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1.
Artigo em Inglês | MEDLINE | ID: mdl-32388682

RESUMO

BACKGROUND: Intraoperative stimulation (IS) mapping has become the preferred standard treatment for eloquent tumors as it permits a more accurate identification of functional areas, allowing surgeons to achieve higher extents of resection (EOR) and decrease postoperative morbidity. For lesions adjacent to the perirolandic area and descending motor tracts, mapping can be done with both awake craniotomy (AC) and under general anesthesia (GA). OBJECTIVE: We aimed to determine which anesthetic protocol-AC vs. GA-provides better patient outcomes by comparing EOR and postoperative morbidity for surgeries using IS mapping in gliomas located near or in motor areas of the brain. METHODS: A systematic literature search was carried out to identify relevant studies from 1983 to 2019. Seven databases were screened. A total of 2351 glioma patients from 17 studies were analyzed. RESULTS: A random-effects meta-analysis revealed a trend towards a higher mean EOR in AC [90.1% (95% C.I. 85.8-93.8)] than with GA [81.7% (95% C.I. 72.4-89.7)] (p = 0.06). Neurological deficits were divided by timing and severity for analysis. There was no significant difference in early neurological deficits [20.9% (95% C.I. 4.1-45.0) vs. 25.4% (95% C.I. 13.6-39.2)] (p = 0.74), late neurological deficits [17.1% (95% C.I. 0.0-50.0) vs. 3.8% (95% C.I. 1.1-7.6)] (p = 0.06), or in non-severe [28.4% (95% C.I. 0.0-88.5) vs. 20.1% (95% C.I. 7.1-32.2)] (p = 0.72), and severe morbidity [2.6% (95% C.I. 0.0-15.5) vs. 4.5% (95% C.I. 1.1-9.6)] (p = 0.89) between patients who underwent AC versus GA, respectively. CONCLUSION: Mapping during resection of gliomas located in or near the perirolandic area and descending motor tracts can be safely carried out with both AC and GA.

2.
World Neurosurg ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32360916

RESUMO

BACKGROUND: Three-dimensional (3D) printing is a powerful tool for replicating patient-specific anatomical features for education and surgical planning. The advent of "desktop" 3D printing has created a cost-effective and widely available means for institutions with limited resources to implement a 3D printing workflow into their clinical applications. The ability to physically manipulate the desired components of a "dynamic" 3D printed model provides an additional dimension of anatomical understanding. There is currently a gap in the literature describing a cost-effective and time-efficient means of creating dynamic brain tumor 3D printed models. METHODS: Using free, open access software (3D Slicer) for patient imaging to STL (standard tessellation language) file conversion as well as open access STL editing software (Meshmixer), both intra-axial and extra-axial brain tumor models of patient-specific pathology are created. RESULTS: A step-by-step methodology and demonstration of the software manipulation techniques required for creating cost-effective multi-dimensional brain tumor models for patient education and surgical planning is exhibited using a detailed written guide, images, and video display. CONCLUSIONS: In this technical note, we describe in detail the specific functions of free, open access software and desktop 3D printing techniques to create dynamic and patient specific brain tumor models for education and surgical planning.

3.
J Neurooncol ; 2020 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-32363470

RESUMO

PURPOSE: Glioblastoma multiforme (GBM) is a common and aggressive malignancy associated with poor prognosis. Characteristics and treatment of long-term survivors are of particular interest in efforts to improve outcomes. Therefore, the objective of this study was to examine trends and prognostic factors for 3-year survival from a national database. METHODS: The National Cancer Database (NCDB) was queried for patients diagnosed with cranial GBM from 2004 to 2013 and with 3-year follow-up. Trends in 3-year and overall survival, patient characteristics, tumor properties, and treatment modalities were examined. Multivariable logistic regression was utilized to investigate the association of these factors with 3-year survival. Predictor importance analysis was conducted using a metric defined as Wald χ2 penalized by degrees of freedom. RESULTS: A total of 88,919 GBM patients with 3-year follow-up were identified. Overall, 8757 (9.8%) patients survived ≥ 3 years. Three-year survival significantly improved from 8.0 to 10.5% (p < 0.001) from 2004 to 2013. Trimodal treatment administration also significantly increased from 38.7 to 55.9% (p < 0.001). During this span, patients increasingly presented as older (p = 0.040), without private insurance (p < 0.001), and with a higher comorbidity index (p < 0.001). On multivariable regression, factors such as trimodal treatment (p < 0.001), younger age (p < 0.001), and MGMT methylation (p < 0.001) were significantly associated with increased odds of 3-year survival. Predictor importance analysis indicated that MGMT methylation, age, and treatment modality were the most significant relative determinants of 3-year survival. CONCLUSION: These findings illustrate an improved 3-year survival rate for GBM patients from 2004 to 2013 with a concurrent increase in trimodal treatment administration despite more adverse patient presenting characteristics.

4.
Sci Adv ; 6(15): eaaz9664, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32300661

RESUMO

Current minimally invasive optical techniques for in vivo deep-brain imaging provide a limited resolution, field of view, and speed. These limitations prohibit direct assessment of detailed histomorphology of various deep-seated brain diseases at their native state and therefore hinder the potential clinical utilities of those techniques. Here, we report an ultracompact (580 µm in outer diameter) theranostic deep-brain microneedle combining 800-nm optical coherence tomography imaging with laser ablation. Its performance was demonstrated by in vivo ultrahigh-resolution (1.7 µm axial and 5.7 µm transverse), high-speed (20 frames per second) volumetric imaging of mouse brain microstructures and optical attenuation coefficients. Its translational potential was further demonstrated by in vivo cancer visualization (with an imaging depth of 1.23 mm) and efficient tissue ablation (with a 1448-nm continuous-wave laser at a 350-mW power) in a deep mouse brain (with an ablation depth of about 600 µm).

5.
Artigo em Inglês | MEDLINE | ID: mdl-32253638

RESUMO

Extracellular acidification is a well-known driver of tumorigenesis that has been extensively studied. In contrast, the role of endosomal pH is novel and relatively unexplored. There is emerging evidence from a growing number of studies showing that the pH of endosomal compartments controls proliferation, migration, stemness, and sensitivity to chemoradiation therapy in a variety of tumors. Endosomes are a crucial hub, mediating cellular communication with the external environment. By finely regulating the sorting and trafficking of vesicular cargo for degradation or recycling, endosomal pH determines the fate of plasma membrane proteins, lipids, and extracellular signals including growth factor receptors and their ligands. Several critical regulators of endosomal pH have been identified, including multiple isoforms of the family of electroneutral Na+/H+ exchangers (NHE) such as NHE6 and NHE9. Recent studies have shed light on molecular mechanisms linking endosomal pH to cancer malignancy. Manipulating endosomal pH by epigenetic reprogramming, small molecules, or nanoparticles may offer promising new options in cancer therapy. In this review, we summarize evidence linking endosomal pH to cancer, with a focus on the role of endosomal Na+/H+ exchangers and how they affect the prognosis of cancer patients, and also suggest how regulation of endosomal pH may be exploited to develop new cancer therapies.

6.
J Neurooncol ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32236779

RESUMO

BACKGROUND: Access to treatment for glioblastoma (GBM) can be impacted by multiple demographic parameters. Barriers specific to the Hispanic population of the United States (US) are not fully understood. Therefore, the aim of this study was to elucidate geographic disparities for access to GBM treatment in the US Hispanic population. METHODS: All GBM patients with known Hispanic ethnicity status (and Caucasian race) in the US National Cancer Database (NCDB) between the years 2005-2016 were retrospectively reviewed. Treatment statuses of surgical resection, chemotherapy, radiation therapy and triple therapy (resection, chemotherapy and radiation) were summarized, and analyzed by comparison and regression analyses over US Census regions. RESULTS: A total cohort size of 40,232 Caucasian GBM patients were included, with 3,111 (8%) identifying as Hispanic. The odds of treatment by chemotherapy (OR 0.78, P < 0.01), radiation therapy (OR 0.82, P < 0.01) and triple therapy (OR 0.84, P < 0.01) were all significantly lower in the Hispanic group versus non-Hispanic group. The odds of being treated in the Hispanic group were significantly lower in multiple Census regions with respect to surgical resection (New England, OR 0.51; Mountain, OR 0.68), chemotherapy (East North Central, OR 0.77; Middle Atlantic, OR 0.71; Pacific, OR 0.77), radiation therapy (Middle Atlantic, OR 0.77) and triple therapy (New England, OR 0.49; Middle Atlantic, OR 0.87; Pacific, OR 0.84). Significant barriers to triple therapy in the Hispanic group within these regions were older age (OR 0.97; P < 0.01), treatment in a community facility (OR 0.85, P = 0.03), lack of insurance (OR 0.71, P = 0.03), yearly income < $40,227 (OR 0.69, P < 0.01), low education levels (OR 0.75, P = 0.03) and presence of co-morbidity (OR 0.82; P < 0.01). CONCLUSIONS: Currently in the US, there exists heterogenous geographic disparities for Hispanic GBM patients to access different treatments compared to non-Hispanic patients. Multiple circumstances can influence access to treatment within the Hispanic community of these regions, and greater investigation with more granularity required to reveal mechanisms in which these disparities may be addressed in the future.

7.
J Neurooncol ; 147(2): 297-307, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32157552

RESUMO

INTRODUCTION: Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities. METHODS: A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation. RESULTS: The central tendency of median overall survival (MOS) was 13.5 months (2.3-29.6) and cumulative 5-year survival was 5.8% (0.01%-29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3-28) vs 15.6 (3.8-29.6) months, P < 0.001]. In clinical trials, bevacizumab [18.2 (10.6-23.0) months], tumor treating fields (TTF) [20.7 (20.5-20.9) months], and vaccines [19.2 (15.3-26.0) months] reported the highest central measure of median survival. CONCLUSION: Coadministration with radiotherapy and temozolomide provided a statistically significant increase in survival for patients suffering from glioblastoma. However, the natural history for GBM remains poor. Therapies including TTF pooled values of MOS and provide means of prolonging the survival of GBM patients.

8.
Clin Neurophysiol ; 131(4): 828-835, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32066101

RESUMO

OBJECTIVE: To evaluate intraoperative use of a novel high-density circular grid in detecting after-discharges (AD) on electrocorticography (ECoG) during functional brain mapping (FBM). METHODS: FBM during glioma surgery (10/2016 to 5/2019) recorded ADs using a 22-channel circular grid compared to conventional strip electrodes. ADs were analyzed for detection, duration, amplitude, morphology, histology, direction, and clinical signs. RESULTS: Thirty-two patients (mean age 54.2 years; r = 30-75) with glioma (WHO grade II-IV; 20 grade IV) had surgery. ADs during FBM were more likely in patients with wild-type as opposed to IDH-1 mutants (p < 0.0001) using more contacts compared with linear strip electrodes (p = 0.0001). More sensors tended to be involved in ADs detected by the circular grid vs strips (6.61 vs 3.43; p = 0.16) at lower stimulus intensity (3.14 mA vs 4.13 mA; p = 0.09). No difference in the number of cortical stimulations before resection was present (38.9 mA vs 47.9 mA; p = 0.26). ADs longer than 10 seconds were 32.5 seconds (circular grid) vs 58.4 (strips) (p = 0.12). CONCLUSIONS: High-density circular grids detect ADs in 360 degrees during FBM for glioma resection. Provocation of ADs was more likely in patients with wild-type than IDH-1 mutation. SIGNIFICANCE: Circular grids offer high-resolution ECoG during intraoperative FBM for detection of ADs.

9.
Cancer Res ; 80(8): 1644-1655, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32094299

RESUMO

Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. SIGNIFICANCE: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p-dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.

10.
Small ; 16(10): e1904064, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32067382

RESUMO

Extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti-inflammatory properties of adipose tissue-derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC-EVs, lipoaspirate nanoparticles (Lipo-NPs) take less time to process (hours compared to months) and cost less to produce (clinical-grade cell culture facilities are not required). The physicochemical characteristics and anti-inflammatory properties of Lipo-NPs are evaluated and compared to those of patient-matched ADSC-EVs. Moreover, guanabenz loading in Lipo-NPs is evaluated for enhanced anti-inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo-NPs compared to ADSC-EVs. Additionally, the uptake of Lipo-NPs in hepatocytes and macrophages is higher. Lipo-NPs and ADSC-EVs have comparable protective and anti-inflammatory effects. Specifically, Lipo-NPs reduce toll-like receptor 4-induced secretion of inflammatory cytokines in macrophages. Guanabenz-loaded Lipo-NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.

11.
J Clin Neurosci ; 74: 202-204, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32094069

RESUMO

BACKGROUND: Deep Brain Stimulation (DBS) was approved by the FDA in the 1990s and is used to treat a variety of movement disorders. Patients are increasingly turning to the internet for information regarding their ailments. In this study, we aim to evaluate the accuracy and reliability of information presented in DBS-related YouTube videos. METHODS: Using the "Relevance-Based Ranking" strategy for analysis we assessed the first 3 pages of YouTube for each of the following keywords: "Deep Brain Stimulation", "DBS", "DBS for Parkinson's disease", "DBS for essential tremor", and "DBS for movement disorders". Four independent healthcare personnel evaluated the videos' education quality and informational material using the validated DISCERN tool. RESULTS: Our study found that only 24% of the 42 published videos analyzed scored above a 3 on the DISCERN scoring scale (considered a "good" video). The search term "Deep Brain Stimulation" had the highest percentage of good videos (DISCERN > 3) (32%). We also found that the duration of videos was longer for the "good" videos (Good = 25.6 min vs Unhelpful = 3.0 min, P = 0.01). CONCLUSION: YouTube is one of the largest video platforms; the uploaded videos lack reliability and institutional oversight by the experts. We believe that medical institutions should explore this way of communicating to patients by publishing evidence-based and informative videos on diseases and their management. As it is imperative that the medical field advance to combat medical misinformation.

13.
World Neurosurg ; 136: 146-149, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31954897

RESUMO

BACKGROUND: Intramedullary spinal cord cysts are benign, rare, fluid-filled lesions that can present anywhere along the craniospinal axis. However, when present at the level of the ventriculus terminalis, conus medullaris syndrome may occur. Radical resection of the cyst wall and evacuation of the cyst content are the 2 surgical procedures of choice. CASE DESCRIPTION: We present the case of a 54-year-old woman with a long-lasting history of left lower-extremity weakness and recent onset of bladder dysfunction. On further assessment, magnetic resonance imaging of the thoracic and lumbar spine showed a T10-L3 intramedullary cystic lesion. Surgical fenestration of the cyst was rendered, but no biopsy was taken due to the highly functional tissue along the full extension of lesion. CONCLUSIONS: Cystic lesions of the ventriculus terminalis are rare entities with a common presentation of severe, progressive neurologic impairment. Our case matches the classic presentation of conus medullaris syndrome. We describe and demonstrate through an operative video novel surgical techniques used to achieve successful fenestration of the cyst wall with remarkable neurologic symptom improvement. Moreover, the present case does not correlate with the classic radiographic characteristics available in current literature, such as involvement of 5 spinal segments.


Assuntos
Cistos do Sistema Nervoso Central/diagnóstico por imagem , Compressão da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/diagnóstico por imagem , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/cirurgia , Drenagem , Feminino , Humanos , Pessoa de Meia-Idade , Compressão da Medula Espinal/etiologia , Neoplasias da Medula Espinal/complicações , Neoplasias da Medula Espinal/cirurgia
14.
J Control Release ; 319: 311-321, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31911154

RESUMO

Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain cancer. Despite surgery and chemo/radiation therapy, recurrence often takes place and leads to patient death. We report here on the development of a camptothecin (CPT)-based self-assembling prodrug (SAPD) hydrogel that can be used as an adjunct therapy for local treatment of GBM following maximal tumor resection. When dispersed in aqueous solution, the designed CPT prodrug spontaneously assembles into supramolecular filaments with a 100% CPT loading. In both in vitro and ex vivo assays, we show that the designed CPT prodrug can be steadily released from its supramolecular filament hydrogel, effectively killing primary GBM cells derived from patients. We also found that the solution containing self-assembling CPT filaments can be directly applied to the tumor cavity after surgical removal, and forms a gel immediately upon contact with the brain tissue. Our in vivo studies with a resection and recurrence mouse model suggest that this prodrug hydrogel can release cancer therapeutics into brain parenchyma over a long period of time, suppressing tumor recurrence and leading to prolonged survival. We believe that the simplicity in prodrug design and the high efficacy in suppressing GBM growth enable the unique potential of this SAPD hydrogels for clinical translation as an adjunct therapy for GBM treatment.

15.
Clin Exp Metastasis ; 37(2): 341-352, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31950392

RESUMO

Brain metastases are the most common malignant tumors of the brain. Leptomeningeal dissemination is a late-stage complication of intracranial metastasis and portends an extremely poor prognosis. An increased risk of leptomeningeal disease (LMD) from metastatic breast cancer compared to other cancer types after stereotactic radiosurgery (SRS) has been reported. Validation of this observation has significant public health ramifications. The aim of this study was to determine the consistency of this association in the available literature via formal meta-analysis and systematic review of the literature. Searches of seven electronic databases from inception to August 2019 were conducted following PRISMA guidelines and appropriate selection criteria. Prognostic hazard ratios (HRs) for LMD in breast cancer brain metastases derived from multivariate regression analysis were analyzed using meta-analysis of proportions. Our search strategy identified 8 studies meeting inclusion criteria which provided data on 2555 unique brain metastases patients treated with SRS. The risk of LMD in the setting of breast cancer brain metastasis was significantly greater compared to other histologic cancer types (pooled HR = 2.22; 95% CI 1.69-2.93; P < 0.001). Statistical assessment of small studies bias and heterogeneity were negative. Outcome certainty was low. Breast cancer brain metastases are associated with an increased risk of LMD compared to other cancer types after SRS. The certainty of this outcome will be improved with future prospective studies. Providers should factor this increased susceptibility for LMD in breast cancer brain metastasis to allow for appropriate risk stratification and the development of appropriate surveillance paradigms.

16.
Clin Neurol Neurosurg ; 188: 105585, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756619

RESUMO

OBJECTIVE: Overlapping surgery, accepted by many as two distinct operations occurring at the same time but without coincident critical portions, has been said to improve patient access to surgical care. With recent controversy, some are opposed to this practice due to concerns regarding its safety. In this manuscript, we sought to investigate the perceptions of overlapping surgery among neurosurgical leadership and the association of these perceptions with neurosurgical case volume. PATIENTS AND METHODS: We conducted a self-administered survey of neurosurgery department chair and residency program directors of institutions participating in the Vizient Clinical Database/Resource (CDB/RM), an administrative database of 117 United States (US) medical centers and their 300 affiliated hospitals. We queried participants regarding yearly departmental case-volume, frequency of overlapping surgery in daily practice and the degree of overlapping they find acceptable. RESULTS: Of the 236 surveys disseminated, a total of 70 responses were received with a response rate of 29.7.%, which is comparable to previously reported response rates among neurosurgeons and other physicians. Our respondents consisted of 43 of 165 chairs (26.1.%) and 27 of 66 program directors (40.0.%) representing 64 unique hospitals/institutions out of 216 (29.6.%). Based on the responses to question involving case volume, we divided our responders into high volume hospitals (HVH) (n = 44; > 2000 cases per year) and low volume hospitals (LVH) (N = 26). More HVH were found to have frequent occurrence of overlapping surgery (50% weekly and 20.9.% daily vs LVH's 26.9.% weekly and 3.8.% daily, p = 0.003) and considered two overlapping surgeries without overlap of critical portion as acceptable (38.6.% vs 26.9.%, p = 0.10). CONCLUSIONS: Our survey results showed that neurosurgical departments with high-volume practices were more likely to practice overlapping surgery on a regular basis and to view it as an acceptable practice. The association between overlapping surgery and the volume-outcome relationship should be further evaluated.

18.
Pharmacogenomics J ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31772310

RESUMO

Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.

19.
Nanoscale ; 11(42): 20045-20057, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31612183

RESUMO

Improved delivery materials are needed to enable siRNA transport across biological barriers, including the blood-brain barrier (BBB), to treat diseases like brain cancer. We engineered bioreducible nanoparticles for systemic siRNA delivery to patient-derived glioblastoma cells in an orthotopic mouse tumor model. We first utilized a newly developed biomimetic in vitro model to evaluate and optimize the performance of the engineered bioreducible nanoparticles at crossing the brain microvascular endothelium. We performed transmission electron microscopy imaging which indicated that the engineered nanoparticles are able to cross the BBB endothelium via a vesicular mechanism. The nanoparticle formulation engineered to best cross the BBB model in vitro led to safe delivery across the BBB to the brain in vivo. The nanoparticles were internalized by human brain cancer cells, released siRNA to the cytosol via environmentally-triggered degradation, and gene silencing was obtained both in vitro and in vivo. This study opens new frontiers for the in vitro evaluation and engineering of nanomedicines for delivery to the brain, and reports a systemically administered biodegradable nanocarrier for oligonucleotide delivery to treat glioma.

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