RESUMO
Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.
Assuntos
Nanomedicina , Trombose , Humanos , Polifenóis/farmacologia , Chá , Terapia Trombolítica , Verde de Indocianina/farmacologia , Verde de Indocianina/uso terapêutico , Inflamação/tratamento farmacológico , Trombose/tratamento farmacológicoRESUMO
Gene therapy that employs therapeutic nucleic acids to modulate gene expression has shown great promise for diseases therapy, and its clinical application relies on the development of effective gene vector. Herein a novel gene delivery strategy by just using natural polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) as raw material is reported. EGCG first intercalates into nucleic acids to yield a complex, which then oxidizes and self-polymerizes to form tea polyphenols nanoparticles (TPNs) for effective nucleic acids encapsulation. This is a general method to load any types of nucleic acids with single or double strands and short or long sequences. Such TPNs-based vector achieves comparable gene loading capacity to commonly used cationic materials, but showing lower cytotoxicity. TPNs can effectively penetrate inside cells, escape from endo/lysosomes, and release nucleic acids in response to intracellular glutathione to exert biological functions. To demonstrate the in vivo application, an anti-caspase-3 small interfering ribonucleic acid is loaded into TPNs to treat concanavalin A-induced acute hepatitis, and excellent therapeutic efficacy is obtained in combination with the intrinsic activities of TPNs vector. This work provides a simple, versatile, and cost-effective gene delivery strategy. Given the biocompatibility and intrinsic biofunctions, this TPNs-based gene vector holds great potential to treat various diseases.
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Ácidos Nucleicos , Polifenóis , Polifenóis/farmacologia , Chá , Polimerização , Terapia GenéticaRESUMO
Manganese oxide nanomaterials (MONs) are emerging as a type of highly promising nanomaterials for diseases diagnosis, and surface modification is the basis for colloidal stability and targeting delivery of the nanomaterials. Here, we report the in-situ functionalization of MnO2 with DNA through a biomineralization process. Using adsorption-oxidation method, DNA templated Mn2+ precursor to biomineralize into nano-cubic seed, followed by the growth of MnO2 to form cube/nanosheet hybrid nanostructure. Among four types of DNA homopolymers, poly-thymine (poly-T) was found to stably attach on MnO2 surface to resist various biological displacements (phosphate, serum, and complementary DNA). Capitalized on this finding, a di-block DNA was rationally designed, in which the poly-T block stably anchored on MnO2 surface, while the AS1411 aptamer block was not only an active ligand for tumor targeting delivery, but also a carrier for photosensitizer (Ce6) loading. Upon targeting delivery into tumor cells, the MnO2 acted as catalase-mimic nanozyme for oxygenation to sensitize photodynamic therapy, and the released Mn2+ triggered chemodynamic therapy via Fenton-like reaction, achieving synergistic anti-tumor effect with full biocompatibility. This work provides a simple yet robust strategy to functionalize metal oxides nanomaterials for biological applications via DNA-templated biomineralization.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Óxidos/química , Timina/uso terapêutico , Compostos de Manganês/farmacologia , Compostos de Manganês/química , Biomineralização , Neoplasias/tratamento farmacológico , DNA/química , Nanopartículas/químicaRESUMO
Photodynamic therapy (PDT) has emerged as a promising tumor treatment method via light-triggered generation of reactive oxygen species (ROS) to kill tumor cells. However, the efficacy of PDT is usually restricted by several biological limitations, including hypoxia, excess glutathione (GSH) neutralization, as well as tumor resistance. To tackle these issues, herein we developed a new kind of DNA nanozyme to realize enhanced PDT and synergistic tumor ferroptosis. The DNA nanozyme was constructed via rolling circle amplification, which contained repeat AS1411 G quadruplex (G4) units to form multiple G4/hemin DNAzymes with catalase-mimic activity. Both hemin, an iron-containing porphyrin cofactor, and chlorine e6 (Ce6), a photosensitizer, were facilely inserted into G4 structure with high efficiency, achieving in-situ catalytic oxygenation and photodynamic ROS production. Compared to other self-oxygen-supplying tools, such DNA nanozyme is advantageous for high biological stability and compatibility. Moreover, the nanostructure could achieve tumor cells targeting internalization and intranuclear transport of Ce6 by virtue of specific nucleolin binding of AS1411. The nanozyme could catalyze the decomposition of intracellular H2O2 into oxygen for hypoxia relief as evidenced by the suppression of hypoxia-inducible factor-1α (HIF-1α), and moreover, GSH depletion and cell ferroptosis were also achieved for synergistic tumor therapy. Upon intravenous injection, the nanostructure could effectively accumulate into tumor, and impose multi-modal tumor therapy with excellent biocompatibility. Therefore, by integrating the capabilities of O2 generation and GSH depletion, such DNA nanozyme is a promising nanoplatform for tumor PDT/ferroptosis combination therapy.
Assuntos
DNA Catalítico , Ferroptose , Fotoquimioterapia , Porfirinas , Catalase , DNA , Glutationa/metabolismo , Hemina , Humanos , Peróxido de Hidrogênio , Hipóxia/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia , Ferro , Oxigênio , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Porfirinas/química , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Through self-polymerization of serotonin monomer, polyserotonin (PST) can coat on arbitrary surfaces with pH-responsive degradation, which was employed for nanoparticle coating and controlled drug release, achieving a robust anti-tumor effect when combined with its intrinsic photothermal effect.
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Hipertermia Induzida , Nanopartículas , Doxorrubicina , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , FototerapiaRESUMO
Sepsis, a life-threating illness caused by deregulated host immune responses to infections, is characterized by overproduction of multiple reactive oxygen and nitrogen species (RONS) and excessive pyroptosis, leading to high mortality. However, there is still no approved specific molecular therapy to treat sepsis. Here we reported drug-free tea polyphenols nanoparticles (TPNs) with intrinsic broad-spectrum RONS scavenging and pyroptosis-blocking activities to treat endotoxin (LPS)-induced sepsis in mice. The RONS scavenging activities originated from the polyphenols-derived structure, while the pyroptosis blockage was achieved by inhibiting gasdermin D (GSDMD) mediating the pore formation and membrane rupture, showing multifunctionalities for sepsis therapy. Notably, TPNs suppress GSDMD by inhibiting the oligomerization of GSDMD rather than the cleavage of GSDMD, thus displaying high pyroptosis-inhibition efficiency. As a result, TPNs showed an excellent therapeutic efficacy in sepsis mice model, as evidenced by survival rate improvement, hypothermia amelioration, and the organ damage protection. Collectively, TPNs present biocompatible candidates for the treatment of sepsis.
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Nanopartículas , Sepse , Animais , Endotoxinas , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Camundongos , Proteínas de Ligação a Fosfato/uso terapêutico , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Piroptose , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , CháRESUMO
BACKGROUND: Most chemotherapeutics used in cancer therapies exhibit considerable side effects to the patients. Thus, developing new chemo agents to treat cancer patients with minimal toxic and side effects is urgently needed. Recently, the combination of different chemotherapeutics has become a promising strategy to treat malignancies. Thymoquinone (TQ) is a primary bioactive compound derived from the folk medicinal plant Nigella sativa, which has been found an antitumor, chemopreventive and chemopotentiating agent against human neoplastic diseases. PURPOSE: We briefly summarize the current research of the biomolecular mechanisms of TQ and evaluate the existing literature on TQ adjuvant therapies against various cancers. METHOD: The data in this review were gathered by several search engines including, Google Scholar, PubMed and ScienceDirect. We highlighted and classified the outcomes of both in vitro and in vivo experiments of TQ adjuvant therapies against human cancers and their chemopreventive activities on vital organs. RESULTS: Several studies have shown that TQ synergistically potentiated the antitumor activity of numerous chemo agents against human neoplastic disease, including lung, breast, liver, colorectal, skin, prostate, stomach, bone and blood cancers. TQ also acted as a chemopreventive agent and reduced the toxicity of many chemo agents to vital organs, such as the heart, liver, kidneys and lungs. CONCLUSION: In summary, we highly recommend an advanced evaluation of TQ adjuvant therapies at the level of preclinical and clinical trials, which could lead to a novel combinatorial therapy for cancer treatment with low or tolerable adverse effects on patients.
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Atherosclerosis (AS) is a leading cause of vascular diseases that severely threats the human health due to the lack of efficient therapeutic methods. During the development and progress of AS, macrophages play critical roles, which are polarized into pro-inflammatory M1 phenotype to excrete abundant cytokines and overproduce reactive oxygen species (ROS), and take up excess amount of lipid to form foam cells. In this work, we developed a MnO2-based nanomedicine to re-educate macrophages for targeting AS therapy. The MnO2 was one-pot synthesized under mild condition, showing intrinsic catalase-mimic activity for self-oxygenation by using endogenous H2O2 as substrate. Moreover, the mesoporous structure as well as the abundant metal coordination sites in MnO2 structure facilitated the loading of an anti-AS drug of curcumin (Cur), achieving extraordinarily high drug loading capacity of 54%. Cur displayed a broad spectrum of anti-oxidant and anti-inflammatory capabilities to repolarize M1 macrophages into M2 phenotype, and the catalytic MnO2 recovered the function of lipid efflux transporter to remove lipid from cells by suppressing HIF-1α. Collectively, the nanocarrier and the payload drug functioned as an all-active nanoplatform to synergistically alleviate the syndromes of AS. In ApoE-/- mice model, the nanosystem could significantly prolong the circulation half-life of Cur by sixfold, and enhance drug accumulation in atherosclerotic lesion by 3.5-fold after intravenous injection by virtue of surface hyaluronic acid (HA) modification. As a result, a robust anti-AS efficacy was achieved as evidenced by the decrease of atherosclerotic lesion, plaque area, lipid level.
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Aterosclerose , Nanopartículas , Animais , Aterosclerose/tratamento farmacológico , Peróxido de Hidrogênio , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Camundongos , Nanopartículas/química , Óxidos/químicaRESUMO
Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As4S4) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As4S4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As4S4 nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As4S4/IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while As4S4 degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of As4S4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Nanopartículas , Animais , Antineoplásicos/uso terapêutico , Apoptose , Arsenicais , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , SulfetosRESUMO
L-glutamate is an important component of protein. It can prevent gastrointestinal damage caused by NSAIDs. We constructed two-phase enteric-coated granules of aspirin and L-glutamate compound by extrusion spheronization method and fluidized bed coating. The subliminal effective dose of L-glutamate is 100 mg/kg tested by model of gastric ulcer of rats induced by aspirin and drug administration. HPLC-UV and UV-Vis methods were adopted to determine content and cumulative release of aspirin and L-glutamate as quality analysis method indexes. The prescription and process optimization were carried out with yield, sphericity and dissolution. The two-phase compound granules have good sphericity of 0.93 ± 0.05 (aspirin pellets) and 0.94 ± 0.02 (L-glutamate pellets), content of salicylic acid (0.24 ± 0.03)%, dissolution of aspirin (2.36 ± 0.11)%. Quality evaluation and preliminary stability meet the commercial requirements. The stored environment of compound preparation should be sealed in a cool and dark place.
Assuntos
Aspirina , Composição de Medicamentos , Ácido Glutâmico , Animais , Aspirina/administração & dosagem , Aspirina/síntese química , Aspirina/farmacologia , Química Farmacêutica/métodos , Química Farmacêutica/normas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Composição de Medicamentos/métodos , Composição de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Mucosa Gástrica/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/síntese química , Ácido Glutâmico/farmacologia , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Comprimidos com Revestimento EntéricoRESUMO
Capillary electrophoresis (CE) presents a promising possibility for analyzing traditional Chinese medicine (TCM) due to its low reagent consumption, high analysis speed, and enhanced efficiency. Herein we review the employment of CE for analyzing the effective components in TCM and identifying TCM via a fingerprint. Furthermore, we discuss the application of state-of-the-art capillary electrophoresis modes for screening enzyme inhibitors and investigating the interactions between TCM and plasma proteins. The review concludes with recommendations for future studies and improvements in this field of research. The general development trend identified in this review indicates that the application of CE has significantly improved TCM assay performance.
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Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Eletroforese Capilar , Inibidores EnzimáticosRESUMO
BACKGROUND: Reactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy. METHODS: Indocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model. RESULTS: Compared with DOX·HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX·HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed. CONCLUSIONS: Lipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Lipossomos , Espécies Reativas de Oxigênio , Animais , Linhagem Celular Tumoral , Terapia Combinada , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Células HEK293 , Humanos , Verde de Indocianina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Pró-Fármacos , Oxigênio Singlete , Distribuição TecidualRESUMO
Cooperative photothermal therapy (PTT) and photodynamic therapy (PDT) represents a promising strategy to conquer tumor with synergistic effect, while their long-term efficacy has been strictly limited by the multiple resistances of tumor. Here, we reported a core-shell nanoplatform for enhanced PTT/PDT combination against metastatic breast cancer. The nanosystem had photosensitizer chlorin e6 (Ce6) and rapamycin (RAP) pure drugs core and the polydopamine (PDA) shell, with surface PEGylation. Notably, we found that RAP was a highly robust sensitizer to boost the efficacy of both PTT and PDT by inhibiting the expression of heat shock protein 70 (HSP 70) and hypoxia inducible factor-1α (HIF-1α), respectively, resulting in cooperatively enhanced antitumor efficiency. Moreover, metastasis, the fatal risk of breast cancer, was also inhibited by virtue of RAP-mediated matrix metalloproteinases-2 (MMP-2) suppression. Upon intravenous injection, the nanosystem could passively accumulate into the tumor and impose potent phototherapies upon dual laser irradiations for complete tumor elimination and metastasis inhibition, giving rise to 100% mice survival over a long observation period. Collectively, this work offers a general solution to address the key limitations of tumor-resistant phototherapies and provides a highly promising nanoplatform for the management of metastatic cancer.
Assuntos
Neoplasias da Mama/terapia , Movimento Celular , Neoplasias Pulmonares/terapia , Nanopartículas/administração & dosagem , Fototerapia/métodos , Sirolimo/farmacologia , Cicatrização , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Nanopartículas/química , Fármacos Fotossensibilizantes/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Uranium pollution in environment and food chain is a serious threat to public security and human health. Herein, we proposed a temperature-robust, ratiometric, and label-free bioassay based on G-quadruplex proximate DNAzyme (G4DNAzyme), accommodating us to precisely monitor uranium pollution and biosorption. The proximity of split G-quadruplex probes was proposed to sense UO22+-activated DNAzyme activity, thus eliminating the use of chemically labeled nucleic acid probes. And the simultaneous monitoring of G-quadruplex and double-stranded structures of DNAzyme probes contributed to a ratiometric and robust detection of UO22+. Particularly, the separation of enzymatic digestion and fluorescence monitoring endued a robust and highly responsive detection of UO22+ upon the temperature of enzymatic digestion process ranged from 18° to 41⯰C. Consequently, G4DNAzyme assay allowed a robust, label-free and ratiometric quantification of uranium. We demonstrated the feasibility of G4DNAzyme assay for estimating uranium pollution in water and aquatic product samples. Ultimately, G4DNAzyme assay was adopted to serve as the platform to screen bacterial species and conditions for uranium biosorption, promising its roles in uranium associated biosafety control.
Assuntos
Técnicas Biossensoriais , DNA Catalítico , Quadruplex G , Urânio , Bioensaio , Hemina , Humanos , Limite de Detecção , TemperaturaRESUMO
Multi-modal nanomedicines that synergistically combine chemo-, gene-, and photothermal therapy have shown great potential for cancer treatment. In this study, a core-shell nanosystem-based on a zinc oxide (ZnO) nanocore and a polydopamine (PDA) shell was constructed to integrate chemo- (doxorubicin, DOX), gene- (DNAzyme, DZ), and photothermal (PDA layer) therapy in one system. Instead of small interfering RNAs, we employed DZ for tumor-related gene (survivin) regulation owing to its higher stability, biocompatibility, and predictable activity. DOX and amino-modified DZ were loaded onto the PDA shell via physisorption and covalent conjugation, respectively. Specifically, the ZnO nanocore was designed as a metal cofactor reservoir to release Zn2+ in response to intracellular stimuli, which triggered the activation of DZ for gene silencing after endocytosis into cells. Both in vitro and in vivo experiments demonstrated the enhanced anti-tumor efficacy of these multifunctional nanocomposites and highlighted the advantages of these nano-drug delivery systems to alleviate the side effects of DOX. This study provides a strategy for synergistic cancer therapy via chemo/gene/photothermal combination and offers a strategy to harness DZ as a gene-silencing tool for disease treatment in combination with other therapeutic modalities. STATEMENT OF SIGNIFICANCE: In this work, we constructed a core-shell nanosystem containing a zinc oxide (ZnO) nanocore and a polydopamine (PDA) outer layer, which integrated chemo- (doxorubicin, DOX), gene- (DNAzyme, DZ), and photothermal (PDA layer) therapies for multimodal cancer therapy. Specifically, the ZnO core was incorporated to solve the key issue of DZ for gene silencing applications, which acted as the metal cofactor reservoir to release Zn2+ inside cells for effective DZ activation. In addition, the PDA shell could detoxify the ZnO by scavenging the reactive oxygen species produced by ZnO, thus increasing the biocompatibility of the nanocarrier. This work solves the key issue of DZ for RNAi-based applications, offers a platform to combine DZ with other therapeutic modalities, and also provides a smart strategy to achieve triggered activation of biocatalytic reactions for therapeutic applications.
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DNA Catalítico , Hipertermia Induzida , Nanocompostos , Nanopartículas , Óxido de Zinco , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Indóis , Fototerapia , Terapia Fototérmica , Polímeros , Óxido de Zinco/farmacologiaRESUMO
Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.
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Antitussígenos/administração & dosagem , Codeína/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Morfina/farmacocinética , Administração Oral , Adulto , Antitussígenos/química , China , Cromatografia Líquida de Alta Pressão , Codeína/análise , Estudos Cross-Over , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Humanos , Masculino , Medicina Tradicional Chinesa , Morfina/análise , Distribuição Aleatória , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
DNAzymes are catalytically active DNA molecules that are obtained via in vitro selection. RNA-cleaving DNAzymes have attracted significant attention for both therapeutic and diagnostic applications due to their excellent programmability, stability, and activity. They can be designed to cleave a specific mRNA to down-regulate gene expression. At the same time, DNAzymes can sense a broad range of analytes. By combining these two functions, theranostic DNAzymes are obtained. This review summarizes the progress of DNAzyme for theranostic applications. First, in vitro selection of DNAzymes is briefly introduced, and some representative DNAzymes related to biological applications are summarized. Then, the applications of DNAzyme for RNA cleaving are reviewed. DNAzymes have been used to cleave RNA for treating various diseases, such as viral infection, cancer, inflammation and atherosclerosis. Several formulations have entered clinical trials. Next, the use of DNAzymes for detecting metal ions, small molecules and nucleic acids related to disease diagnosis is summarized. Finally, the theranostic applications of DNAzyme are reviewed. The challenges to be addressed include poor DNAzyme activity under biological conditions, mRNA accessibility, delivery, and quantification of gene expression. Possible solutions to overcome these challenges are discussed, and future directions of the field are speculated.
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DNA Catalítico/metabolismo , RNA/metabolismo , Nanomedicina Teranóstica/métodos , Animais , Terapia Biológica/métodos , Pesquisa Biomédica/tendências , Testes Diagnósticos de Rotina/métodos , HumanosRESUMO
Molecular beacons typically use organic molecules or nanomaterials as quenchers. Many transition-metal ions have excellent fluorescence quenching ability, and the aim of this study was to recruit them as small quenchers in DNA detection. Cr3+ has a slow ligand exchange rate, forming stable adducts with DNA. With its strong fluorescence quenching ability, the site-specific labeling of Cr3+ on DNA to form a new type of molecular beacon was investigated. The kinetics of quenching by Cr3+ were measured for single- and double-stranded DNA as a function of salt concentration, pH, and Cr3+ ion concentration. The goal was to achieve a selective reaction with the single-stranded but not double-stranded regions. The reaction mechanism was also probed by adding adenosine triphosphate, revealing two Cr3+ -binding modes: fast but unstable, and slow but stable. A partially complementary duplex was designed with a short polyguanine overhang, which, under optimal conditions, enabled selective labeling of the overhanging region with Cr3+ . The resulting sequence was tested as a molecular beacon with a detection limit of 0.3â nm DNA and a saturated fluorescence enhancement of fivefold. With a 13-nucleotide target DNA, the single mismatch discrimination of the beacon was 22-fold. This study demonstrates the possibility of forming useful Cr3+ adducts with DNA. Such adducts are not only useful for developing biosensors but also for constructing new materials.
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The objective of the present study is to formulate and characterize propranolol hydrochloride (PPL · HCl) gel, and to evaluate the efficacy of this formulation in transdermal treatment for superficial infantile hemangioma (IH). The transdermal PPL · HCl gel was prepared by a direct swelling method, which chose hydroxypropyl methylcellulose (HPMC) as the matrix and used terpenes plus alcohols as permeation enhancer. Permeation studies of PPL · HCl were carried out with modified Franz diffusion cells through piglet skin. Our results pointed to that among all studied permeation enhancers, farnesol plus isopropanol was the most effective combination (Q24, 6027.4 ± 563.1 µg/cm(2), ER, 6.8), which was significantly higher than that of control gel (p < 0.05). High percutaneous penetration with related lower plasma drug level of PPL · HCl gel was confirmed by microdialysis technique in rats using the homemade PPL · HCl oral solution as a control. Clinical studies also confirmed the excellent therapeutic response and few side effects of the PPL · HCl gel. These results suggest that transdermal application of the PPL · HCl gel is an effective and safe formulation in treating superficial IH.