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Developing biomaterials with high osteogenic properties is crucial for achieving rapid bone repair and regeneration. This study focuses on the application of nanocrystal hydroxyapatite (nHAp) as a drug carrier to load Fu Yuan Huo Xue Decoction (FYHXD), a traditional Chinese medicine derived from Angelica sinensis, aiming to achieve improved efficacy in treating bone diseases such as osteoporosis. Through a facile physical adsorption approach, the FTIR result emerges new characteristic absorption peaks in the range of 1200-950â¯cm-1, proving the successful absorption of FYHXD onto the nHAp with a loading efficiency of 39.76â¯%. The modified nHAp exhibits a similar shape to the bone-derived hydroxyapatite nanocrystals, and their diameter increases slightly after modification. The drug release assay implies the rapid release of FYHXD in the first 10â¯h, followed by a continuously slow release within 70â¯h. The developed nHAp effectively enhances the adhesion, spreading, and proliferation of MC3T3-E1 cells in vitro, and significantly promotes their osteogenic differentiation, as indicated by increased alkaline phosphatase activity. Overall, the biocomposites hold great promise as active ingredients for integration into bone-associated biomaterials, offering the potential to stimulate spontaneous osteogenesis without requiring exogenous osteogenic factors.
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Aortic dissection (AD) is a severe cardiovascular disease necessitating active therapeutic strategies for early intervention and prevention. Nucleic acid drugs, known for their potent molecule-targeting therapeutic properties, offer potential for genetic suppression of AD. Piwi-interacting RNAs, a class of small RNAs, hold promise for managing cardiovascular diseases. Limited research on these RNAs and AD exists. This study demonstrates that an antagomir targeting heart-apoptosis-associated piRNA (HAAPIR) effectively regulates vascular remodeling, mitigating AD occurrence and progression through the myocyte enhancer factor 2D (Mef2D) and matrix metallopeptidase 9 (MMP9) pathways. Green tea-derived plant exosome-like nanovesicles (PELNs) are used for oral administration of antagomir. The antagomir-HAAPIR-nanovesicle complex, after purification and optimization, exhibits a high packing rate, while the antagomir is resistant to enzyme digestion. Administered to mice, the complex targets the aortic lesion, reducing AD incidence and improving survival. Moreover, MMP9 and Mef2D expression decrease significantly, inhibiting the phenotypic conversion of human aortic smooth muscle cells. PELNs encapsulate the antagomir-HAAPIR complex, maintaining stability, mediating transport into the bloodstream, and delivering Piwi-interacting RNAs to AD sites. Thus, HAAPIR is a potential target for persistent clinical AD prevention and treatment, and nanovesicle-encapsulated nucleic acids offer a promising cardiovascular disease treatment, providing insights for other therapeutic targets.
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Ischemic stroke poses significant challenges in terms of mortality and disability rates globally. A key obstacle to the successful treatment of ischemic stroke lies in the limited efficacy of administering therapeutic agents. Leveraging the unique properties of nanoparticles for brain targeting and crossing the blood-brain barrier, researchers have engineered diverse nanoparticle-based drug delivery systems to improve the therapeutic outcomes of ischemic stroke. This review provides a concise overview of the pathophysiological mechanisms implicated in ischemic stroke, encompassing oxidative stress, glutamate excitotoxicity, neuroinflammation, and cell death, to elucidate potential targets for nanoparticle-based drug delivery systems. Furthermore, the review outlines the classification of nanoparticle-based drug delivery systems according to these distinct physiological processes. This categorization aids in identifying the attributes and commonalities of nanoparticles that target specific pathophysiological pathways in ischemic stroke, thereby facilitating the advancement of nanomedicine development. The review discusses the potential benefits and existing challenges associated with employing nanoparticles in the treatment of ischemic stroke, offering new perspectives on designing efficacious nanoparticles to enhance ischemic stroke treatment outcomes.
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Barrera Hematoencefálica , Sistemas de Liberación de Medicamentos , Accidente Cerebrovascular Isquémico , Nanopartículas , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Animales , Barrera Hematoencefálica/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Estrés Oxidativo/efectos de los fármacos , Sistema de Administración de Fármacos con Nanopartículas/química , Isquemia Encefálica/tratamiento farmacológico , Nanomedicina/métodos , Encéfalo/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/químicaRESUMEN
Small extracellular vesicles (sEVs) hold considerable promise for drug delivery due to their natural origin and inherent qualities. However, their clinical application is impeded by two main challenges: low yield and potential side effects. Therefore, it is crucial to obtain substantial quantities of sEVs that adhere to rigorous biosafety standards to ensure successful translation into clinical practice. To address this need, we propose exploring optimized methods for sourcing and separating sEVs, taking inspiration from clinical blood transfusion. In particular, we have identified blood sEVs as a viable alternative and developed a novel separation technique for their isolation. Our approach involves incubating dopamine solution with serum, resulting in the formation of polydopamine (PDA) nanoparticles on the surface of blood sEVs. These nanoparticles have minimal impact on blood sEVs, facilitating their easy separation under standard centrifugal conditions with high purity. This innovative technique enables the development of nanocarriers using blood sEVs with efficient drug-loading capabilities and enhanced pharmacokinetics. Additionally, the incorporation of PDA nanoparticles imparts a photothermal effect to the nanomedicines, enabling the integration of chemotherapy and photothermal therapy. Moreover, the photothermal effect holds the potential to facilitate the membrane fusion of sEVs and cells. In summary, our straightforward surface functionalization technique utilizing PDA effectively isolates blood sEVs and enables chemo-thermal tumor therapy. This approach significantly enhances the feasibility of translating sEV-based nanomedicines into clinical applications.
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Vesículas Extracelulares , Indoles , Nanopartículas , Polímeros , Indoles/química , Polímeros/química , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Nanopartículas/química , Humanos , Animales , Ratones , Portadores de Fármacos/química , Terapia Fototérmica , Doxorrubicina/química , Doxorrubicina/farmacologíaRESUMEN
Post-translational modifications (PTM) are covalent modifications of proteins or peptides caused by proteolytic cleavage or the attachment of moieties to one or more amino acids. PTMs play essential roles in biological function and regulation and have been linked with several diseases. Modifications of protein acylation (Kac), a type of PTM, are known to induce epigenetic regulatory processes that promote various diseases. Thus, an increasing number of studies focusing on acylation modifications are being undertaken. Butyrylation (Kbu) is a new acylation process found in animals and plants. Kbu has been recently linked to the onset and progression of several diseases, such as cancer, cardiovascular diseases, diabetes, and vascular dementia. Moreover, the mode of action of certain drugs used in the treatment of lymphoma and colon cancer is based on the regulation of butyrylation levels, suggesting that butyrylation may play a therapeutic role in these diseases. In addition, butyrylation is also commonly involved in rice gene expression and thus plays an important role in the growth, development, and metabolism of rice. The tools and analytical methods that could be utilized for the prediction and detection of lysine butyrylation have also been investigated. This study reviews the potential role of histone Kbu, as well as the mechanisms underlying this process. It also summarizes various enzymes and analytical methods associated with Kbu, with the goal of providing new insights into the role of Kbu in gene regulation and diseases.
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Tooth extraction commonly causes uncontrolled bleeding, loss of blood clots, and bacterial infection, leading to the dry socket and bone resorption. Thus, it is highly attractive to design a bio-multifunctional scaffold with outstanding antimicrobial, hemostatic, and osteogenic performances for avoiding dry sockets in clinical applications. Herein, alginate (AG)/quaternized chitosan (Qch)/diatomite (Di) sponges were fabricated via electrostatic interaction, Ca2+ cross-linking, as well as lyophilization methods. The composite sponges are facilely made into the shape of the tooth root, which could be well integrated into the alveolar fossa. The sponge shows a highly interconnected and hierarchical porous structure at the macro/micro/nano levels. The prepared sponges also possess enhanced hemostatic and antibacterial abilities. Moreover, in vitro cellular assessment indicates that the developed sponges have favorable cytocompatibility and significantly facilitate osteogenesis by upregulating the formation of alkaline phosphatase and calcium nodules. The designed bio-multifunctional sponges display great potential for trauma treatment after tooth extraction.
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Alveolo Seco , Hemostáticos , Humanos , Osteogénesis , Antibacterianos , Alginatos , HemostasisRESUMEN
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology is the ideal tool of the future for treating diseases by permanently correcting deleterious base mutations or disrupting disease-causing genes with great precision and efficiency. A variety of efficient Cas9 variants and derivatives have been developed to cope with the complex genomic changes that occur during diseases. However, strategies to effectively deliver the CRISPR system to diseased cells in vivo are currently lacking, and nonviral vectors with target recognition functions may be the focus of future research. Pathological and physiological changes resulting from disease onset are expected to serve as identifying factors for targeted delivery or targets for gene editing. Diseases are both varied and complex, and the choice of appropriate gene-editing methods and delivery vectors for different diseases is important. Meanwhile, there are still many potential challenges identified when targeting delivery of CRISPR/Cas9 technology for disease treatment. This paper reviews the current developments in three aspects, namely, gene-editing type, delivery vector, and disease characteristics. Additionally, this paper summarizes successful examples of clinical trials and finally describes possible problems associated with current CRISPR applications.
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Sistemas CRISPR-Cas , Edición Génica , Sistemas CRISPR-Cas/genética , Terapia Genética/métodosRESUMEN
Mesenchymal stromal cells (MSCs) are attractive candidates for treating hepatic disorders given their potential to enhance liver regeneration and function. The paracrine paradigm may be involved in the mechanism of MSC-based therapy, and exosomes (Exo) play an important role in this paracrine activity. Hypoxia significantly improves the effectiveness of MSC transplantation. However, whether hypoxia preconditioned MSCs (Hp-MSCs) can enhance liver regeneration, and whether this enhancement is mediated by Exo, are unknown. In this study, mouse bone marrow-derived MSCs (BM-MSCs) and secreted Exo were injected through the tail vein. We report that Hp-MSCs promote liver regeneration after partial hepatectomy in mice through their secreted exosomes. Interestingly, MSC-Exo were concentrated in liver 6 h after administration and mainly taken up by macrophages, but not hepatocytes. Compared with normoxic MSC-Exo (N-Exo), hypoxic MSC-Exo (Hp-Exo) enhanced M2 macrophage polarization both in vivo and in vitro. Microarray analysis revealed significant enrichment of microRNA (miR)-182-5p in Hp-Exo compared with that in N-Exo. In addition, miR-182-5p knockdown partially abolished the beneficial effect of Hp-Exo. Finally, Hp-MSC-derived exosomal miR-182-5p inhibited theprotein expression of forkhead box transcription factor 1 (FOXO1) in macrophages, which inhibited toll-like receptor 4 (TLR4) expression and subsequently induced an anti-inflammatory response. These results highlight the therapeutic potential of Hp-Exo in liver regeneration and suggest that miR-182-5p from Hp-Exo facilitates macrophage polarization during liver regeneration by modulating the FOXO1/TLR4 signaling pathway.
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Regeneración Hepática , Macrófagos , Células Madre Mesenquimatosas , MicroARNs , Animales , Médula Ósea/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Hipoxia/metabolismo , Regeneración Hepática/genética , Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , MicroARNs/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Cardiovascular disease (CVD) has overtaken infectious illnesses as the leading cause of mortality and disability worldwide. The pathology that underpins CVD is atherosclerosis, characterized by chronic inflammation caused by the accumulation of plaques in the arteries. As our knowledge about the microenvironment of blood vessel walls deepens, there is an opportunity to fine-tune treatments to target the mechanisms driving atherosclerosis more directly. The application of non-coding RNAs (ncRNAs) as biomarkers or intervention targets is increasing. Although these ncRNAs play an important role in driving atherosclerosis and vascular dysfunction, the cellular and extracellular environments pose a challenge for targeted transmission and therapeutic regulation of ncRNAs. Specificity, delivery, and tolerance have hampered the clinical translation of ncRNA-based therapeutics. Nanomedicine is an emerging field that uses nanotechnology for targeted drug delivery and advanced imaging. Recently, nanoscale carriers have shown promising results and have introduced new possibilities for nucleic acid targeted drug delivery, particularly for atherosclerosis. In this review, we discuss the latest developments in nanoparticles to aid ncRNA-based drug development, particularly miRNA, and we analyze the current challenges in ncRNA targeted delivery. In particular, we highlight the emergence of various kinds of nanotherapeutic approaches based on ncRNAs, which can improve treatment options for atherosclerosis.
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Aterosclerosis , Enfermedades Cardiovasculares , MicroARNs , Aterosclerosis/genética , Aterosclerosis/terapia , Biomarcadores , Enfermedades Cardiovasculares/genética , Humanos , MicroARNs/genética , ARN no Traducido/genéticaRESUMEN
Inorganic nanoparticles (INPs) have been paid great attention in the field of oncology in recent past years since they have enormous potential in drug delivery, gene delivery, photodynamic therapy (PDT), photothermal therapy (PTT), bio-imaging, driven motion, etc. To overcome the innate limitations of the conventional INPs, such as fast elimination by the immune system, low accumulation in tumor sites, and severe toxicity to the organism, great efforts have recently been made to modify naked INPs, facilitating their clinical application. Taking inspiration from nature, considerable researchers have exploited cell membrane-camouflaged INPs (CMCINPs) by coating various cell membranes onto INPs. CMCINPs naturally inherit the surface adhesive molecules, receptors, and functional proteins from the original cell membrane, making them versatile as the natural cells. In order to give a timely and representative review on this rapidly developing research subject, we highlighted recent advances in CMCINPs with superior unique merits of various INPs and natural cell membranes for cancer therapy applications. The opportunity and obstacles of CMCINPs for clinical translation were also discussed. The review is expected to assist researchers in better eliciting the effect of CMCINPs for the management of tumors and may catalyze breakthroughs in this area.
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Hipertermia Inducida , Nanopartículas , Neoplasias , Fotoquimioterapia , Membrana Celular , Humanos , Hipertermia Inducida/métodos , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fototerapia/métodosRESUMEN
Oral gene therapy has emerged as a potential optimal treatment for ulcerative colitis (UC). Nucleic acid drugs possessing versatility can not only inhibit inflammation but realize colon mucosal healing, fulfilling the clinical objective of UC therapy. However, the effective accumulation and distribution of oral nucleic acid drugs in the colon remain a considerable challenge. Furthermore, current delivery systems pay more attention to the accumulation of nucleic acid drugs in the colon, while the distribution of nucleic acid drugs in the colon, which plays a key role in the UC treatment, never catches the attention of researchers. Here, we used miR-320 as a model nucleic acid drug to develop a kind of multistage-responsive nanocomplexes (MSNs) based on polymeric nanocapsules and alginate. MSNs possess the pH responsiveness in the stomach, the enzyme responsiveness in the colonic lumen, and the redox responsiveness in the cytoplasm. In vivo imaging results showed that MSNs reach the colon within 2 h and effectively release miR-320 nanocapsules in the colonic lumen. The nanocapsules can further deliver miR-320 to the submucosal layer and even the muscular layer. Moreover, MSNs decreased the activity of myeloperoxidase and proinflammatory cytokines and exhibited anti-inflammatory activity by inhibiting the phosphorylation of IκBα and AKT, reducing colonic inflammation and enhancing mucosal repair. Therefore, MSNs can successfully alleviate UC by improving the accumulation and distribution of oral nucleic acid drugs in the colon, promoting the clinical translational application of nucleic acid drugs in the treatment of UC.
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Antiinflamatorios no Esteroideos/farmacología , Materiales Biocompatibles/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , MicroARNs/farmacología , Nanopartículas/química , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Materiales Biocompatibles/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Sistemas de Liberación de Medicamentos , Humanos , Ensayo de Materiales , MicroARNs/administración & dosificación , Estructura MolecularRESUMEN
Infections induced by bacteria at present are a severe threat to public health. Compared with extracellular bacteria, intracellular bacteria are harder to get rid of and readily induce chronic inflammation as well as autoimmune disorders. As the development of new antibiotics becomes more and more difficult, the construction of new antibiotic dosage forms is one of the optimal choices for the elimination of intracellular bacteria, and, to date, various nanomedicines have been exploited. However, current nanomedicines have limited treatment efficiency for intracellular bacteria due to the multiple biological barriers. Here in this short review, we focus on systemically administered nanomedicines and divide the treatment of intracellular bacteria with nanomedicines into three steps: 1) Accumulation at the infection site; 2) Recognition of infected cells; 3) Targeting of intracellular bacteria. Furthermore, we summarize how nanomedicines are elaborately designed to achieve the "ART" principle and discuss the problems of experimental models construction. Through this review, we want to remind that the golden approach for the building of cell and animal experimental models should be established, and nanomedicines should be also endowed with the versatility to follow the "ART" principle, efficiently improving the treatment efficiency of nanomedicines for intracellular bacteria.
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Extracellular vesicles are cellular secretory particles that can be used as natural drug delivery carriers. They have successfully delivered drugs including chemotherapeutics, proteins, and genes to treat various diseases. Oxidative stress is an abnormal physiological phenomenon, and it is associated with nearly all diseases. In this short review, we summarize the regulation of EVs on oxidative stress. There are direct effects and indirect effects on the regulation of oxidative stress through EVs. On the one hand, they can deliver antioxidant substances or oxides to recipient cells, directly relieving or aggravating oxidative stress. On the other hand, regulate factors of oxidative stress-related signaling pathways can be delivered to recipient cells by the mediation of EVs, realizing the indirect regulation of oxidative stress. To the best of our knowledge, however, only endogenous drugs have been delivered by EVs to regulate oxidative stress till now. And the heterogeneity of EVs may complicate the regulation of oxidative stress. Therefore, this short review aims to draw more attention to the EVs-based regulation of oxidative stress, and we hope excellent EVs-based delivery carriers that can deliver exogenous drugs to regulate oxidative stress can be exploited.
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Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1-MDM2-MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment. SIGNIFICANCE: This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1-MDM2-MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.
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Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Animales , Femenino , Humanos , Ratones , TransfecciónRESUMEN
[This corrects the article DOI: 10.7150/thno.37220.].
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The metabolic enzyme-based arginine deprivation represents a tremendous opportunity to treat argininosuccinate synthetase (ASS1)-deficient tumors. Arginine deiminase (ADI), a typical representative, has aroused great interest. To date, the functional modification of ADI, such as PEGylation, has been applied to improve its weakness significantly, reducing its immunogenicity and extending its blood circulation time. However, the advantages of ADI, such as the cellular non-uptake property, are often deprived by current modification methods. The cellular non-uptake property of ADI only renders extracellular arginine degradation that negligibly influences normal cells. However, current-functionalized ADIs can be readily phagocytized by cells, causing the imbalance of intracellular amino acids and the consequent damage to normal cells. Therefore, it is necessary to exploit a new method that can simultaneously improve the weakness of ADI and maintain its advantage of cellular non-uptake. Here, we utilized a kind of phosphorylcholine (PC)-rich nanocapsule to load ADI. These nanocapsules possessed extremely weak cellular interaction and could avoid uptake by endothelial cells (HUVEC), immune cells (RAW 264.7), and tumor cells (H22), selectively depriving extracellular arginine. Besides, these nanocapsules increased the blood half-life time of ADI from the initial 2 h to 90 h and efficiently avoided its immune or inflammatory responses. After a single injection of ADI nanocapsules into H22 tumor-bearing mice, tumors were stably suppressed for 25 d without any detectable side effects. This new strategy first realizes the selective extracellular arginine deprivation for the treatment of ASS1-deficient tumors, potentially promoting the clinical translation of metabolic enzyme-based amino acid deprivation therapy. Furthermore, the research reminds us that the functionalization of drugs can not only improve its weakness but also maintain its advantages.
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Arginina , Nanocápsulas , Animales , Línea Celular Tumoral , Células Endoteliales , Hidrolasas , Ratones , PolietilenglicolesRESUMEN
OBJECTIVE: The healing of osteoporotic fractures in the elderly patients is a difficult clinical problem. Currently, based on the internal fixation of fractures, the available drug treatments mainly focus on either inhibiting osteoclast function, such as bisphosphonate, calcitonin, oestrogen or promoting osteogenesis, such as parathyroid hormones. However, the availability of current antiosteoporotic drugs in promoting osteoporotic fracture healing is limited. The objective of the present study was to investigate the ability of the MiR-21/nanocapsule to enhance the early bone repair of osteoporotic fractures. METHODS: Based on the presence of matrix metalloproteinases that are overexpressed at the fracture site, we designed the matrix metalloproteinase-sensitive nanocapsules which were formed by in situ free radical polymerisation on the surface of MiR-21 with 2-(methacryloyloxy) ethyl phosphorylcholine and the bisacryloylated VPLGVRTK peptide. The MiR-21/nanocapsule [n (miR-21)] and O-carboxymethyl chitosan (CMCS) were mixed until they formed a gel-like material [CMCS/n (miR-21)] with good fluidity and injectability. Thirty elderly Sprague Dawley (SD) rats (female, 14-month-old, 380 ± 10 g) were subjected to bilateral removal of the ovaries (ovariectomised). All rats were subjected to bilateral bone defects (2 mm diameter) of the proximal tibia and randomly divided into three groups (groups A, B, and C): separately injected with CMCS/n (miR-21), CMCS/n (NC-miR), and saline. Micro-computed tomography (CT) imaging was performed to evaluate newly formed bone volume and connectivity. Nondecalcified histology and toluidine blue staining were performed to measure the effects of CMCS/n (miR-21) on bone repair. In vitro, the effect of n (miR-21) on osteogenic differentiation to bone marrow mesenchymal stem cells (BMSCs) which derived from the ovariectomised rat model was observed. RESULTS: The morphology of n (miR-21) was a regular spherical nanocapsule with a uniform small size (25-35 nm). The results confirmed that n (miR-21) could be efficiently phagocytosed by BMSCs and released in the cytoplasm to promote osteogenesis. The expression level of alkaline phosphatase and Runt-related transcription factor 2 mRNA in the n (miR-21) group was higher than that in the n (NC-miR) group. Animal experiments proved that CMCS/n (miR-21) produced better bone repair compared with the CMCS/n (NC-miR) group in the early stages of fracture healing at 4 weeks. In the late stage of fracture healing (8 weeks), micro-CT quantitative analysis showed that the new bone trabeculae in the CMCS/n (miR-21) group has decreased compared with the CMCS/n (NC-miR) group. In the CMCS/n (miR-21) group, the new cancellous bone had been absorbed, and the process of bone healing was almost completed. In contrast, the new bone in the CMCS/n (NC-miR) and the control groups was still in the healing process. CONCLUSION: The cytological tests confirmed that n (miR-21) can promote osteogenic differentiation of BMSCs derived from the osteoporosis rat model. Furthermore, the results of animal tests demonstrated that local injection of CMCS/n (miR-21) promoted the early healing of osteoporotic bone defects. Consequently CMCS/n (miR-21) promoted the bone repair process to enter the moulding phase earlier. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: CMCS/n (miR-21) can be widely applied to elderly patients with osteoporotic fractures. This method can help patients with osteoporotic fractures recover earlier and avoid serious complications. It provides a potential approach for the clinical treatment of osteoporotic fractures in the elderly.
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Rationale: Developing an effective nanoplatform to realize 'multi-in-one' is essential to broaden the therapeutic potential of combination therapy. Exosomes are ideal candidates since their intrinsic abilities of integrating multiple contents and functions. However, only limited efforts have been devoted to engineering exosomes to integrate the needed properties, also considering the safety and yield, for tumor-targeted and efficient gene/chemo combination therapy. Methods: Herein, by manipulating the exosome membrane, blood exosomes with high abundance and safety are engineered as a versatile combinatorial delivery system, where the doxorubicin (Dox) and cholesterol-modified miRNA21 inhibitor (miR-21i) are co-embedded into the lipid bilayer of exosomes, and the magnetic molecules and endosomolytic peptides L17E are bind to the exosome membrane through ligand-receptor coupling and electrostatic interactions, respectively. Results: It is proved that such engineering strategy not only preserves their intrinsic features, but also readily integrates multiple properties of tumor targeting, efficient transfection and gene/chemo combination therapy into blood exosomes. The lipid bilayer structure of exosomes allows them to co-load Dox and miR-21i with high-payloads. Moreover, profiting from the integration of magnetic molecules and L17E peptides, the engineered exosomes exhibit an enhanced tumor accumulation and an improved endosome escape ability, thereby specifically and efficiently delivering encapsulated cargos to tumor cells. As a result, a remarkable inhibition of tumor growth is observed in the tumor-bearing mice, and without noticeable side effects. Conclusions: This study demonstrates the potential of engineered blood exosomes as feasible co-delivery nanosystem for tumor-targeted and efficient combination therapy. Further development by replacing the drugs combined regimens can potentially make this engineered exosome become a general platform for the design of safe and effective combination therapy modality.
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Ingeniería Química/métodos , Sistemas de Liberación de Medicamentos/métodos , Exosomas/química , Terapia Genética/métodos , Neoplasias/terapia , Animales , Línea Celular Tumoral , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Regulación Neoplásica de la Expresión Génica , Terapia Genética/efectos adversos , Humanos , Nanopartículas Magnéticas de Óxido de Hierro , Ratones , MicroARNs/antagonistas & inhibidores , Neoplasias/genética , Neoplasias/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Objective: The introduction of therapeutic antibodies (tAbs) into clinical practice has revolutionized tumor treatment strategies, but their tumor therapy efficiency is still far below expectations because of the rapid degradation and limited tumor accumulation of tAbs. Methods: We developed a nanocapsule-based delivery system to induce the self-augmentation of the enhanced permeability and retention (EPR) effect. This system constantly penetrated across the blood-tumor barrier into the tumor while avoiding the attack of tAbs by the immune system. The biodistribution and therapeutic effect were tested with single dose administration of nanocapsule-tAbs in vivo. Results: The accumulation of Nano(cetuximab) within subcutaneous PC9 tumors was gradually enhanced over 6 days after single dose administration, which was contrary to the biodistribution of native cetuximab. Nano(cetuximab) accumulated in tumor tissues via the EPR effect and released cetuximab. The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and induce self-augmentation of the EPR effect, which in turn contributed to further tumor accumulation of long-circulating Nano(cetuximab). Compared with single dose administration of native cetuximab, Nano(cetuximab) showed an effective tumor suppressive effect for 3 weeks. Conclusions: The nanocapsule-based delivery system efficiently delivered tAbs to tumor tissues and released them to boost the EPR effect, which facilitated further tumor accumulation of the tAbs. This novel self-augmentation of the EPR effect facilitated by the biological characteristics of tAbs and nanotechnology contributed to the improvement of the therapeutic effect of tAbs, and stimulated new ideas for antibody-based tumor therapy.
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Cetuximab/farmacología , Células Endoteliales/efectos de los fármacos , Nanocápsulas , Animales , Sistemas de Liberación de Medicamentos , Femenino , Ratones , Ratones Desnudos , Permeabilidad , Células RAW 264.7 , Distribución TisularRESUMEN
The use of circulating microRNAs as biomarkers opens up new opportunities for the diagnosis of cardiovascular diseases because of their specific expression profiles. The aim of the present study was to identify circulating microRNAs in human plasma as potential biomarkers of heart failure and related diseases. We used real-time quantitative PCR to screen microRNA in plasma samples from 62 normal controls and 62 heart failure samples. We found that circulating miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 expressed differently between healthy controls and heart failure patients. Plasma levels of miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 were unaffected by hemolysis. Correlation analysis showed any two of these miRNAs possess a strong correlation, indicating a possibility of combined analysis. MiR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 could be combined in two or three or more combinations. The results suggest that miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 may be a new diagnostic biomarker for heart failure and related diseases.