RESUMO
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.
Assuntos
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.
Assuntos
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
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.
Assuntos
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.
Assuntos
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
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.
Assuntos
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
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
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.
Assuntos
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.
Assuntos
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.
Assuntos
DNA Catalítico/metabolismo , RNA/metabolismo , Nanomedicina Teranóstica/métodos , Animais , Terapia Biológica/métodos , Pesquisa Biomédica/tendências , Testes Diagnósticos de Rotina/métodos , HumanosRESUMO
Shenfu Injection (SFI) is a well-defined Chinese herbal formulation that is obtained from red ginseng and processed aconite root. The main active constituents in SFI are ginsenosides and aconitum alkaloids. In this work, ginsenosides (ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rc) and aconitum alkaloids (benzoylmesaconine and fuziline) were used as the index components to explore the pharmacokinetic behavior of SFI. A selective and sensitive HPLC-MS/MS method was developed for the quantification of ginsenosides and aconitum alkaloids in dog plasma and was used to characterize the pharmacokinetics of the five index components after intravenous drip of three different dosages of SFI in beagle dogs. The pharmacokinetic properties of the index components were linear over the dose range of 2-8 mL/kg.
RESUMO
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.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Hemangioma/tratamento farmacológico , Propranolol/administração & dosagem , Absorção Cutânea , Administração Cutânea , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Química Farmacêutica , Pré-Escolar , Método Duplo-Cego , Excipientes/química , Feminino , Humanos , Derivados da Hipromelose/química , Lactente , Masculino , Permeabilidade , Propranolol/farmacocinética , Propranolol/uso terapêutico , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Suínos , Terpenos/químicaRESUMO
AIM: Evodiamine (EVO) and rutaecapine (RUT), the major active components from Evodia rutaecarpa extract (EE), are recognized as a depended analgesic agent. This study was designed to investigate the effect of purity and chemical enhancers on the transdermal behavior of EVO and RUT, and the pharmacological effect of their topical cream in vivo. MATERIAL AND METHODS: Transdermal delivery across a full thickness pig abdominal skin was detected in vitro by Franz-type diffusion cell, with HPLC for quantification of the permeation of EVO and RUT. The activity of topical cream in vivo was evaluated by a mice pain model induced by formalin and hot plate. RESULTS: Transdermal characters of EVO and RUT showed a low transdermal rate, long lag time and low cumulative amount. The transdermal rate and cumulative amount could be promoted by lipophilic enhancers, whereas lag time was shortened by hydrophilic surfactant, but these permeation parameters were not markedly influenced by purity of EE (p>0.05). The effect in vivo was confirmed by analgesic models in topical cream of EE, which produced a significant (p<0.05) inhibitory effects on pain response in dose-dependent manner. CONCLUSION: The purity of EVO and RUT from EE has no significant effect on their permeation through porcine skin, but oleic acid or nerolidol can markedly elevate the transdermal rate of EVO and RUT. High purity of EE is the best choice for topical preparation to increase the drug loading. The effect of EE in vivo is verified by formalin model and hot plate test.
Assuntos
Analgésicos/administração & dosagem , Evodia/química , Alcaloides Indólicos/administração & dosagem , Dor/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Quinazolinas/administração & dosagem , Pele/metabolismo , Administração Cutânea , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Alcaloides Indólicos/metabolismo , Alcaloides Indólicos/uso terapêutico , Masculino , Camundongos , Ácido Oleico/administração & dosagem , Ácido Oleico/metabolismo , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Quinazolinas/metabolismo , Quinazolinas/uso terapêutico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/metabolismo , SuínosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Wu-Chu-Yu is a well-known herbal drug used for hypertension. Rutaecarpine and evodiamine are main bioactive components of the medicine. MATERIALS AND METHODS: A sensitive and specific HPLC method was developed to analyze rutaecarpine (Rut) and evodiamine (Evo) in rat whole blood. The pharmacokinetics of Rut and Evo after oral administration of Wu-Chu-Yu extracts with different purities to rats was compared to evaluate the effect of purity of Wu-Chu-Yu extracts on the absorption of Rut and Evo. Male Sprague-Dawley rats were given Wu-Chu-Yu extracts with different purities (high, medium and low) approximately the same doses of equivalent to Rut (40 mg/kg) and Evo (31 mg/kg). The contents of Rut and Evo were 45 and 35%, 28 and 21%, 9 and 7% in high, medium and low purity extracts, respectively. At different time points (0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3 and 4h) after administration, the concentrations of Rut and Evo in rat whole blood were determined by HPLC, and main pharmacokinetic parameters were calculated. RESULTS: The results indicated that the absorption of Rut and Evo in Wu-Chu-Yu extracts was improved when compared with the pure Rut and Evo and there were significant differences among different groups. CONCLUSIONS: The bioavailability of Rut and Evo was increased along with the increasing of purity (16%-80%) in Wu-Chu-Yu extracts.
Assuntos
Alcaloides/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Alcaloides Indólicos/farmacocinética , Extratos Vegetais/farmacocinética , Quinazolinas/farmacocinética , Quinolinas/farmacocinética , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/sangue , Alcaloides/química , Animais , Disponibilidade Biológica , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Evodia/química , Alcaloides Indólicos/administração & dosagem , Alcaloides Indólicos/análise , Alcaloides Indólicos/sangue , Absorção Intestinal , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Extratos Vegetais/química , Quinazolinas/administração & dosagem , Quinazolinas/análise , Quinazolinas/sangue , Quinolinas/administração & dosagem , Quinolinas/sangue , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Padrões de ReferênciaRESUMO
Previous investigations have shown that calcitonin gene-related peptide (CGRP) protects gastric mucosa against injury induced by acetylsalicylic acid (ASA) and that rutaecarpine activates vanilloid receptors to evoke CGRP release. In the present study, we examined the protective effects of rutaecarpine on gastric mucosa injury, and explored whether the protective effects of rutaecarpine are related to stimulation of endogenous CGRP release via activating vanilloid receptors in rats. In an ASA-induced ulceration model, gastric mucosal ulcer index, pH value of gastric juice and plasma concentrations of CGRP were determined. ASA significantly increased the gastric mucosal ulcer index and the back-diffusion of H+ through the mucosa. Rutaecarpine at the doses of 100 or 300 microg/kg (i.v.), and 300 or 600 microg/kg (intragastric, i.g.) reduced the ulcer index and back-diffusion of H+, which was abolished by pretreatment with capsaicin (50 mg/kg, s.c.) or capsazepine (3 mg/kg, i.v.), a competitive vanilloid receptor antagonist. Rutaecarpine significantly increased the plasma concentration of CGRP, which was also abolished by capsazepine. In a stress-induced ulceration model, rutaecarpine reduced gastric mucosal damages, which was abolished by capsazepine (5 mg/kg, i.p.). These results suggest that rutaecarpine protects the gastric mucosa against injury induced by ASA and stress, and that the gastroprotective effect of rutaecarpine is related to a stimulation of endogenous CGRP release via activation of the vanilloid receptor.