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1.
Adv Funct Mater ; 31(44)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34924915

RESUMO

To date, the scaled-up manufacturing and efficient drug loading of exosomes are two existing challenges limiting the clinical translation of exosome-based drug delivery. Herein, we developed a facile magnetic extrusion method for preparing endosome-derived vesicles, also known as exosome mimetics (EMs), which share the same biological origin and similar morphology, composition, and biofunctions with native exosomes. The high yield and consistency of this magnetic extrusion method help to overcome the manufacturing bottleneck in exosome research. Moreover, the proposed standardized multi-step method readily facilitates the ammonium sulfate gradient approach to actively load chemodrugs such as doxorubicin into EMs. The engineered EMs developed and tested here exhibit comparable drug delivery properties as do native exosomes and potently inhibit tumor growth by delivering doxorubicin in an orthotopic breast tumor model. These findings demonstrate that EMs can be prepared in a facile and scaled-up manner as a promising biological nanomedicine for cancer drug delivery.

2.
Mol Cell Proteomics ; : 100176, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34774759

RESUMO

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain, and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 subjects was performed. The subjects included patients with UCPPS (n=82), healthy controls (HC) (n=94) and disparate chronic pain diseases, termed positive controls (PC) (n=68). Utilizing training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n=9) and UCPPS from PC (n=3). Validated UCPPS: HC proteins were predominantly ECM/ECM modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue and increased bleeding. Comparison with the PC cohort enabled evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, IL6, EGF, and TGFB1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.

3.
Neurology ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675105

RESUMO

BACKGROUND AND OBJECTIVES: Sport-related concussions affect millions of individuals across the United States each year and current techniques to diagnose and monitor them rely largely on subjective measures. Our goal was to discover and validate objective, quantifiable non-invasive biomarkers with the potential to be used in sport-related concussion diagnosis. METHODS: Urine samples from a convenience series of healthy control collegiate athletes who had not sustained a concussion and athletes who sustained a concussion as diagnosed by a sports medicine physician within seven days were collected prospectively and studied. Participants also completed an instrumented single-task gait analysis as a functional measure. Participants were recruited from a single collegiate athletic program, were ≥18 years old, and were excluded if they had a concomitant injury, active psychiatric conditions or pre-existing neurological disorders. Using Tandem Mass Tags (TMT) mass spectroscopy and enzyme-linked immunosorbent assays (ELISA), urinary biomarkers of concussion were identified and validated. RESULTS: Forty-eight control and 47 concussion age- and sex-matched athletes were included in the study (51.6%F, 48.4%M, average age 19.6y). Participants represented both contact and non-contact sports. All but one of the post-concussion participants reported experiencing symptoms at the time of data collection. Insulin-like growth factor 1 (IGF-1) and IGF binding protein 5 (IGFBP5) were downregulated in the urine of athletes with concussions compared to healthy controls. Multivariable risk algorithms developed to predict the probability of sport-related concussion showed that IGF-1 multiplexed with single-task gait velocity predicts concussion risk across a range of post-injury timepoints (AUC=0.786; 95% CI:0.690-0.884). When IGF-1 and IGFBP5 are multiplexed with single-task gait velocity, they accurately distinguish between healthy controls and concussion at acute timepoints (AUC=0.835, 95% CI:0.701-0·968, p<0.001). DISCUSSION: These noninvasive biomarkers, discovered in an objective and validated manner, may be useful in diagnosing and monitoring sport-related concussions in both acute phases of injury in addition to several days post-injury. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urinary IGF-1 and IGFBP5 multiplexed with single-task gait velocity may be useful in diagnosing sport-related concussion. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov identifier NCT02354469, submitted February 2015, first patient enrolled August 2015 (https://clinicaltrials.gov/ct2/show/NCT02354469).

4.
BMJ Open ; 11(9): e046590, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593486

RESUMO

INTRODUCTION: Clinically diagnosed pneumonia in children is a leading cause of paediatric hospitalisation and mortality. The aetiology is usually bacterial or viral, but malaria can cause a syndrome indistinguishable from clinical pneumonia. There is no method with high sensitivity to detect a bacterial infection in these patients and, as result, antibiotics are frequently overprescribed. Conversely, unrecognised concomitant bacterial infection in patients with malarial infections occur with omission of antibiotic therapy from patients with bacterial infections. Previously, we identified two combinations of blood proteins with 96% sensitivity and 86% specificity for detecting bacterial disease. The current project aimed to validate and improve these combinations by evaluating additional biomarkers in paediatric patients with clinical pneumonia. Our goal was to describe combinations of a limited number of proteins with high sensitivity and specificity for bacterial infection to be incorporated in future point-of-care tests. Furthermore, we seek to explore signatures to prognosticate clinical pneumonia. METHODS AND ANALYSIS: Patients (n=900) aged 2-59 months presenting with clinical pneumonia at two Gambian hospitals will be enrolled and classified according to criteria for definitive bacterial aetiology (based on microbiological tests and chest radiographs). We will measure proteins at admission using Luminex-based immunoassays in 90 children with definitive and 160 with probable bacterial aetiology, and 160 children classified according to the prognosis of their disease. Previously identified diagnostic signatures will be assessed through accuracy measures. Moreover, we will seek new diagnostic and prognostic signatures through machine learning methods, including support vector machine, penalised regression and classification trees. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Gambia Government/Medical Research Council Unit The Gambia Joint Ethics Committee (protocol 1616) and the institutional review board of Boston University Medical Centre (STUDY00000958). Study results will be disseminated to the staff of the study hospitals, in scientific seminars and meetings, and in publications. TRIAL REGISTRATION NUMBER: H-38462.


Assuntos
Pneumonia Bacteriana , África ao Sul do Saara , Antibacterianos/uso terapêutico , Biomarcadores , Criança , Humanos , Estudos Observacionais como Assunto , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/tratamento farmacológico , Prognóstico
5.
FASEB Bioadv ; 3(9): 665-675, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34485835

RESUMO

Extracellular vesicles (EVs) are a subclass of biological nanoparticles secreted by most cell types. Once secreted, EVs can travel long distances to deliver their content to target cells thereby playing a key role in cell-to-cell communication and supporting both physiological and pathological processes. In recent years, the functional versatility of EVs has come to be more widely appreciated. Their heterogeneous structure encloses solubilized bioactive cargoes including proteins and nucleic acids. EVs mirror the secreting cell in composition therefore representing a novel source of diagnostic and prognostic biomarkers. Moreover, due to their unique structure, EVs constitute a promising class of biocompatible nanovehicles for drug delivery as well. Importantly, and of burgeoning interest, is the fact that EVs have the intrinsic ability to breach biological barriers including the complex blood-brain barrier (BBB), whose restrictive nature represents a significant therapeutic challenge. EVs have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer, neurodegenerative diseases, and acute pathologies including infections and ischemia. In this review, the role of EVs in the maintenance and regulation of the BBB under normal physiological and pathologic conditions are discussed. Applications of EVs as therapeutic and diagnostic tools in the treatment of diseases that affect the central nervous system are presented as are limitations hindering their broad translation and potential solutions to resolve them.

6.
J Urol ; 205(2): 514-523, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33026902

RESUMO

PURPOSE: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome. MATERIALS AND METHODS: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers. RESULTS: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/µg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling. CONCLUSIONS: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.


Assuntos
Dor Crônica/urina , Dor Pélvica/urina , Doenças Urológicas/urina , Biomarcadores/urina , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome
7.
Adv Sci (Weinh) ; 7(24): 2002852, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33344137

RESUMO

Outcomes for pancreatic cancer (PC) patients remain strikingly poor with a 5-year survival of less than 8% due to the lack of effective treatment modalities. Here, a novel precision medicine approach for PC treatment is developed, which is composed of a rationally designed tumor-targeting ICAM1 antibody-drug conjugate (ADC) with optimized chemical linker and cytotoxic payload, complemented with a magnetic resonance imaging (MRI)-based molecular imaging approach to noninvasively evaluate the efficiency of ICAM1 ADC therapy. It is shown that ICAM1 is differentially overexpressed on the surface of human PC cells with restricted expression in normal tissues, enabling ICAM1 antibody to selectively recognize and target PC tumors in vivo. It is further demonstrated that the developed ICAM1 ADC induces potent and durable tumor regression in an orthotopic PC mouse model. To build a precision medicine, an MRI-based molecular imaging approach is developed that noninvasively maps the tumoral ICAM1 expression that can be potentially used to identify ICAM1-overexpressing PC patients. Collectively, this study establishes a strong foundation for the development of a promising ADC to address the critical need in the PC patient care.

8.
Trends Pharmacol Sci ; 41(10): 730-742, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32873407

RESUMO

Nanomedicine represents an important class of cancer therapy. Clinical translation of cancer nanomedicine has significantly reduced the toxicity and adverse consequences of standard-of-care chemotherapy. Recent advances in new cancer treatment modalities (e.g., gene and immune therapies) are profoundly changing the oncology landscape, bringing with them new requirements and challenges for next-generation cancer nanomedicines. We present an overview of cancer nanomedicines in four emerging oncology-associated fields: (i) gene therapy, (ii) immunotherapy, (iii) extracellular vesicle (EV) therapy, and (iv) machine learning-assisted therapy. We discuss the incorporation of nanomedicine into these emerging disciplines, present prominent examples, and evaluate their advantages and challenges. Finally, we discuss future opportunities for next-generation cancer nanomedicines.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Imunoterapia , Oncologia , Nanomedicina , Neoplasias/tratamento farmacológico
9.
Blood Adv ; 4(13): 3011-3023, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32614966

RESUMO

During inflammation, steady-state hematopoiesis switches to emergency hematopoiesis to repopulate myeloid cells, with a bias toward the megakaryocytic lineage. Soluble inflammatory cues are thought to be largely responsible for these alterations. However, how these plasma factors rapidly alter the bone marrow (BM) is not understood. Inflammation also drives platelet activation, causing the release of platelet-derived extracellular vesicles (PEVs), which package diverse cargo and reprogram target cells. We hypothesized that PEVs infiltrate the BM, providing a direct mode of communication between the plasma and BM environments. We transfused fluorescent, wild-type (MPL+) platelets into recipient cMpl-/-mice before triggering systemic inflammation. Twenty hours postinfusion, we observed significant infiltration of donor platelet-derived particles in the BM, which we tracked immunophenotypically (MPL+ immunohistochemistry staining) and quantified by flow cytometry. To determine if this phenomenon relates to humans, we extensively characterized both megakaryocyte-derived and PEVs generated in vitro and in vivo, and found enrichment of extracellular vesicles in bone marrow compared with autologous peripheral blood. Last, BM from cMpl-/- mice was cultured in the presence or absence of wild-type (MPL+) PEVs. After 72 hours, flow cytometry revealed increased megakaryocytes only in cultures with added PEVs. The majority of CD41+ cells were bound to PEVs, suggesting a PEV-mediated rescue of megakaryopoiesis. In conclusion, we report for the first time that plasma-residing PEVs infiltrate the BM. Further, PEVs interact with BM cells in vivo and in vitro, causing functional reprogramming that may represent a novel model of inflammation-induced hematopoiesis.


Assuntos
Plaquetas , Vesículas Extracelulares , Animais , Medula Óssea , Inflamação , Megacariócitos , Camundongos
10.
Int J Mol Sci ; 21(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481745

RESUMO

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood-brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.


Assuntos
Astrócitos/metabolismo , Barreira Hematoencefálica , Neoplasias da Mama/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Meios de Cultivo Condicionados/metabolismo , Endocitose , Matriz Extracelular/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Prognóstico , Proteômica , Inibidor Tecidual de Metaloproteinase-2/metabolismo
11.
ACS Biomater Sci Eng ; 6(5): 2563-2569, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33463296

RESUMO

The promise of antiangiogenic therapy for the treatment of breast cancer has been limited by the inability to selectively disrupt the established tumor vasculature. Here, we report the development of rationally designed antibody drug conjugates (ADCs) that can selectively recognize and attack breast tumor-associated endothelial cells (BTECs), while sparing normal endothelial cells (NECs). We first performed a quantitative and unbiased screening of a panel of cancer-related antigens on human BTECs and identified CD105 as the optimal ADC target on these cells. We then used clinically approved ADC linkers and cytotoxic drugs to engineer two CD105-targeted ADCs: CD105-DM1 and CD105-MMAE and evaluated their in vitro efficacy in human BTECs and NECs. We found that both CD105-DM1 and CD105-MMAE exhibited highly potent and selective cytotoxicity against BTECs with IC50 values of 3.2 and 3.7 nM, respectively, significantly lower than their IC50 values on NECs (8-13 fold). Our proof-of-principle study suggests that CD105-targeted ADCs are promising antiangiogenic agents that have the potential to be used to inhibit the established tumor vasculature of breast tumors in a safe and precise manner.


Assuntos
Neoplasias da Mama , Imunoconjugados , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Células Endoteliais , Endotélio , Humanos , Imunoconjugados/farmacologia
12.
Anat Rec (Hoboken) ; 303(6): 1557-1572, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168956

RESUMO

It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many of the hallmarks associated with them. The activity of these enzymes has been directly implicated in extracellular matrix remodeling, the processing of growth factors and receptors, the modulation of cell migration, proliferation, and invasion, the epithelial to mesenchymal transition, the regulation of immune responses, and the control of angiogenesis. Certain MMP family members have been validated as biomarkers of a variety of human cancers including those of the breast, brain, pancreas, prostate, ovary, and others. The related metalloproteinases, the A disintegrin and metalloproteinases (ADAMs), share a number of these functions as well. Here, we explore these essential metalloproteinases and some of their disease-associated activities in detail as well as some of their complementary translational potential. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Matriz Extracelular/metabolismo , Metaloproteinases da Matriz/metabolismo , Neoplasias/metabolismo , Humanos , Neovascularização Patológica/metabolismo
13.
ACS Nano ; 13(12): 13853-13865, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31479239

RESUMO

The restrictive nature of the blood-brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown. Here, we demonstrate that tumor-derived EVs can breach the intact BBB in vivo, and by using state-of-the-art in vitro and in vivo models of the BBB, we have identified transcytosis as the mechanism underlying this process. Moreover, high spatiotemporal resolution microscopy demonstrated that the endothelial recycling endocytic pathway is involved in this transcellular transport. We further identify and characterize the mechanism by which tumor-derived EVs circumvent the low physiologic rate of transcytosis in the BBB by decreasing the brain endothelial expression of rab7 and increasing the efficiency of their transport. These findings identify previously unknown mechanisms by which tumor-derived EVs breach an intact BBB during the course of brain metastasis and can be leveraged to guide and inform the development of drug delivery approaches to deliver therapeutic cargoes across the BBB for treatment of a variety of brain diseases including, but not limited to, brain malignancies.


Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias da Mama/metabolismo , Vesículas Extracelulares/metabolismo , Transcitose , Animais , Neoplasias Encefálicas/secundário , Caveolinas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Endossomos/metabolismo , Endotélio/metabolismo , Vesículas Extracelulares/ultraestrutura , Feminino , Humanos , Camundongos Nus , Transporte Proteico , Proteínas SNARE/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
14.
Sci Rep ; 9(1): 13316, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527632

RESUMO

Ovarian cancer (OvCa), while accounting for only 3% of all women's cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.


Assuntos
Adipócitos/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Ovarianas/metabolismo , Adipócitos/fisiologia , Ácido Araquidônico/metabolismo , Ácido Araquidônico/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lipidômica/métodos , Lipídeos/fisiologia , Neoplasias Ovarianas/fisiopatologia , Ovário/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
15.
Proc Natl Acad Sci U S A ; 116(37): 18295-18303, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451668

RESUMO

Triple-negative breast cancer (TNBC), which has the highest mortality rate of all breast cancer, is in urgent need of a therapeutic that hinders the spread and growth of cancer cells. CRISPR genome editing holds the promise of a potential cure for many genetic diseases, including TNBC; however, its clinical translation is being challenged by the lack of safe and effective nonviral delivery systems for in vivo therapeutic genome editing. Here we report the synthesis and application of a noncationic, deformable, and tumor-targeted nanolipogel system (tNLG) for CRISPR genome editing in TNBC tumors. We have demonstrated that tNLGs mediate a potent CRISPR knockout of Lipocalin 2 (Lcn2), a known breast cancer oncogene, in human TNBC cells in vitro and in vivo. The loss of Lcn2 significantly inhibits the migration and the mesenchymal phenotype of human TNBC cells and subsequently attenuates TNBC aggressiveness. In an orthotopic TNBC model, we have shown that systemically administered tNLGs mediated >81% CRISPR knockout of Lcn2 in TNBC tumor tissues, resulting in significant tumor growth suppression (>77%). Our proof-of-principle results provide experimental evidence that tNLGs can be used as a safe, precise, and effective delivery approach for in vivo CRISPR genome editing in TNBC.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Edição de Genes , Nanopartículas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Terapia Genética/métodos , Vetores Genéticos , Humanos , Molécula 1 de Adesão Intercelular/genética , Lipídeos/química , Lipocalina-2/genética , Lipossomos/química , Camundongos , Camundongos Nus
16.
Cytometry A ; 95(8): 843-853, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31294926

RESUMO

A rapid, high-throughput, and quantitative method for cell entry route characterization is still lacking in nanomedicine research. Here, we report the application of imaging flow cytometry for quantitatively analyzing cell entry routes of actively targeted nanomedicines. We first engineered ICAM1 antibody-directed fusogenic nanoliposomes (ICAM1-FusoNLPs) and ICAM1 antibody-directed endocytic nanolipogels (ICAM1-EndoNLGs) featuring highly similar surface properties but different cell entry routes: receptor-mediated membrane fusion and receptor-mediated endocytosis, respectively. By using imaging flow cytometry, we characterized their intracellular delivery into human breast cancer MDA-MB-231 cells. We found that ICAM1-FusoNLPs mediated a 2.8-fold increased cell uptake of fluorescent payload, FITC-dextran, with a 2.4-fold increased intracellular distribution area in comparison with ICAM1-EndoNLGs. We also investigated the effects of incubation time and endocytic inhibitors on the cell entry routes of ICAM1-FusoNLP and ICAM1-EndoNLG. Our results indicate that receptor-mediated membrane fusion is a faster and more efficient cell entry route than receptor-mediated endocytosis, bringing with it a significant therapeutic benefit in a proof-of-principle nanomedicine-mediated siRNA transfection experiment. Our studies suggest that cell entry route may be an important design parameter to be considered in the development of next-generation nanomedicines. © 2019 International Society for Advancement of Cytometry.


Assuntos
Endocitose/genética , Citometria de Fluxo , Molécula 1 de Adesão Intercelular/ultraestrutura , Lipossomos/química , Anticorpos/química , Linhagem Celular Tumoral , Humanos , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/genética , Lipossomos/ultraestrutura , Nanomedicina , RNA Interferente Pequeno/química , RNA Interferente Pequeno/ultraestrutura , Internalização do Vírus
17.
J Extracell Vesicles ; 8(1): 1627164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275532

RESUMO

Brain malignancies, including primary and metastatic brain tumours, are often associated with high mortality, reflecting a need for more effective diagnostics and therapeutics. Despite the different cells of origin, primary and metastatic brain tumours share the same microenvironment, which affects the survival mechanisms adopted by these tumours. Elucidating the mechanisms by which primary and metastatic brain tumours interact with the brain microenvironment can uncover potential targets for clinical applications. Extracellular vesicles have been recognized as intercellular communicators that can contribute to cancer progression and have shown promise as potential cancer biomarkers and therapeutics. Here, we outline the contribution of extracellular vesicles in the tumour-microenvironment interactions in primary and metastatic brain tumours with the goal of providing a guide for future translational research in this area.

18.
Sci Rep ; 9(1): 6195, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996239

RESUMO

High grade gliomas, including glioblastoma (GBM), are the most common and deadly brain cancers in adults. Here, we performed a quantitative and unbiased screening of 70 cancer-related antigens using comparative flow cytometry and, for the first time, identified integrin alpha-2 (ITGA2) as a novel molecular target for GBM. In comparison to epidermal growth factor receptor (EGFR), a well-established GBM target, ITGA2 is significantly more expressed on human GBM cells and significantly less expressed on normal human glial cells. We also found that ITGA2 antibody blockade significantly impedes GBM cell migration but not GBM cell proliferation. To investigate the utility of ITGA2 as a therapeutic target in GBM, we designed and engineered an ITGA2 antibody-directed liposome that can selectively deliver doxorubicin, a standard-of-care chemotherapeutic agent, to GBM cells. This novel approach significantly improved antitumor efficacy. We also demonstrated that these ITGA2 antibody-directed liposomes can effectively breach the blood-brain tumor barrier (BBTB) in vitro via GBM-induced angiogenesis effects. These findings support further research into the use of ITGA2 as a novel nanotherapeutic target for GBM.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Integrina alfa2/imunologia , Anticorpos/química , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Integrina alfa2/metabolismo , Lipossomos/química , Lipossomos/uso terapêutico , Neuroglia/metabolismo
19.
Pediatr Neurol ; 96: 30-36, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30853154

RESUMO

BACKGROUND: Sturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. METHODS: The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS: Bilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. CONCLUSION: The extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.


Assuntos
Epilepsia , Glaucoma , Deficiência Intelectual , Deficiências da Aprendizagem , Procedimentos Neurocirúrgicos , Procedimentos Cirúrgicos Oftalmológicos , Mancha Vinho do Porto , Acidente Vascular Cerebral , Síndrome de Sturge-Weber , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Suscetibilidade a Doenças , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Epilepsia/etiologia , Epilepsia/cirurgia , Feminino , Glaucoma/diagnóstico , Glaucoma/epidemiologia , Glaucoma/etiologia , Glaucoma/cirurgia , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Deficiências da Aprendizagem/diagnóstico , Deficiências da Aprendizagem/epidemiologia , Deficiências da Aprendizagem/etiologia , Masculino , Procedimentos Neurocirúrgicos/estatística & dados numéricos , Procedimentos Cirúrgicos Oftalmológicos/estatística & dados numéricos , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/epidemiologia , Mancha Vinho do Porto/etiologia , Prognóstico , Índice de Gravidade de Doença , Fatores Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/diagnóstico , Síndrome de Sturge-Weber/epidemiologia , Síndrome de Sturge-Weber/cirurgia , Adulto Jovem
20.
Sci Adv ; 5(3): eaav5010, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30906868

RESUMO

Distinguishing malignant cells from non-neoplastic ones is a major challenge in triple-negative breast cancer (TNBC) treatment. Here, we developed a complementary targeting strategy that uses precisely matched, multivalent ligand-receptor interactions to recognize and target TNBC tumors at the primary site and metastatic lesions. We screened a panel of cancer cell surface markers and identified intercellular adhesion molecule-1 (ICAM1) and epithelial growth factor receptor (EGFR) as optimal candidates for TNBC complementary targeting. We engineered a dual complementary liposome (DCL) that precisely complements the molecular ratio and organization of ICAM1 and EGFR specific to TNBC cell surfaces. Our in vitro mechanistic studies demonstrated that DCLs, compared to single-targeting liposomes, exhibited increased binding, enhanced internalization, and decreased receptor signaling. DCLs consistently exhibited substantially increased tumor targeting activity and antitumor efficacy in orthotopic and lung metastasis models, indicating that DCLs are a platform technology for the design of personalized nanomedicines for TNBC.


Assuntos
Molécula 1 de Adesão Intercelular/genética , Lipossomos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Lipossomos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Terapia de Alvo Molecular , Metástase Neoplásica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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