug resistance and its poor antimetastatic effects greatly limit its clinical application. In this work, dual-drug nanoparticles (NPs) containing albendazole (ABZ) and doxorubicin (DOX), named AD@PLGA-PEG NPs, were prepared to solve the problems of chemotherapeutic drug resistance and poor antimetastasis effects. Compared with free DOX, ABZ combined with DOX can increase intracellular reactive oxygen species (ROS) and induce more tumor cell apoptosis; therefore, AD@PLGA-PEG NPs produced more mitochondria-mediated oxidative stress and better apoptosis efficiency. Importantly, ABZ can also effectively inhibit the expression of hypoxia inducible factor-1α (HIF-1α) and then reduce the expression of its downstream vascular endothelial growth factor (VEGF); thus, the AD@PLGA-PEG NPs effectively inhibited tumor metastasis in vivo. Collectively, the dual-drug AD@PLGA-PEG NPs delivery system provided prominent antitumor and antimetastatic efficacy and might be a promising treatment for osteosarcoma.
Asunto(s)
Neoplasias Óseas , Nanopartículas , Osteosarcoma , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Hipoxia , Neoplasias Óseas/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Chemotherapy still accounts for a large proportion of the treatments of tumors, but the drug resistance and side effects caused by long-term chemotherapy should not be underestimated. In this work, the drug combination strategy has been widely developed to overcome the side effects brought by the use of single drugs and improve the therapeutic effect. However, in clinical applications, the co-delivery of drugs is very difficult, and different in vivo kinetics due to different drug properties will lead to a decrease in efficacy. Thus, the design of novel antitumor therapeutic agents, including new platinum agents, represents an area in need of urgent attention. Our investigation implies a promising strategy for the design of a platinum prodrug to enhance the treatment of breast cancer. A dual-drug delivery nanoparticle was developed for enhanced treatment of breast cancer based on a two-into-one co-delivery strategy. Through the synergistic effect of released cisplatin hydrate and tolfenamic acid (COX-2 inhibitor) from the coordination prodrug, the tumor growth is significantly suppressed, and the survival time is greatly extended in breast tumor-bearing mice.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Nanopartículas/química , Platino (Metal)/farmacología , Profármacos/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Sistemas de Liberación de Medicamentos/métodos , Femenino , Ratones , Ratones Endogámicos BALB CRESUMEN
Chitosan, which exhibits good biocompatibility, safety, microbial degradation and other excellent performances, has found application in all walks of life. In the field of medicine, usage of chitosan for the delivery of vaccine is favored by a wide range of researchers. However, due to its own natural limitations, its application has been constrained to the beginning of study. In order to improve the applicability for vaccine delivery, researchers have carried out various chemical modifications of chitosan. This review summarizes a variety of modification methods and applications of chitosan and its derivatives in the field of vaccine delivery.
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Quitosano/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Vacunas/administración & dosificación , Animales , Materiales Biocompatibles/química , Quitosano/análogos & derivados , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Estructura Molecular , Polietilenglicoles/química , Vacunas/química , Vacunas/genética , Vacunas de ADN/administración & dosificación , Vacunas de ADN/química , Vacunas de ADN/genéticaRESUMEN
Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein-protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/efectos de los fármacos , Chaperoninas/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Saponinas/toxicidad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triterpenos/toxicidad , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Everolimus/farmacología , Humanos , Inmunosupresores/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteína Oncogénica v-akt/antagonistas & inhibidores , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inhibidoresRESUMEN
Combination therapy has been developed as a promising therapeutic approach for hepatocellular carcinoma therapy. Here we report a low toxicity and high performance nanoparticle system that was self-assembled from a poly(ethylenimine)-glycyrrhetinic acid (PEI-GA) amphiphilic copolymer as a versatile gene/drug dual delivery nanoplatform. PEI-GA was synthesized by chemical conjugation of hydrophobic GA moieties to the hydrophilic PEI backbone via an acylation reaction. The PEI-GA nanocarrier could encapsulate doxorubicin (DOX) efficiently with loading level about 12% and further condense DNA to form PEI-GA/DOX/DNA complexes to codeliver drug and gene. The diameter of the complexes is 102 ± 19 nm with zeta potential of 19.6 ± 0.2 mV. Furthermore, the complexes possess liver cancer targeting ability and could promote liver cancer HepG2 cell internalization. Apoptosis of cells could be induced by chemotherapy of DOX, and PI3K/Akt/mTOR signaling pathway acts a beneficial effect on the modulation of autophagy. Here, it is revealed that utilizing PEI-GA/DOX/shAkt1 complexes results in effective autophagy and apoptosis, which are useful to cause cell death. The induction of superfluous autophagy is reported to induce type-II cell death and also could increase the sensity of chemotherapy to tumor cells. In this case, combining autophagy and apoptosis is meaningful for oncotherapy. In this study, PEI-GA/DOX/shAkt1 has demonstrated favorable tumor target ability, little side effects, and ideal antitumor efficacy.
Asunto(s)
Autofagia/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Ácido Glicirretínico/química , Nanopartículas/química , Polietileneimina/química , Polímeros/farmacología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Animales , Doxorrubicina/uso terapéutico , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Nanopartículas/uso terapéutico , Polímeros/química , Polímeros/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
Non-small cell lung cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)-phosphoethanolamine (PEG-PE), we obtain Fluplatin@PEG-PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Nanopartículas , Fosfatidiletanolaminas , Polietilenglicoles , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/farmacología , Cisplatino/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Resistencia a Antineoplásicos/genética , Fluvastatina/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , MutaciónRESUMEN
During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.
Asunto(s)
Células Endoteliales , Liposomas , Nanopartículas , Animales , Células Endoteliales/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapéutico , Cirrosis Hepática , Hígado/metabolismoRESUMEN
Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH2) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.
Asunto(s)
Ferroptosis , Neoplasias de la Mama Triple Negativas , Humanos , Dihidroorotato Deshidrogenasa , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Peróxidos Lipídicos , Albúmina Sérica Bovina , Atovacuona , Glutatión , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Pancreatic fibrosis (PF) is primarily characterized by aberrant production and degradation modes of extracellular matrix (ECM) components, resulting from the activation of pancreatic stellate cells (PSCs) and the pathological cross-linking of ECM mediated by lysyl oxidase (LOX) family members. The excessively deposited ECM increases matrix stiffness, and the over-accumulated reactive oxygen species (ROS) induces oxidative stress, which further stimulates the continuous activation of PSCs and advancing PF; challenging the strategy toward normalizing ECM homeostasis for the regression of PF. Herein, ROS-responsive and Vitamin A (VA) decorated micelles (named LR-SSVA) to reverse the imbalanced ECM homeostasis for ameliorating PF are designed and synthesized. Specifically, LR-SSVA selectively targets PSCs via VA, thereby effectively delivering siLOXL1 and resveratrol (RES) into the pancreas. The ROS-responsive released RES inhibits the overproduction of ECM by eliminating ROS and inactivating PSCs, meanwhile, the decreased expression of LOXL1 ameliorates the cross-linked collagen for easier degradation by collagenase which jointly normalizes ECM homeostasis and alleviates PF. This research shows that LR-SSVA is a safe and efficient ROS-response and PSC-targeted drug-delivery system for ECM normalization, which will propose an innovative and ideal platform for the reversal of PF.
Asunto(s)
Matriz Extracelular , Fibrosis , Nanopartículas , Especies Reactivas de Oxígeno , Especies Reactivas de Oxígeno/metabolismo , Matriz Extracelular/metabolismo , Animales , Fibrosis/metabolismo , Resveratrol/farmacología , Humanos , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Enfermedades Pancreáticas/metabolismo , Modelos Animales de Enfermedad , Estrés Oxidativo/efectos de los fármacos , Vitamina A/metabolismo , Ratones , Ratas , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Stem cells have garnered significant attention in regenerative medicine owing to their abilities of multi-directional differentiation and self-renewal. Despite these encouraging results, the market for stem cell products yields limited, which is largely due to the challenges faced to the safety and viability of stem cells in vivo. Besides, the fate of cells re-infusion into the body unknown is also a major obstacle to stem cell therapy. Actually, both the functional protection and the fate tracking of stem cells are essential in tissue homeostasis, repair, and regeneration. Recent studies have utilized cell engineering techniques to modify stem cells for enhancing their treatment efficiency or imparting them with novel biological capabilities, in which advances demonstrate the immense potential of engineered cell therapy. In this review, we proposed that the "engineered stem cells" are expected to represent the next generation of stem cell therapies and reviewed recent progress in this area. We also discussed potential applications of engineered stem cells and highlighted the most common challenges that must be addressed. Overall, this review has important guiding significance for the future design of new paradigms of stem cell products to improve their therapeutic efficacy.
Asunto(s)
Ingeniería Celular , Medicina Regenerativa , Medicina Regenerativa/métodos , Trasplante de Células Madre , Diferenciación CelularRESUMEN
In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug-loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG-E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG-E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage-focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.
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Cirrosis Hepática , Macrófagos , Humanos , Cirrosis Hepática/terapia , Macrófagos/metabolismo , Colágeno , FenotipoRESUMEN
Mesenchymal stem cell (MSC)-based therapies show great potential in treating various diseases. However, control of the fate of injected cells needs to be improved. In this work, we developed an efficient methodology for modulating chondrogenic differentiation of MSCs. We fabricated heterospheroids with two sustained-release depots, a quaternized chitosan microsphere (QCS-MP) and a poly (lactic-co-glycolic acid) microsphere (PLGA-MP). The results show that heterospheroids composed of 1 × 104 to 5 × 104 MSCs formed rapidly during incubation in methylcellulose medium and maintained high cell viability in long-term culture. The MPs were uniformly distributed in the heterospheroids, as shown by confocal laser scanning microscopy. Incorporation of transforming growth factor beta 3 into QCS-MPs and of dexamethasone into PLGA-MPs significantly promoted the expression of chondrogenic genes and high accumulation of glycosaminoglycan in heterospheroids. Changes in crucial metabolites in the dual drug depot-engineered heterospheroids were also evaluated using 1H NMR-based metabolomics analysis to verify their successful chondrogenic differentiation. Our heterospheroid fabrication platform could be used in tissue engineering to study the effects of various therapeutic agents on stem cell fate.
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Quitosano , Células Madre Mesenquimatosas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacología , Microesferas , Quitosano/farmacología , Ácido Poliglicólico/farmacología , Ácido Láctico/farmacología , Glicoles , Preparaciones de Acción Retardada/farmacología , Células Cultivadas , Diferenciación Celular , CondrogénesisRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.
Asunto(s)
Quistes , Fibrosis Pulmonar Idiopática , Nanopartículas , Humanos , Verteporfina , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , PulmónRESUMEN
BACKGROUND: Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases. METHODS: Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR. RESULTS: The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process. CONCLUSION: This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.
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Bencilaminas , Colitis , Ciclamas , Sulfato de Dextran , Ratones Endogámicos C57BL , Tacrolimus , Animales , Colitis/inducido químicamente , Colitis/terapia , Colitis/tratamiento farmacológico , Colitis/patología , Ratones , Masculino , Ciclamas/farmacología , Ciclamas/uso terapéutico , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Modelos Animales de Enfermedad , Terapia de Inmunosupresión , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Microesferas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.
Asunto(s)
Técnicas de Transferencia de Gen , Mitocondrias , Nanoestructuras , Humanos , Mitocondrias/metabolismo , Nanoestructuras/química , Animales , Transporte Biológico , ADN Mitocondrial/genética , Edición Génica/métodosRESUMEN
Achievement of long-term survival of patients with lung cancer treated with conventional chemotherapy is still difficult for treatment of metastatic and advanced tumors. Despite recent progress in investigational therapies, survival rates are still disappointingly low and novel adjuvant and systemic therapies are urgently needed. A recently elucidated secretory pathway is attracting considerable interest as a promising anticancer target. The cis-Golgi matrix protein, GOLGA2/GM130, plays an important role in glycosylation and transport of protein in the secretory pathway. In this study, the effects of short hairpin RNA (shRNA) constructs targeting GOLGA2/GM130 (shGOLGA2) on autophagy and lung cancer growth were evaluated in vitro and in vivo. Downregulation of GOLGA2/GM130 led to induction of autophagy and inhibition of glycosylation in A549 cells and in the lungs of K-ras(LA1) mice. Furthermore, downregulation of GOLGA2/GM130 decreased angiogenesis and cancer cell invasion in vitro and suppressed tumorigenesis in lung cancer mice model. The tumor specificity of sequence targeting GOLGA2/GM130 was also demonstrated. Taken together, these results suggest that induction of autophagy by shGOLGA2 may induce cell death rather than cell survival. Therefore, downregulation of GOLGA2/GM130 may be a potential therapeutic option for lung cancer.
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Adenocarcinoma/terapia , Autoantígenos/genética , Terapia Genética , Neoplasias Pulmonares/terapia , Proteínas de la Membrana/genética , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/patología , Animales , Autoantígenos/metabolismo , Autofagia , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Técnicas de Silenciamiento del Gen , Glicosilación , Humanos , Pulmón/patología , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/patología , Proteínas de la Membrana/metabolismo , Ratones , Invasividad Neoplásica , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Neovascularización Patológica/terapia , Proteínas Proto-Oncogénicas p21(ras)/genética , Interferencia de ARN , ARN Interferente Pequeño/genéticaRESUMEN
Small interfering RNA (siRNA) is a promising candidate for gene therapy due to the strong and specific gene silencing effects. However, to effectively silence any protein, lack of an efficient delivery system is major obstacle for siRNA therapeutics. In the present study, we report on the development of a novel poly(ester amine) (PEA) as an efficient siRNA carrier. The PEA was prepared by a Michael addition reaction between trimethylolpropane triacrylate (TT) and spermine (SPE). The composition of the PEA was characterized by 1H nuclear magnetic resonance (1H NMR) and the molecular weight was measured using gel permeability chromatography (GPC). This TT-SPE effectively condensed siRNA into a compact nanoscale structure (size: 76 nm) with homogenous size distribution and provided superior protection of siRNA from RNase A enzyme. Furthermore, TT-SPE/ siRNA complexes showed good intracellular uptake and had efficacious gene silencing effect with low toxicity compared to PEI 25K. These findings demonstrated that TT-SPE has potential as an alternative to PEI 25K for siRNA-based gene therapy.
Asunto(s)
Acrilatos/química , Aminas/química , Poliésteres/química , ARN Interferente Pequeño/química , Espermina/química , Materiales Biocompatibles , Línea Celular Tumoral , Membrana Celular/metabolismo , Supervivencia Celular , Cromatografía , Geles , Silenciador del Gen , Terapia Genética/métodos , Humanos , Espectroscopía de Resonancia Magnética , Nanoestructuras/química , Permeabilidad , Ribonucleasa Pancreática/químicaRESUMEN
Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.
RESUMEN
Osteosarcoma (OS) is the most common malignant tumor of the bone that affects children and adolescents, and its treatment usually involves doxorubicin hydrochloride (DOX). However, the drug resistance and side effects caused by high-dose DOX infusion greatly hinder its therapeutic effects. To achieve efficient OS treatment with low toxicity, an injectable rhein (RH)-assisted crosslinked hydrogel (PVA@RH@DOX hydrogel, PRDH) was designed, which was prepared by loading DOX and RH into a polyvinyl alcohol (PVA) solution. The cytotoxicity assay and live/dead staining results showed that the combination of RH and DOX more effectively killed OS cells, producing excellent effects at low concentrations of DOX. The wound healing and transwell test results proved that PRDH could significantly inhibit the metastasis and invasion of OS cells. PRDH showed a long-lasting antitumor effect after injection of a single dose, significantly suppressing the proliferation and metastasis of OS and achieving the strategy of a single administration for long-term treatment. Excitingly, RH facilitated hydrogel formation by assisting with PVA crosslinking. This system provides an alternative regimen and broadens the horizon for the clinical treatment of OS.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Niño , Humanos , Adolescente , Hidrogeles/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Doxorrubicina/farmacología , Neoplasias Óseas/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Pancreatic fibrosis is mainly manifested by imbalance in extracellular matrix (ECM) homeostasis due to excessive deposition of collagen in pancreas by activated pancreatic stellate cells (PSCs). Recently, some drugs have exhibited therapeutic potentials for the treatment of pancreatic fibrosis; however, currently, no effective clinical strategy is available to remodel imbalanced ECM homeostasis because of inferior targeting abilities of drugs and collagen barriers that hinder the efficient delivery of drugs. Herein, we design and prepare collagen-binding peptide (CBP) and collagenase I co-decorated dual drug-loaded lipid nanoparticles (named AT-CC) for pancreatic fibrosis therapy. Specifically, AT-CC can target fibrotic pancreas via the CBP and degrade excess collagen by the grafted collagenase I, thereby effectively delivering all-trans-retinoic acid (ATRA) and ammonium tetrathiomolybdate (TM) into pancreas. The released ATRA can reduce collagen overproduction by inhibiting the activation of PSCs. Moreover, the released TM can restrain lysyloxidase activation, consequently reducing collagen cross-linking. The combination of ATRA and TM represses collagen synthesis and reduces collagen cross linkages to restore ECM homeostasis. The results of this research suggest that AT-CC is a safe and efficient collagen-targeted degradation drug-delivery system for reversing pancreatic fibrosis. Furthermore, the strategy proposed herein will offer an innovative platform for the treatment of chronic pancreatitis.