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1.
J Mater Chem B ; 10(11): 1858-1874, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35229088

RESUMO

The development of new antimicrobial drugs is urgently required to overcome bacterial resistance which is a serious threat to human health. Antimicrobial peptides (AMPs) which are ideal substitutes for traditional antibiotics have a unique mechanism of action and do not easily cause bacterial resistance. Herein, a series of new AMPs were designed and synthesized based on the biological characteristics of natural AMPs (such as the positive charge, α-helical structure and amphiphilicity). Biological screening of the AMPs provided an antimicrobial lipopeptide LP21 with efficient antimicrobial activity, serum stability, low cytotoxicity and high membrane-disruptive activity. Besides, LP21 could self-assemble into spherical aggregates in aqueous solutions which encapsulated TC to form LP21@TC nanomedicine, and the encapsulation efficiency was about 50.03 ± 3.03%. More impressively, both LP21 and LP21@TC nanomedicine displayed significant therapeutic effects in vivo, and the LP21@TC nanomedicine could exert a synergistic antimicrobial effect. This work is expected to provide a new research vision for the design of AMPs and synergistic antibacterial sensitization treatment.


Assuntos
Anti-Infecciosos , Infecções Bacterianas , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/química , Humanos , Lipopeptídeos
2.
Methods Mol Biol ; 2375: 165-176, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34591307

RESUMO

Injectable scaffolds made of biodegradable biomaterials can stabilize a myocardial infarct and promote cardiac repair. Here, we describe an injectable, citrate-containing polyester hydrogel which can release citrate as a cell regulator via hydrogel degradation and simultaneously show sustained release of an encapsulated myeloid-derived growth factor (Mydgf). Xu et al. described the synthesis of hydrogel with biocompatible starting chemicals including citric acid and poly(ethylene glycol) diol. The characterization of materials demonstrated that the developed hydrogels possess tunable degradation and mechanical properties and exhibit sustained drug release. The authors also observed improved postmyocardial infarction (MI) heart repair in a rat MI model through coupling the therapeutic effect of the hydrogel degradation product (citrate) with encapsulated Mydgf. In their study, hematoxylin and eosin (H&E) staining and Masson's trichrome staining were performed on heart samples to evaluate the change in heart structure. Furthermore, immunohistochemistry was used to study neovascularization. Their results showed that the intramyocardial injection of Mydgf-loaded citrate-containing hydrogel significantly reduced scar formation and infarct size, increased wall thickness and neovascularization, and improved heart function.


Assuntos
Engenharia Tecidual , Animais , Citratos , Coração , Hidrogéis , Infarto do Miocárdio/tratamento farmacológico , Ratos
3.
Adv Healthc Mater ; 10(8): e2001812, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33458958

RESUMO

Nucleic acid vaccines are a method of immunization aiming to elicit immune responses akin to live attenuated vaccines. In this method, DNA or messenger RNA (mRNA) sequences are delivered to the body to generate proteins, which mimic disease antigens to stimulate the immune response. Advantages of nucleic acid vaccines include stimulation of both cell-mediated and humoral immunity, ease of design, rapid adaptability to changing pathogen strains, and customizable multiantigen vaccines. To combat the SARS-CoV-2 pandemic, and many other diseases, nucleic acid vaccines appear to be a promising method. However, aid is needed in delivering the fragile DNA/mRNA payload. Many delivery strategies have been developed to elicit effective immune stimulation, yet no nucleic acid vaccine has been FDA-approved for human use. Nanoparticles (NPs) are one of the top candidates to mediate successful DNA/mRNA vaccine delivery due to their unique properties, including unlimited possibilities for formulations, protective capacity, simultaneous loading, and delivery potential of multiple DNA/mRNA vaccines. This review will summarize the many varieties of novel NP formulations for DNA and mRNA vaccine delivery as well as give the reader a brief synopsis of NP vaccine clinical trials. Finally, the future perspectives and challenges for NP-mediated nucleic acid vaccines will be explored.


Assuntos
COVID-19 , Nanopartículas , Vacinas , DNA , Humanos , RNA Mensageiro , SARS-CoV-2
4.
J Control Release ; 322: 622-631, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32194173

RESUMO

Gene therapy is one of the most promising medical fields which holds the potential to rapidly advance the treatment of difficult ailments such as cancer as well as inherited genetic diseases. However, clinical translation is limited by several drug delivery hurdles including renal clearance, phagocytosis, enzymatic degradation, protein absorption, as well as cellular internalization barriers. Additionally, successful treatments require sustained release of drug payloads to maintain the effective therapeutic level. As such, controlled and sustained release is a significant concern as the localization and kinetics of nucleic acid therapeutics can significantly influence the therapeutic efficacy. This is an unmet need which calls for the development of controlled-release nanoparticle (NP) technologies to further improve the gene therapy efficacy by prolonging the release of nucleic acid drug payload for sustained, long-term gene expression or silencing. Herein, we present a polymeric NP system with sustained gene delivery properties, which can be synthesized using biodegradable and biocompatible polymers via self-assembly. The NP delivery system is composed of a polymeric NP which acts as a drug depot encapsulating cationic polymer/nucleic acid complexes, facilitating the enhanced retention and prolonged release of the gene payload. The NPs showed excellent cellular biocompatibility and gene delivery efficacy using the green fluorescent protein (GFP) encoded DNA plasmid (pGFP) as a reporter gene. Sustained release of the pGFP payload was shown over a period of 8 days. The physicochemical properties such as morphology, particle size, zeta potential, pGFP encapsulation efficiency and biological properties such as pGFP release profile, in vitro cytotoxicity and transfection efficacy in Hek 293 cells were characterized and evaluated. Importantly, the NP-mediated sustained release of pGFP generates enhanced GFP expression over time. We expect this NP-mediated gene delivery system to provide safe and sustained release of various nucleic acid-based therapeutics with applications in both fundamental biological studies and clinical translations.


Assuntos
Técnicas de Transferência de Genes , Nanopartículas , Terapia Genética , Células HEK293 , Humanos , Transfecção
5.
Nat Commun ; 11(1): 243, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913267

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Nanoscale ; 12(2): 877-887, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31833519

RESUMO

Engineered exosomes have become popular drug delivery carriers for cancer treatment. This is partially due to the interesting property, i.e. exosome organotropism, which plays an important role in organ distribution post systemic administration. Here, we demonstrated that breast cancer (MDA-MB-231) cell-derived exosomes (231-Exo) could be specifically internalized by non-small cell lung cancer cells via a specific interaction between overexpressed integrin ß4 (on exosomes) and surfactant protein C (SPC) on the cancer cells. We showed that 231-Exo was capable of recognizing A549 cells in blood and effectively escaping from the immune surveillance system in vitro. Once loaded with microRNA molecules in the exosome carriers, the resulting, miRNA-126 loaded 231-Exo (miRNA-231-Exo) strongly suppressed A549 lung cancer cell proliferation and migration through the interruption of the PTEN/PI3K/AKT signaling pathway. Intravenous administration of the miRNA-126 laden exosomes led to an effective lung homing effect in mice. When tested in a lung metastasis model, miRNA-231-Exo resulted in an efficacious effect in inhibiting the formulation of lung metastasis in vivo. Collectively, our data demonstrated the possibility of using the organotropism feature of exosomes in exosome carrier design, generating a potent anti-metastasis effect in a mouse model.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Exossomos , Neoplasias Pulmonares/terapia , MicroRNAs/uso terapêutico , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Exossomos/metabolismo , Técnicas de Transferência de Genes , Humanos , Integrina beta4/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Neoplásicas Circulantes/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual
7.
Nat Commun ; 10(1): 5476, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792209

RESUMO

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi's sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.


Assuntos
Sangue/metabolismo , Exossomos/metabolismo , Intestino Delgado/metabolismo , Nanopartículas/metabolismo , Células A549 , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Análise Química do Sangue , Endocitose , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exossomos/química , Hepatócitos/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ratos , Dióxido de Silício/química , Dióxido de Silício/metabolismo
8.
Curr Cancer Drug Targets ; 19(4): 257-276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29956629

RESUMO

BACKGROUND: Effective cancer therapy is still a great challenge for modern medical research due to the complex underlying mechanisms of tumorigenesis and tumor metastasis, and the limitations commonly associated with currently used cancer therapeutic options. Nanotechnology has been implemented in cancer therapeutics with immense potential for improving cancer treatment. OBJECTIVE: Through information about the recent advances regarding cancer hallmarks, we could comprehensively understand the pharmacological effects and explore the mechanisms of the interaction between the nanomaterials, which could provide opportunities to develop mechanism-based nanomedicine to treat human cancers. METHODS: We collected related information and data from articles. RESULTS: In this review, we discussed the characteristics of cancer including tumor angiogenesis, abnormalities in tumor blood vessels, uncontrolled cell proliferation markers, multidrug resistance, tumor metastasis, cancer cell metabolism, and tumor immune system that provide opportunities and challenges for nanomedicine to be directed to specific cancer cells and portray the progress that has been accomplished in application of nanotechnology for cancer treatment. CONCLUSION: The information presented in this review can provide useful references for further studies on developing effective nanomedicine for the treatment of cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Animais , Humanos , Nanoestruturas/administração & dosagem , Neoplasias/patologia
9.
Mol Pharm ; 15(11): 5146-5161, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30296375

RESUMO

The outcome of molecular targeted therapies is restricted by the ambiguous molecular subtypes of nonsmall cell lung cancer (NSCLC), which are difficult to be defined with druggable mutations, and the inevitable emergence of drug-resistance. Here we used the Cu-catalyzed click chemistry to synthesize a chitosan-based self-assembled nanotheranostics (CE7Ns) composed of a near-infrared (NIR) fluorescent photosensitizer Cy7 and molecular targeted drug erlotinib. The well-characterized CE7Ns can release erlotinib and Cy7 fast under acidic condition in the presence of lysozyme, distinguish three molecular subtypes of NSCLC, and specifically bind to the erlotinib-sensitive epidermal growth factor receptor (EGFR)-mutated PC-9 cells. The uptake of CE7Ns is much more in PC-9 cells than in other NSCLC cells, thus generating a notable fluorescence signal in PC-9 cells. Upon NIR irradiation, Cy7 in CE7Ns produces high reactive oxygen species in PC-9 cells. The synergistic effect between erlotinib-targeted therapy and photodynamic therapy significantly up-regulates cancer suppressor p53 and inhibits Survivin, which results in more apoptosis and cell cycle arrest. Upon intravenous administration, the erlotinib-guided CE7Ns significantly accumulate in PC-9-seeded mouse lungs and produce strong fluorescence. Upon NIR irradiation, CE7Ns significantly inhibit the subcutaneously implanted PC-9 tumor growth. This study provides, for the first time, a novel strategy to synthesize a multifunctional theranostic entity to simultaneously distinguish and image druggable mutations and combine targeted therapy with photodynamic therapy to overcome drug resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carbocianinas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/terapia , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/terapia , Nanomedicina Teranóstica/métodos , Administração Intravenosa , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Química Click , Cobre/química , Liberação Controlada de Fármacos/efeitos da radiação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Receptores ErbB/genética , Feminino , Humanos , Raios Infravermelhos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Microscopia Confocal , Microscopia de Fluorescência , Terapia de Alvo Molecular/métodos , Mutação , Fotoquimioterapia/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Transl Stroke Res ; 9(6): 654-668, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30225551

RESUMO

Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe-/-, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice. These changes were associated with an increase in NADPH oxidase 2 (NOX2) expression, an important regulator of both oxidative stress and inflammatory cytokines. Furthermore, immunohistochemical analysis revealed that NOX2 was abundantly expressed in activated M1 microglia. The JAK2/STAT3 signaling pathway, an upstream regulator of NOX2, was increased in WT mice and activated to an even greater extent in Apoe-/- mice; whereas, the JAK2-specific inhibitor, AG490, reduced NOX2 expression, oxidative stress, and inflammation in Apoe-deficient mice. Also, apoE-mimetic peptide COG1410 suppressed the JAK2/STAT3 signaling pathway and significantly reduced M1 microglia activation with subsequent attenuation of oxidative stress and inflammation after SAH. Taken together, apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence through the attenuation of the JAK2/STAT3/NOX2 signaling pathway axis.


Assuntos
Apolipoproteínas E/uso terapêutico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Hemorragia Subaracnóidea/patologia , Animais , Apolipoproteínas E/genética , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Marcação In Situ das Extremidades Cortadas , Janus Quinase 2/metabolismo , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NADPH Oxidase 2/metabolismo , Exame Neurológico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Hemorragia Subaracnóidea/diagnóstico por imagem , Tirfostinas/farmacologia
11.
Nanoscale ; 10(18): 8870-8871, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29707724

RESUMO

Correction for 'A novel nanomissile targeting two biomarkers and accurately bombing CTCs with doxorubicin' by Yu Gao et al., Nanoscale, 2017, 9, 5624-5640.

12.
Exp Neurol ; 299(Pt A): 97-108, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29056364

RESUMO

Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE-/-) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE-/- mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE-/- mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE-/- mice. At 42days after injury, the inflammation was still robust in the injured spinal cord in apoE-/- but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE-/- mice. The spared white matter was significantly decreased in apoE-/- mice compared to wild type ones. Locomotor function was significantly decreased in apoE-/- mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE-/- mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE-/- mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.


Assuntos
Apolipoproteínas E/efeitos dos fármacos , Apolipoproteínas E/genética , Neuroproteção/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/genética , Animais , Apoptose/efeitos dos fármacos , Barreira Alveolocapilar , Inflamação/patologia , Antígenos Comuns de Leucócito , Locomoção , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Neuropeptídeos/uso terapêutico , Neuroproteção/genética , Oligodendroglia/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Substância Branca/patologia
13.
Biomaterials ; 145: 56-71, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28843733

RESUMO

Tumor hypoxia is a common feature of the tumor microenvironment and has been regarded as one of the key factors in driving the emergence of drug resistance in solid tumors. To surmount the hypoxia-associated drug resistance, we fabricated the novel multifunctional liposomal complexes (ACLEP) that could co-deliver oxygen and molecular targeted drug to overcome the hypoxia-induced drug resistance in lung cancer. The ACLEP were fabricated with liposomes anchored with anti-EGFR aptamer-conjugated chitosan to co-administrate erlotinib and PFOB to EGFR-overexpressing non-small-cell lung cancer. Our results showed that the ACLEP possessed desired physicochemistry, good biostability and controlled drug release. The entrapped PFOB in nanoparticle facilitated the uptake of ACLEP in either normoxia or hypoxic condition. Comparing to those nanoparticles loading erlotinib alone, our innovative oxygen/therapeutic co-delivery system showed a promising outcome in fighting against hypoxia-evoked erotinib resistance both in vitro and in vivo. Hence, this work presents a potent drug delivery platform to overcome hypoxia-induced chemotherapy resistance.


Assuntos
Aptâmeros de Nucleotídeos/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib/uso terapêutico , Hipóxia/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oxigênio/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Humanos , Imuno-Histoquímica , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Nus , Modelos Biológicos , Oxigênio/administração & dosagem , Oxigênio/farmacologia , Distribuição Tecidual/efeitos dos fármacos
14.
Neuroscience ; 358: 49-57, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28642167

RESUMO

GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). These studies revealed that one of the proteins most sharply decreased in the brains of Gpr37/Gpr37L1 double knockout mice is the myelin-associated glycoprotein MAG. Follow-up Western blot studies confirmed this finding and demonstrated that genetic deletion of Gpr37, but not Gpr37L1, results in strikingly decreased brain expression of MAG. Further in vitro studies demonstrated that GPR37 and MAG form a complex when expressed together in cells. As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37-/-) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37-/- mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis.


Assuntos
Doenças Desmielinizantes/genética , Regulação da Expressão Gênica/genética , Glicoproteína Associada a Mielina/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Animais , Antígenos/metabolismo , Linhagem Celular Transformada , Imunoprecipitação da Cromatina , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores da Monoaminoxidase/toxicidade , Glicoproteína Associada a Mielina/genética , Oligodendroglia/metabolismo , Proteoglicanas/metabolismo , RNA Mensageiro/metabolismo , Fatores de Tempo , Transfecção
15.
Nanoscale ; 9(17): 5624-5640, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28422250

RESUMO

Rare circulating tumor cells (CTCs) cause >50% of primary colorectal cancer survivors to develop deadly metastasis at 3-5 years after surgery; the current chemotherapies can do nothing about these cells. Herein, we synthesized a novel doxorubicin (DOX)-entrapped mesoporous silica nanoparticle (MSN), covalently-conjugated with two aptamers, for simultaneously targeting EpCAM and CD44, the typical surface biomarkers of colorectal CTCs. The nanomissile can specifically capture the metastasis-prone CTCs spiked in healthy human blood in a competitive-binding manner. The binding not only accurately delivers DOX into the cancer cells via the biomarker-mediated endocytosis to inhibit CTC viability through the DOX-dependent mechanism, but also inhibits the adhesion of cancer cells to the endothelium and the consequent transmembrane migration through the DOX-independent mechanism. The molecular entity of the conjugate and its pharmaceutical DOX encapsulation-releasing capacity are well-demonstrated via various physiochemical characterizations including gel electrophoresis, which proves the >8-hour biostability of the nanomissile in blood, long enough for it to chase CTCs in mice and synergistically inhibit the CTC-induced lung metastasis more potently than its single aptamer-conjugated counterparts and DOX itself. The present strategy may pave a new avenue for safe and effective cancer metastasis chemoprevention.


Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos , Nanopartículas , Células Neoplásicas Circulantes/efeitos dos fármacos , Dióxido de Silício , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
16.
AAPS J ; 19(3): 814-826, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28233244

RESUMO

Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target. We loaded erlotinib into Apt-Cs-anchored liposomal complexes (Apt-CL-E) and characterized the physicochemistry of Apt-CL-E. The nanoparticles showed good biostability and a binding specificity for EGFR-mutated cancer cells guided by the Apt. The specific binding facilitated the uptake of Apt-CL-E into EGFR-mutated cancer cells. A cytotoxicity study showed an advantage of Apt-CL-E over their nontargeted liposomal counterparts in delivering erlotinib to EGFR-mutated cancer cells, resulting in cell cycle arrest and apoptosis. These results provide a good platform for future in vivo animal studies with Apt-CL-E.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Cloridrato de Erlotinib/administração & dosagem , Lipossomos/química , Apoptose/efeitos dos fármacos , Aptâmeros de Nucleotídeos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
17.
J Neurotrauma ; 34(4): 943-951, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27411737

RESUMO

Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and reduces cerebral glucose uptake. Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI, and COG1410 has demonstrated neuroprotective activity in several models of TBI. However, the effects of COG1410 on VEGF and glucose metabolism following TBI are unknown. The current study aimed to investigate the expression of VEGF and glucose metabolism effects in C57BL/6J male mice subjected to experimental TBI. The results showed that controlled cortical impact (CCI)-induced vestibulomotor deficits were accompanied by increases in brain edema and the expression of VEGF, with a decrease in cerebral glucose uptake. COG1410 treatment significantly improved vestibulomotor deficits and glucose uptake and produced decreases in VEGF in the pericontusion and ipsilateral hemisphere of injury, as well as in brain edema and neuronal degeneration compared with the control group. These data support that COG1410 may have potential as an effective drug therapy for TBI.


Assuntos
Apolipoproteínas E/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Glucose/metabolismo , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apolipoproteínas E/administração & dosagem , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
18.
Neurosci Lett ; 627: 92-9, 2016 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27241720

RESUMO

This study investigated the neuroprotective effects of COG1410, an apoliporotein E (apoE)-derived mimic peptide, against early brain injury (EBI) after subarachnoid hemorrhage (SAH). SAH was induced in C57BL/6J mice (n=68) by endovascular perforation. Mice received intravenous injection of COG1410 (2mg/kg) or equal volume of vehicle (saline). The mortality rate, neurological score, rotarod latencies, cell apoptosis, microglial activation, pro-inflammatory cytokines production and protein levels of apoptotic and inflammatory markers were assessed at 24h after sham operation or SAH. Results showed that COG1410 alleviated the neurological deficits associated with SAH. Compared with vehicle treatment group, the number of apoptotic cells and activated microglia decreased significantly in the COG1410 treated group. COG1410 enhanced Akt activation and suppressed caspase-3 cleavage. The imbalance of Bax and Bcl-2 induced by SAH was regulated by COG1410. Additionally, COG1410 attenuated cytokines production of IL-1ß, IL-6 and TNF-α and suppressed the activation of JNK/c-Jun and NF-κB. Taken together, COG1410 protected against EBI via reducing apoptosis and neuroinflammation, through mechanisms that involve the regulation of apoptotic signaling and microglial activation. COG1410 is a potential neuroprotective agent for SAH treatment.


Assuntos
Apolipoproteínas E/administração & dosagem , Apoptose/efeitos dos fármacos , Encefalite/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Hemorragia Subaracnóidea/prevenção & controle , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Encefalite/etiologia , Encefalite/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/fisiologia , Hemorragia Subaracnóidea/complicações , Análise de Sobrevida , Fator de Necrose Tumoral alfa/metabolismo
19.
Eur J Pharm Sci ; 83: 28-35, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26690044

RESUMO

Targeted delivery of anticancer agents by functional nanoparticles is an attractive strategy to increase their therapeutic efficacy while reducing toxicity. In this work, doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) were modified with aptamer (Ap) against the epithelial cell adhesion molecule (EpCAM) for targeted delivery of DOX to colon cancer cells. These nanoparticles (Ap-MSN-DOX) were characterized by particle size, zeta potential, aptamer conjugation efficiency, drug encapsulation efficiency, and drug release properties. The in vitro cell recognition, cellular uptake, EpCAM protein inhibition efficiency, and cytotoxicity of Ap-MSN-DOX were also studied. Results demonstrated that EpCAM conjugation increased binding of Ap-MSN-DOX to EpCAM over-expressing SW620 colon cancer cells but not EpCAM-negative Ramos cells, resulting in enhanced cellular uptake and increased cytotoxicity of the DOX in SW620 cells when compared to non-Ap-modified nanoparticles (MSN-DOX). Additionally, Ap-MSN-DOX exhibited significant inhibition effects on the expression of EpCAM on SW620 cells. These results suggested that Ap-MSN-DOX has the potential for the targeted delivery of therapeutic agents into EpCAM positive colon cancer cells to improve therapeutic index while reducing side effects.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Doxorrubicina/administração & dosagem , Molécula de Adesão da Célula Epitelial/genética , Nanopartículas/administração & dosagem , Dióxido de Silício/administração & dosagem , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aptâmeros de Nucleotídeos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Nanopartículas/química , Porosidade , Dióxido de Silício/química
20.
J Neurotrauma ; 33(2): 175-82, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26192010

RESUMO

The degree of post-traumatic brain edema and dysfunction of the blood-brain barrier (BBB) influences the neurofunctional outcome after a traumatic brain injury (TBI). Previous studies have demonstrated that the administration of apolipoprotein E-mimetic peptide COG1410 reduces the brain water content after subarachnoid hemorrhage, intra-cerebral hemorrhage, and focal brain ischemia. However, the effects of COG1410 on vasogenic edema following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously after a controlled cortical impact (CCI) injury on BBB dysfunction and vasogenic edema at an acute stage in mice. The results demonstrated that treatment with COG1410 suppressed the activity of matrix metalloproteinase-9, reduced the disruption of the BBB and Evans Blue dye extravasation, reduced the TBI lesion volume and vasogenic edema, and decreased the functional deficits compared with mice treated with vehicle, at an acute stage after CCI. These findings suggest that COG1410 is a promising preclinical therapeutic agent for the treatment of traumatic brain injury.


Assuntos
Apolipoproteínas E/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/tratamento farmacológico , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Apolipoproteínas E/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Edema Encefálico/etiologia , Lesões Encefálicas/complicações , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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