RESUMO
Hydrocephalus is routinely treated with ventriculoperitoneal shunt drainage of cerebrospinal fluid (CSF), a procedure plagued by high morbidity and frequent revisions. Vascularized submental lymph node (VSLN) transplants act as lymphatic pumps to drain interstitial fluid (ISF) from lymphedematous extremities. As the field of neuro-lymphatics comes to fruition, we hypothesize the efficacy of VSLN in the drainage of intracranial CSF-ISF. We report novel placement of VSLN in the temporal subdural space in two patients diagnosed with symptomatic communicating hydrocephalus. At a minimum follow-up of 1 month postoperatively, both experienced radiological and clinical improvements.
Assuntos
Hidrocefalia , Linfedema , Humanos , Hidrocefalia/cirurgia , Linfonodos/transplante , Linfedema/cirurgia , Extremidades , PescoçoRESUMO
BACKGROUND: Spinal dural arteriovenous fistula (SDAVF) usually occurs during the 4th to 6th decades of life, and adolescent SDAVF is rarely reported. SDAVF arising around a tumor is also rare, and reported tumors are mostly schwannoma and lipoma. CASE PRESENTATION: We reported a 16-year-old male presented with progressive weakness and numbness of lower limbs for 3 months. A SDAVF was found, which was fed by right radicular arteries from segmental artery at L2 level and drained retrogradely into perimedullary veins. A concomitant spinal extradural nodular fasciitis at right L1/L2 intervertebral foramen was also noted. The SDAVF was completely obliterated by endovascular treatment and the tumor was debulked. The patient recovered well after the procedures. CONCLUSIONS: Our case report suggests SDAVF can occur in adolescent. The concomitant presence with a nodular fasciitis indicates that although it usually arises in subcutaneous tissue but can rarely form on the dura of spine.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Fasciite , Adolescente , Malformações Vasculares do Sistema Nervoso Central/complicações , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/terapia , Fasciite/complicações , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
Cancer is one of the deadliest diseases in human history with extremely poor prognosis. Although many traditional therapeutic modalities-such as surgery, chemotherapy, and radiation therapy-have proved to be successful in inhibiting the growth of tumor cells, their side effects may vastly limited the actual benefits and patient acceptance. In this context, a nanomedicine approach for cancer therapy using functionalized nanomaterial has been gaining ground recently. Considering the ability to carry various anticancer drugs and to act as a photothermal agent, the use of carbon-based nanomaterials for cancer therapy has advanced rapidly. Within those nanomaterials, reduced graphene oxide (rGO), a graphene family 2D carbon nanomaterial, emerged as a good candidate for cancer photothermal therapy due to its excellent photothermal conversion in the near infrared range, large specific surface area for drug loading, as well as functional groups for functionalization with molecules such as photosensitizers, siRNA, ligands, etc. By unique design, multifunctional nanosystems could be designed based on rGO, which are endowed with promising temperature/pH-dependent drug/gene delivery abilities for multimodal cancer therapy. This could be further augmented by additional advantages offered by functionalized rGO, such as high biocompatibility, targeted delivery, and enhanced photothermal effects. Herewith, we first provide an overview of the most effective reducing agents for rGO synthesis via chemical reduction. This was followed by in-depth review of application of functionalized rGO in different cancer treatment modalities such as chemotherapy, photothermal therapy and/or photodynamic therapy, gene therapy, chemotherapy/phototherapy, and photothermal/immunotherapy.
Assuntos
Grafite/uso terapêutico , Nanomedicina/tendências , Nanoestruturas/uso terapêutico , Neoplasias/terapia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Grafite/química , Humanos , Nanoestruturas/química , Neoplasias/patologia , Fotoquimioterapia/métodos , Fototerapia/métodosRESUMO
In this work, we aimed to develop liposomal nanocomposites containing citric-acid-coated iron oxide magnetic nanoparticles (CMNPs) for dual magneto-photothermal cancer therapy induced by alternating magnetic field (AMF) and near-infrared (NIR) lasers. Toward this end, CMNPs were encapsulated in cationic liposomes to form nano-sized magnetic liposomes (MLs) for simultaneous magnetic hyperthermia (MH) in the presence of AMF and photothermia (PT) induced by NIR laser exposure, which amplified the heating efficiency for dual-mode cancer cell killing and tumor therapy. Since the heating capability is directly related to the amount of entrapped CMNPs in MLs, while the liposome size is important to allow internalization by cancer cells, response surface methodology was utilized to optimize the preparation of MLs by simultaneously maximizing the encapsulation efficiency (EE) of CMNPs in MLs and minimizing the size of MLs. The experimental design was performed based on the central composite rotatable design. The accuracy of the model was verified from the validation experiments, providing a simple and effective method for fabricating the best MLs, with an EE of 87% and liposome size of 121 nm. The CMNPs and the optimized MLs were fully characterized from chemical and physical perspectives. In the presence of dual AMF and NIR laser treatment, a suspension of MLs demonstrated amplified heat generation from dual hyperthermia (MH)-photothermia (PT) in comparison with single MH or PT. In vitro cell culture experiments confirmed the efficient cellular uptake of the MLs from confocal laser scanning microscopy due to passive accumulation in human glioblastoma U87 cells originated from the cationic nature of MLs. The inducible thermal effects mediated by MLs after endocytosis also led to enhanced cytotoxicity and cumulative cell death of cancer cells in the presence of AMF-NIR lasers. This functional nanocomposite will be a potential candidate for bimodal MH-PT dual magneto-photothermal cancer therapy.
Assuntos
Glioblastoma/tratamento farmacológico , Hipertermia Induzida/métodos , Lipossomos/química , Nanopartículas de Magnetita/química , Nanocompostos/química , Fototerapia/métodos , Células 3T3 , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ácido Cítrico/química , Endocitose/efeitos dos fármacos , Glioblastoma/radioterapia , Humanos , Hipertermia , Hipertermia Induzida/instrumentação , Lasers , Lipossomos/síntese química , Lipossomos/ultraestrutura , Campos Magnéticos , Nanopartículas de Magnetita/efeitos da radiação , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Nanocompostos/efeitos da radiação , Tamanho da PartículaRESUMO
In this study, we aimed to develop a multifunctional drug/gene delivery system for the treatment of glioblastoma multiforme by combining the ligand-mediated active targeting and the pH-triggered drug release features of graphene oxide (GO). Toward this end, we load irinotecan (CPT-11) to cetuximab (CET)-conjugated GO (GO-CET/CPT11) for pH-responsive drug release after endocytosis by epidermal growth factor receptor (EGFR) over-expressed U87 human glioblastoma cells. The ultimate injectable drug/gene delivery system was designed by co-entrapping stomatin-like protein 2 (SLP2) short hairpin RNA (shRNA) and GO-CET/CPT11 in thermosensitive chitosan-g-poly(N-isopropylacrylamide) (CPN) polymer solution, which offers a hydrogel depot for localized, sustained delivery of the therapeutics after the in situ formation of CPN@GO-CET/CPT11@shRNA hydrogel. An optimal drug formulation was achieved by considering both the loading efficiency and loading content of CPT-11 on GO-CET. A sustained and controlled release behavior was found for CPT-11 and shRNA from CPN hydrogel. Confocal microscopy analysis confirmed the intracellular trafficking for the targeted delivery of CPT-11 through interactions of CET with EGFR on the U87 cell surface. The efficient transfection of U87 using SLP2 shRNA was achieved using CPN as a delivery milieu, possibly by the formation of shRNA/CPN polyplex after hydrogel degradation. In vitro cell culture experiments confirmed cell apoptosis induced by CPT-11 released from acid organelles in the cytoplasm by flow cytometry, as well as reduced SLP2 protein expression and inhibited cell migration due to gene silencing. Finally, in vivo therapeutic efficacy was demonstrated using the xenograft of U87 tumor-bearing nude mice through non-invasive intratumoral delivery of CPN@GO-CET/CPT11@shRNA by injection. Overall, we have demonstrated the novelty of this thermosensitive hydrogel to be an excellent depot for the co-delivery of anticancer drugs and siRNA. The in situ forming hydrogel will not only provide extended drug release but also combine the advantages offered by the chitosan-based copolymer structure for siRNA delivery to broaden treatment modalities in cancer therapy.
Assuntos
Proteínas Sanguíneas , Quitosana , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Glioblastoma , Grafite , Irinotecano , Proteínas de Membrana , Proteínas de Neoplasias , RNA Interferente Pequeno , Proteínas Sanguíneas/antagonistas & inibidores , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Quitosana/química , Quitosana/farmacologia , Receptores ErbB/agonistas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/terapia , Grafite/química , Grafite/farmacologia , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Irinotecano/química , Irinotecano/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP. CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life.
Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Encéfalo/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Imagem Corporal TotalRESUMO
The ATP-binding cassette (ABC) drug transporter ABCG2 can actively efflux a wide variety of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular accumulation of these drugs. Therefore, the overexpression of ABCG2 often contributes to the development of multidrug resistance (MDR) in cancer cells, which is one of the major obstacles to successful cancer chemotherapy. Moreover, ABCG2 is highly expressed in various tissues including the intestine and blood-brain barrier (BBB), limiting the absorption and bioavailability of many therapeutic agents. For decades, the task of developing a highly effective synthetic inhibitor of ABCG2 has been hindered mostly by the intrinsic toxicity, the lack of specificity, and complex pharmacokinetics. Alternatively, considering the wide range of diversity and relatively nontoxic nature of natural products, developing potential modulators of ABCG2 from natural sources is particularly valuable. α-Mangostin is a natural xanthone derived from the pericarps of mangosteen (Garcinia mangostana L.) with various pharmacological purposes, including suppressing angiogenesis and inducing cancer cell growth arrest. In this study, we demonstrated that at nontoxic concentrations, α-mangostin effectively and selectively inhibits ABCG2-mediated drug transport and reverses MDR in ABCG2-overexpressing MDR cancer cells. Direct interactions between α-mangostin and the ABCG2 drug-binding site(s) were confirmed by stimulation of ATPase activity and by inhibition of photolabeling of the substrate-binding site(s) of ABCG2 with [125I]iodoarylazidoprazosin. In summary, our findings show that α-mangostin has great potential to be further developed into a promising modulator of ABCG2 for reversing MDR and for its use in combination therapy for patients with MDR tumors.
Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Xantonas/química , Xantonas/uso terapêutico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Garcinia mangostana/química , Humanos , Mucosa Intestinal/metabolismoRESUMO
Monitoring biomarkers and injected theranostic nanomaterials in tissues and organs plays a pivotal role in numerous medical applications ranging from cancer diagnostics to drug delivery. Scanning electrochemical microscopy has been demonstrated as a powerful tool to create highly resolved maps of the distributions of relevant biomolecules in cells and tissues without suffering from the optical interferences of conventional microscopy. We demonstrate for the first time the application of soft microelectrodes brushing in contact mode over large and thick tissues as well as organs that were immersed in an electrolyte solution. Amperometric currents were recorded based on the local flux of redox-active species locally and specifically generated by the biomarkers and nanomaterials to create maps of the biodistribution of graphene oxide nanoribbons in mouse livers, prognostic protein biomarkers in human melanoma and redox-active proteins in mouse heart.
Assuntos
Biomarcadores/metabolismo , Técnicas Eletroquímicas/métodos , Nanoestruturas/química , Animais , Biomarcadores/análise , Portadores de Fármacos/química , Grafite/química , Humanos , Nanopartículas de Magnetita/química , Microscopia Confocal , Miocárdio/metabolismo , Miocárdio/patologia , Nanotubos de Carbono/química , Oxirredução , Polietilenoglicóis/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Compostos de Rutênio/química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição TecidualRESUMO
The effectiveness of cancer chemotherapy is often circumvented by multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (MDR1, P-glycoprotein). Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been shown previously capable of modulating the function of ABCB1 and reversing ABCB1-mediated MDR in human cancer cells. Furthermore, some TKIs are transported by ABCB1, which results in low oral bioavailability, reduced distribution, and the development of acquired resistance to these TKIs. In this study, we investigated the interaction between ABCB1 and osimertinib, a novel selective, irreversible third-generation EGFR TKI that has recently been approved by the U.S. Food and Drug Administration. We also evaluated the potential impact of ABCB1 on the efficacy of osimertinib in cancer cells, which can present a therapeutic challenge to clinicians in the future. We revealed that although osimertinib stimulates the ATPase activity of ABCB1, overexpression of ABCB1 does not confer resistance to osimertinib. Our results suggest that it is unlikely that the overexpression of ABCB1 can be a major contributor to the development of osimertinib resistance in cancer patients. More significantly, we revealed an additional action of osimertinib that directly inhibits the function of ABCB1 without affecting the expression level of ABCB1, enhances drug-induced apoptosis, and reverses the MDR phenotype in ABCB1-overexpressing cancer cells. Considering that osimertinib is a clinically approved third-generation EGFR TKI, our findings suggest that a combination therapy with osimertinib and conventional anticancer drugs may be beneficial to patients with MDR tumors.
Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Piperazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Células K562 , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzilisoquinolinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Trifosfato de Adenosina , Alcaloides/farmacologia , Humanos , Estrutura MolecularRESUMO
In this work, PtPd concave nanocubes anchored on graphene nanoribbons (PtPd-rGONRs) were successfully fabricated through a hydrothermal process. The structural characterizations confirmed that PtPd concave cubes with an average size of around 11 nm have been successfully synthesized and they are uniformly assembled on the surface of rGONRs. The electrochemical measurements demonstrated that the PtPd-rGONRs composite-modified glassy carbon electrode (GCE) shows much enhanced current signals for TNT reduction, which is 4 and 12-fold higher than rGONRs and bare glassy carbon electrode, respectively. The PtPd-rGONRs exhibited a wide linear range for TNT detection from 0.01 to 3 ppm with the sensing limit of 0.8 ppb. Moreover, the PtPd-rGONRs showed excellent detection stability for the determination of TNT. Most importantly, the PtPd-rGONRs-based electrochemical detection platform can be successfully applied to TNT detection in tap water and real lake water samples. The present study indicates that graphene nanoribbon-supported nanocrystals are promising in designing high performance electrochemical sensors for explosives detection.
Assuntos
Técnicas Eletroquímicas , Grafite/química , Nanopartículas Metálicas/química , Nanotubos de Carbono/química , Paládio/química , Platina/química , Trinitrotolueno/análiseRESUMO
OBJECTIVES: To examine how sleep patterns change over the first year following traumatic brain injury (TBI) and to determine whether specific demographic and disease characteristics predict the trajectories of sleep. DESIGN: Prospective study. PARTICIPANTS: Fifty-three patients with first-ever mild to severe TBI. MAIN MEASUREMENTS: Sleep measured by actigraphy for 7 consecutive days in the first, third, sixth, and twelfth months following TBI: Chinese versions of Beck Anxiety Inventory and Beck Depression Inventory-II (CBDI-II) measured at the same time points. Data were analyzed with a linear mixed model. RESULTS: Sleep efficiency (the ratio of sleep time to the total time spent in bed) showed a significant upward trend during the study period. Scores on the Chinese version of the Beck Anxiety Inventory and the CBDI-II as well as the use of analgesics significantly predicted the slope of change in sleep efficiency over time. CONCLUSIONS: Poor sleep efficiency is a common symptom in the first year among patients with first-ever TBI. Healthcare providers should consider both mental health and pain issues when dealing with sleep complaints in patients with TBI.
Assuntos
Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/psicologia , Sono/fisiologia , Actigrafia , Adolescente , Adulto , Lesões Encefálicas/complicações , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recuperação de Função Fisiológica , Taiwan , Fatores de Tempo , Adulto JovemRESUMO
The piezoresistive characteristics of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) pressure sensors with inter-digitated (IDE) and cross-point electrode (CPE) structures have been investigated. A small variation of the resistance of the pressure sensors with IDE without bottom indium-tin-oxide (b-ITO) film and with CPE structures was observed owing to the single carrier-conducting pathway. For the IDE pressure sensors with b-ITO, the piezoresistive characteristics at low and high pressure were similar to those of the pressure sensors with IDE without b-ITO and with CPE structures, respectively, leading to increased piezoresistive pressure sensitivity as the PEDOT:PSS film thickness decreased. A maximum sensitivity of more than 42 kΩ/Pa was achieved. When the normal pressure was applied, the increased number of conducting points or the reduced distance between the PEDOT oligomers within the PEDOT:PSS film resulted in a decrease of the resistance. The piezoresistive pressure sensors with a single carrier-conducting pathway, i.e., IDE without b-ITO and CPE structures, exhibited a small relaxation time and a superior reversible operation, which can be advantageous for fast piezoresistive response applications.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Impedância Elétrica , Polímeros/química , Poliestirenos/química , Pressão , Eletrodos , Fatores de Tempo , Compostos de Estanho/químicaRESUMO
We use low-molecular-weight branched polyethylenimine (PEI) to produce cytocompatible reduced graphene oxide quantum dots (rGOQD) as a photothermal agent and covalently bind it with the photosensitizer IR-820. The rGOQD/IR820 shows high photothermal conversion efficiency and produces reactive oxygen species (ROS) after irradiation with near-infrared (NIR) light for photothermal/photodynamic therapy (PTT/PDT). To improve suspension stability, rGOQD/IR820 was PEGylated by anchoring with the DSPE hydrophobic tails in DSPE-PEG-Mal, leaving the maleimide (Mal) end group for covalent binding with manganese dioxide/bovine serum albumin (MnO2/BSA) and targeting ligand cell-penetrating peptide (CPP) to synthesize rGOQD/IR820/MnO2/CPP. As MnO2 can react with intracellular hydrogen peroxide to produce oxygen for alleviating the hypoxia condition in the acidic tumor microenvironment, the efficacy of PDT could be enhanced by generating more cytotoxic ROS with NIR light. Furthermore, quercetin (Q) was loaded to rGOQD through π-π interaction, which can be released in the endosomes and act as an inhibitor of heat shock protein 70 (HSP70). This sensitizes tumor cells to thermal stress and increases the efficacy of mild-temperature PTT with NIR irradiation. By simultaneously incorporating the HSP70 inhibitor (Q) and the in situ hypoxia alleviating agent (MnO2), the rGOQD/IR820/MnO2/Q/CPP can overcome the limitation of PTT/PDT and enhance the efficacy of targeted phototherapy in vitro. From in vivo study with an orthotopic brain tumor model, rGOQD/IR820/MnO2/Q/CPP administered through tail vein injection can cross the blood-brain barrier and accumulate in the intracranial tumor, after which NIR laser light irradiation can shrink the tumor and prolong the survival times of animals by simultaneously enhancing the efficacy of PTT/PDT to treat glioblastoma.
Assuntos
Antineoplásicos , Glioblastoma , Grafite , Fotoquimioterapia , Pontos Quânticos , Animais , Compostos de Manganês/farmacologia , Compostos de Manganês/química , Glioblastoma/tratamento farmacológico , Pontos Quânticos/uso terapêutico , Proteínas de Choque Térmico , Espécies Reativas de Oxigênio , Hipóxia Tumoral , Óxidos/farmacologia , Óxidos/química , Fototerapia , Hipóxia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
In this study, magnetic graphene oxide (mGO) was first prepared and modified with chitosan to prepare chitosan-coated mGO (mGOC). Gastrin-releasing peptide (GRP)-conjugated mGOC (mGOCG) was then prepared from mGOC. The chemo drug doxorubicin (DOX) was adsorbed to mGOCG surface for dual active/magnetic targeted drug delivery. The DOX loading to mGOCG is 1.71 mg/mg, and drug release is pH-sensitive to facilitate drug delivery in endosomes. In vitro studies confirmed enhanced mGOCG endocytosis by U87 glioblastoma cells, with which enhanced cytotoxicity towards cancer cells could be achieved. This could be revealed from the drastically reduced half-maximal inhibitory concentration of mGOCG/DOX compared with DOX and mGOC/DOX. Furthermore, mGOCG/DOX can be localized under the influence of a magnetic field (MF) to exert this cytotoxic effect. An orthotopic brain tumor model by implanting U87 cells in the intracranial area of BALB/c nude mice was used to study the in vivo anti-tumor efficacy by intravenous injection of different samples and followed with bioluminescence imaging. The tumor size in the mGOCG/DOX + MF group demonstrated the best potency to suppress tumor growth and prolong animal survival time compared with mGOCG/DOX, mGOC/DOX, or DOX groups, indicating this new dual-targeting delivery system for DOX can effectively treat glioblastoma.
Assuntos
Antineoplásicos , Quitosana , Glioblastoma , Grafite , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Nanomedicina , Camundongos Nus , Óxido de Magnésio , Doxorrubicina/farmacologia , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Fenômenos Magnéticos , Linhagem Celular TumoralRESUMO
Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.
Assuntos
Neoplasias Encefálicas , Membrana Celular , Células Dendríticas , Imunoterapia , Raios Infravermelhos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Animais , Camundongos , Humanos , Membrana Celular/química , Linhagem Celular Tumoral , Micelas , Nanopartículas/química , Terapia Fototérmica , Polietilenoglicóis/química , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/patologia , Apoptose/efeitos dos fármacosRESUMO
The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.
Assuntos
Neoplasias Pulmonares , Humanos , Porosidade , Linfócitos T Citotóxicos , Imunoterapia , Antígenos de Neoplasias , Células Dendríticas , CatecóisRESUMO
Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(µ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(µ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (â¼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.
RESUMO
PURPOSE: This clinical study was conducted to evaluate factors affecting outcome in the cases following major intraoperative rupture (MIOR) of the intracranial aneurysms. METHODS: Thirty cases with MIOR in a series of 467 surgeries for ruptured aneurysms were enrolled in this study. Clinical parameters, including: age, Hunt-Hess grading, Fisher grading, aneurysm size, aneurysm contour, operative timing, aneurysm location, and rupture timing were studied and compared with the prognosis in this particular cohort. The outcome was evaluated using the Glasgow Outcome Scale at least 3 months after surgery. Severe disability, vegetative survival, and death were classified as poor outcome. RESULTS: Among the 30 cases with MIOR, 11 resulted in poor outcomes (36.7%). Age was an important prognostic factor in this cohort. Those patients with poor outcome after MIOR were significantly older than those with good outcome (mean age: 64.6 vs 51.4 years, P=0.006). In this study, a trend toward poor outcome was observed in cases with MIOR on internal carotid artery aneurysms (8/14, 57.1% vs 2/9, 22.2% and 1/6, 16.7% on middle cerebral artery and anterior communicating artery aneurysms, P=0.197, after adjustment for age factor). There was a higher incidence of a poor outcome when MIOR occurred during clip application (5/6, 83.3% vs 1/5, 20.0% and 5/19, 26.3% when MIOR happened during brain retraction and aneurysm dissection, P=0.041 after adjustment with the factor of age). CONCLUSION: Although a larger sample population is required for a more conclusive result, MIOR occuring in older age, during clip application, or on an internal carotid artery aneurysm possibly has the trend to bear a worse outcome in the cohort of patients with MIOR during aneurysm surgery.
Assuntos
Aneurisma Roto/epidemiologia , Aneurisma Roto/etiologia , Aneurisma Intracraniano/cirurgia , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/cirurgia , Adulto , Fatores Etários , Idoso , Feminino , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de Doença , Estatísticas não ParamétricasRESUMO
Thermosensitive cationic magnetic liposomes (TCMLs), prepared from dipalmitoylphosphatidylcholine (DPPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]-2000, and didodecyldimethylammonium bromide (DDAB) were used in this study for the controlled release of drug/gene for cancer treatment. After co-entrapping citric-acid-coated magnetic nanoparticles (MNPs) and the chemotherapeutic drug irinotecan (CPT-11) in the core of TCML (TCML@CPT-11), SLP2 shRNA plasmids were complexed with DDAB in the lipid bilayer to prepare TCML@CPT-11/shRNA with a 135.6 ± 2.1 nm diameter. As DPPC has a melting temperature slightly above the physiological temperature, drug release from the liposomes can be triggered by an increase in solution temperature or by magneto-heating induced with an alternating magnetic field (AMF). The MNPs in the liposomes also endow the TCMLs with magnetically targeted drug delivery with guidance by a magnetic field. The successful preparation of drug-loaded liposomes was confirmed by various physical and chemical methods. Enhanced drug release, from 18% to 59%, at pH 7.4 was observed when raising the temperature from 37 to 43 °C, as well as during induction with an AMF. The in vitro cell culture experiments endorse the biocompatibility of TCMLs, whereas TCML@CPT-11 shows some enhancement of cytotoxicity toward U87 human glioblastoma cells when compared with free CPT-11. The U87 cells can be transfected with the SLP2 shRNA plasmids with very high efficiency (~100%), leading to silencing of the SLP2 gene and reducing the migration ability of U87 from 63% to 24% in a wound-healing assay. Finally, an in vivo study, using subcutaneously implanted U87 xenografts in nude mice, demonstrates that the intravenous injection of TCML@CPT11-shRNA, plus magnetic guidance and AMF treatment, can provide a safe and promising therapeutic modality for glioblastoma treatment.