RESUMO
Despite the development of various novel therapies, glioblastoma (GBM) remains a devastating disease, with a median survival of less than 15 months. Recently, targeted radionuclide therapy has shown significant progress in treating solid tumors, with the approval of Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This achievement has shed light on the potential of targeted radionuclide therapy for other solid tumors, including GBM. This review presents the current status of targeted radionuclide therapy in GBM, highlighting the commonly used therapeutic radionuclides emitting alpha, beta particles, and Auger electrons that could induce potent molecular and cellular damage to treat GBM. We then explore a range of targeting vectors, including small molecules, peptides, and antibodies, which selectively target antigen-expressing tumor cells with minimal or no binding to healthy tissues. Considering that radiopharmaceuticals for GBM are often administered locoregionally to bypass the blood-brain barrier (BBB), we review prominent delivery methods such as convection-enhanced delivery, local implantation, and stereotactic injections. Finally, we address the challenges of this therapeutic approach for GBM and propose potential solutions.
Assuntos
Glioblastoma , Radioisótopos , Compostos Radiofarmacêuticos , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/química , Radioisótopos/uso terapêutico , Radioisótopos/química , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos da radiaçãoRESUMO
Objective.Pulsed focused ultrasound (FUS) can deliver therapeutics to the brain by using intravenous microbubbles (MBs) to open the blood-brain barrier (BBB). MB emissions indicate treatment outcomes, like BBB opening (harmonics) and damage (broadband). Typically, a pulse repetition frequency (PRF) of 1 Hz is used, but the effect of PRF on MBs is not fully understood. We investigated the effect of PRF on MB activity and tracer delivery.Approach.The effect of PRF (0.125, 0.25, 0.5, 1, and 2 Hz) on MB activity was monitored through harmonic and wideband emissions during FUS sonications of the rat brain at 274.3 kHz. BBB opening was quantified through fluorescence imaging to estimate the concentration of Trypan Blue (TB) dye following a 75-pulse FUS exposure for PRFs of 1 and 0.25 Hz.Main results.At a fixed acoustic pressure, the percentage change in maximum harmonic amplitude compared to the control (PRF = 1 Hz) decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and -38.3% at 2 Hz. There was no difference in the pressure threshold for broadband emissions between PRFs of 0.25 and 1 Hz. PRF = 0.25 Hz, led to a 68.2% increase in the mean concentration of TB measured after FUS, with a 53.9% increase in the mean harmonic sum, compared with PRF = 1 Hz. Harmonic emissions-based control at PRF = 0.25 Hz yielded similar TB delivery, with less damage at histology, compared with 1 Hz.Significance.For a fixed number of FUS pulses, reducing the PRF was shown to increase the magnitude of harmonic emissions and TB delivery, but not the threshold for broadband emissions. While further research is necessary to understand the mechanisms involved, these results may be useful to improve clinical safety margins and sensitivity to detecting small harmonic signals from cavitating MBs.
Assuntos
Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Microbolhas , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos da radiação , Animais , Ratos , Ondas Ultrassônicas , Ratos Sprague-Dawley , Masculino , Sonicação/métodosRESUMO
Background: Owing to the long penetration depth of gamma (γ)-rays, individuals working in ionizing radiation environments are chronically exposed to low-dose γ-radiation, resulting in cognitive changes. Dose rate significantly affects radiation-induced biological effects; however, its role in chronic low-dose γ-irradiation-induced cognitive impairment remains unclear. We aimed to investigate whether chronic low-dose γ-irradiation at low-dose-rate (LDR) could induce cognitive impairment and to compare the cognitive alteration caused by chronic low-dose γ-irradiation at LDR and high-dose-rate (HDR). Methods: The rats were exposed to γ-irradiation at a LDR of 6 mGy/h and a HDR of 20 mGy/h for 30 days (5 h/day). Functional imaging was performed to assess the brain inflammation and blood-brain barrier (BBB) destruction of rats. Histological and immunofluorescence analyses were used to reveal the neuron damage and the activation of microglia and astrocytes in the hippocampus. RNA sequencing was conducted to investigate changes in gene expression in hippocampus. Results: The rats in the LDR group exhibited more persistent cognitive impairment than those in the HDR group. Furthermore, irradiated rats showed brain inflammation and a compromised BBB. Histologically, the number of hippocampal neurons were comparable in the LDR group but were markedly decreased in the HDR. Additionally, activated M1-like microglia and A1-like astrocytes were observed in the hippocampus of rats in the LDR group; however, only M1-like microglia were activated in the HDR group. Mechanistically, the PI3K-Akt signaling pathway contributed to the different cognitive function change between the LDR group and HDR group. Conclusion: Compared with chronic low-dose γ-irradiation at HDR, LDR induced more severe cognitive impairment which might involve PI3K/Akt signaling pathway.
Assuntos
Disfunção Cognitiva , Raios gama , Animais , Raios gama/efeitos adversos , Ratos , Disfunção Cognitiva/etiologia , Masculino , Hipocampo/efeitos da radiação , Ratos Sprague-Dawley , Relação Dose-Resposta à Radiação , Barreira Hematoencefálica/efeitos da radiaçãoRESUMO
The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.
Assuntos
Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Barreira Hematoencefálica/efeitos da radiação , Humanos , Sistemas de Liberação de Medicamentos/métodos , Animais , Terapia por Ultrassom/métodosRESUMO
PURPOSE: Synchrotron microbeam radiation therapy (MRT), based on an inhomogeneous geometric and microscopic irradiation pattern of the tissues with high-dose and high-dose-rate x-rays, enhances the permeability of brain tumor vessels. This study attempted to determine the time and size range of the permeability window induced by MRT in the blood-brain (tumor) barrier. METHODS AND MATERIALS: Rats-bearing 9L gliomas were exposed to MRT, either unidirectional (tumor dose, 406 Gy) or bidirectional (crossfired) (2 × 203 Gy). We measured vessel permeability to molecules of 3 sizes (Gd-DOTA, Dotarem, 0.56 kDa; gadolinium-labeled albumin, â¼74 kDa; and gadolinium-labeled IgG, 160 kDa) by daily in vivo magnetic resonance imaging, from 1 day before to 10 days after irradiation. RESULTS: An equivalent tumor dose of bidirectional MRT delivered from 2 orthogonal directions increased tumor vessel permeability for the smallest molecule tested more effectively than unidirectional MRT. Bidirectional MRT also affected the permeability of normal contralateral vessels to a different extent than unidirectional MRT. Conversely, bidirectional MRT did not modify the permeability of normal or tumor vessels for both larger molecules (74 and 160 kDa). CONCLUSIONS: High-dose bidirectional (cross-fired) MRT induced a significant increase in tumor vessel permeability for small molecules between the first and the seventh day after irradiation, whereas permeability of vessels in normal brain tissue remained stable. Such a permeability window could facilitate an efficient and safe delivery of intravenous small molecules (≤0.56 kDa) to tumoral tissues. A permeability window was not achieved by molecules larger than gado-grafted albumin (74 kDa). Vascular permeability for molecules between these 2 sizes has not been determined.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Permeabilidade Capilar , Meios de Contraste , Imageamento por Ressonância Magnética , Compostos Organometálicos , Ratos Endogâmicos F344 , Síncrotrons , Animais , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Permeabilidade Capilar/efeitos da radiação , Ratos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos da radiação , Imageamento por Ressonância Magnética/métodos , Compostos Organometálicos/farmacocinética , Meios de Contraste/farmacocinética , Gadolínio/farmacocinética , Fatores de Tempo , Masculino , Imunoglobulina G , Albuminas/metabolismo , Albuminas/farmacocinética , Glioma/radioterapia , Glioma/irrigação sanguínea , Glioma/metabolismo , Glioma/diagnóstico por imagem , Glioma/patologia , Dosagem Radioterapêutica , Compostos HeterocíclicosRESUMO
BACKGROUND: Approximately 20% of all cancer patients will develop brain metastases in their lifespan. The standard of care for patients with multiple brain metastases is whole-brain radiation therapy, which disrupts the blood-brain barrier. Previous studies have shown inflammatory mediators play a role in the radiation-mediated increase in permeability. Our goal was to determine if differential permeability post-radiation occurs between immunocompetent and immunocompromised mice. METHODS: We utilized a commissioned preclinical irradiator to irradiate brains of C57Bl/6J wild-type and athymic nude mice. Acute (3-24 h) effects on blood-brain barrier integrity were evaluated with our in-situ brain perfusion technique and quantitative fluorescent and phosphorescent microscopy. The presence of inflammatory mediators in the brain and serum was determined with a proinflammatory cytokine panel. RESULTS: Blood-brain barrier integrity and efflux transporter activity were altered in the immunocompetent mice 12 h following irradiation without similar observations in the immunocompromised mice. We observed increased TNF-α concentrations in the serum of wild-type mice immediately post-radiation and nude mice 12 h post-radiation. The brain concentration of CXCL1 was also increased in both mouse strains at the 12-h time point. CONCLUSIONS: The immune response plays a role in the magnitude of blood-brain barrier disruption following irradiation in a time- and size-dependent manner.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Camundongos , Animais , Barreira Hematoencefálica/efeitos da radiação , Camundongos Nus , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/efeitos adversos , Encéfalo/efeitos da radiação , Camundongos Endogâmicos C57BLRESUMO
Glioblastoma is considered one of the most aggressive and dangerous brain tumors. However, treatment of GBM has been still challenged due to blood-brain barrier (BBB). BBB prevents that the chemotherapeutic molecules are extravasated to brain. In this study, sonosensitive liposome encapsulating doxorubicin (DOX) was developed for enhancement of GBM penetration in combination with focused ultrasound (FUS) and microbubbles. Upon ultrasound (US) irradiation, microbubbles induce cavitation resulting in the tight junction of BBB endothelium to temporarily open. In addition, the composition of sonosensitive liposome was optimized by comparison of sonosensitivity and intracellular uptake to U87MG cells. The optimal sonosensitive liposome, IMP301-DC, resulted 123.9 ± 38.2 nm in size distribution and 98.2 % in loading efficiency. Related to sonosensitivity of IMP301-DC, US-triggered release ratio of doxorubicin was 69.2 ± 12.3 % at 92 W/cm2 of US intensity for 1 min. In the in vivo experiments, the accumulation of DiD fluorescence probe labeled IMP301-DC-shell in the brain through the BBB opening was increased more than two-fold compared to that of Doxil-shell, non-sonosensitive liposome. US exposure significantly increased GBM cytotoxicity of IMP301-DC. In conclusion, this study demonstrated that IMP301-DC could serve as an alternative solution to enhance the penetration to GBM treatment via BBB opening by non-invasive FUS combined with microbubbles.
Assuntos
Lipossomos , Microbolhas , Barreira Hematoencefálica/efeitos da radiação , Encéfalo , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , PolietilenoglicóisRESUMO
Ultrasound and microbubbles, an ultrasound contrast agent, have recently increased attention to developing novel drug delivery systems. Ultrasound exposure can induce mechanical effects derived from microbubbles behaviors such as an expansion, contraction, and collapse depending on ultrasound conditions. These mechanical effects induce several biological effects, including enhancement of vascular permeability. For drug delivery, one promising approach is enhancing vascular permeability using ultrasound and microbubbles, resulting in improved drug transport to targeted tissues. This approach is applied to several tissues and drugs to cure diseases. This review describes the enhancement of vascular permeability by ultrasound and microbubbles and its therapeutic application, including our recent study. We also discuss the current situation of the field and its potential future perspectives.
Assuntos
Antineoplásicos/administração & dosagem , Fármacos do Sistema Nervoso Central/administração & dosagem , Meios de Contraste/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Microbolhas , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/efeitos da radiação , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/efeitos da radiação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos da radiação , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/patologia , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ultrassonografia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Amyloid-ß deposition is one of the neuropathological hallmarks of Alzheimer's disease (AD), but pharmacological strategies toward its reduction are poorly effective.Preclinical studies indicate that low-dose radiation therapy (LD-RT) may reduce brain amyloid-ß. Animal models and proof-of-concept preliminary data in humans have shown that magnetic resonance guided focused ultrasound (MRgFUS) can reversibly open the blood-brain-barrier and facilitate the delivery of targeted therapeutics to the hippocampus, to reduce amyloid-ß and promote neurogenesis in AD. Ongoing clinical trials on AD are exploring whole-brain LD-RT, which may damage radio-sensitive structures, i.e., hippocampus and white matter, thus contributing to reduced neurogenesis and radiation-induced cognitive decline. However, selective irradiation of cortical amyloid-ß plaques through advanced LD-RT techniques might spare the hippocampus and white matter. We propose combined use of advanced LD-RT and targeted drug delivery through MRgFUS for future clinical trials to reduce amyloid-ß deposition in AD since its preclinical stages.
Assuntos
Doença de Alzheimer/radioterapia , Imageamento por Ressonância Magnética , Placa Amiloide/radioterapia , Doses de Radiação , Ultrassonografia , Barreira Hematoencefálica/efeitos da radiação , Encéfalo/efeitos da radiação , Sistemas de Liberação de Medicamentos , Humanos , NeurogêneseRESUMO
The blood-brain barrier (BBB) opening induced by electromagnetic pulses (EMPs) may be a drug delivery strategy of central nervous system (CNS) diseases. However, the mechanism of EMP-induced BBB opening is still ambiguous. Previous studies have shown the relation between the external field and the extent of BBB permeation (referred to as the effect), while the connection between the internal field and the effect remains unknown. Here, the influence of individual differences on the field distribution in the human brain with EMPs is investigated, the dielectric parameters of the specific anthropomorphic mannequin (SAM) and structural parameters of the spherical brain are adjusted, and the field distribution in the brain illuminated by EMPs at the frequency range of 0-0.5 GHz is simulated based on the Computer Simulation Technology (CST) Studio Suite. The results show that the average electric field in the brain is about 1/100-1/5 of the incident field within the studied frequency range, individual differences have little effect on the field distribution in the human brain; and thus, it is reliable to establish the connection between the internal field and the effect, which is of great theoretical significance for further study of the mechanism of an EMP on the brain.
Assuntos
Encéfalo/efeitos da radiação , Campos Eletromagnéticos , Adulto , Barreira Hematoencefálica/efeitos da radiação , Simulação por Computador , Humanos , Individualidade , Masculino , Modelos AnatômicosRESUMO
An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood-brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.
Assuntos
Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos da radiação , Neuronavegação/métodos , Ondas Ultrassônicas , Animais , Comportamento Animal , Transporte Biológico/efeitos da radiação , Biomarcadores , Barreira Hematoencefálica/diagnóstico por imagem , Cognição , Imageamento por Ressonância Magnética , Microbolhas , Modelos Animais , Primatas , Característica Quantitativa HerdávelRESUMO
The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.
Assuntos
Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos da radiação , Neoplasias Encefálicas/metabolismo , Sistemas de Liberação de Medicamentos , Microambiente Tumoral/efeitos da radiação , Ondas Ultrassônicas , Animais , Transporte Biológico/efeitos da radiação , Variação Biológica da População , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Ablação por Ultrassom Focalizado de Alta Intensidade/efeitos adversos , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Humanos , Metástase Neoplásica , Permeabilidade/efeitos da radiação , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Terapia por UltrassomRESUMO
PURPOSE: The blood-brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma. EXPERIMENTAL DESIGN: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice. RESULTS: Mice treated with anti-PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti-PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 (P < 0.005) and 72 (P < 0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T-cell glioma infiltration during the therapeutic window (P = 0.004) and markedly enhanced survival (P < 0.05). CONCLUSIONS: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain.
Assuntos
Barreira Hematoencefálica/efeitos da radiação , Neoplasias Encefálicas/terapia , Glioma/terapia , Imunoterapia , Ondas Ultrassônicas , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Resultado do TratamentoRESUMO
Microbubbles (MBs), being gas bubbles encapsulated inside a solid shell, have been investigated extensively in the field of therapeutic ultrasound as acoustic cavitation enhancers. Hard-shell MBs have an advantage over soft-shell MBs due to their improved stability. Poly(lactic-co-glycolic acid) (PLGA) is one of the most attractive polymers for hard-shell MB synthesis; however, very little is known regarding the effect of synthesis parameters on the acoustic cavitation activity of PLGA MBs and the tunability of this activity. In this study, by manipulating the synthesis parameters, we were able to control the characteristics of the MBs, such as their internal structure, gas core, size distribution, and shell thickness, which significantly affect the total acoustic cavitation activity that they exhibit (i.e., their cavitation dose). We showed that single-core MBs filled with C3F8 gas can produce cavitation effects for extended periods under continuous circulation. These MBs exhibited high stability, and their cavitation activity was not affected by prior circulation in the system. Preliminary in vivo results demonstrated that intravenously injected MBs did not cause adverse effects and produced cavitation activity that increased the permeability of the pig blood-brain barrier. Although more tests should be performed to evaluate the MB long-term safety and activity in vivo, these encouraging results suggest that our PLGA MBs have potential for future therapeutic applications as cavitation enhancers.
Assuntos
Barreira Hematoencefálica/efeitos da radiação , Encéfalo/fisiologia , Microbolhas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Terapia por Ultrassom/métodos , Acústica , Animais , Encéfalo/efeitos da radiação , Feminino , SuínosRESUMO
The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.
Assuntos
Barreira Hematoencefálica/efeitos da radiação , Sistemas de Liberação de Medicamentos/métodos , Lipossomos , Microbolhas , Receptores da Transferrina , Ondas Ultrassônicas , Animais , Permeabilidade/efeitos da radiação , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: At present, gamma knife radiosurgery plays an important role in neurosurgical procedures. Gamma knife radiosurgery has been used to treat many types of brain tumors and as a functional intervention. However, gamma knife treatment has a devastating effect on the normal brain parenchyma surrounding the target point. It causes increased vascular permeability, vasodilation, and swelling in endothelial cells. Ozone has antioxidant, antiapoptotic, and anti-inflammatory effects in the body. Thus, we evaluated the radioprotective effects of ozone in rats undergoing gamma knife radiation. METHODS: In the present study, 24 Sprague-Dawley male rats weighing 250-300 g in 3 groups of 8 rats each were used. The rats were selected randomly. The control group did not receive any gamma knife radiation. The other 2 groups received 50 Gy of radiation, with 1 group given ozone treatment and the other group not given ozone treatment after gamma knife radiosurgery. At 12 weeks after gamma knife radiation, the rats were sacrificed with high-dose anesthetic agents and the tissues prepared for evaluation. The slides were evaluated for necrosis, vacuolization, glial proliferation, and vascular proliferation using hematoxylin-eosin staining. Vascular endothelial growth factor (VEGF) and extracellular matrix metalloproteinase inducer (also known as CD147) were evaluated using immunohistochemical staining. RESULTS: VEGF expression in glial tissue was significantly less in the group receiving ozone (χ2 = 15.00; df = 4; P = 0.005) compared with the group that had not received ozone and was similar to the expression in the control group. CONCLUSIONS: The lower expression of VEGF in the group receiving ozone might cause less edema in the surrounding tissue owing to less degradation of vascular permeability in the rat brain tissue.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Ozônio/farmacologia , Radiocirurgia/efeitos adversos , Vasodilatação/efeitos dos fármacos , Animais , Basigina/efeitos dos fármacos , Basigina/metabolismo , Basigina/efeitos da radiação , Barreira Hematoencefálica/efeitos da radiação , Encéfalo/patologia , Encéfalo/efeitos da radiação , Edema Encefálico , Permeabilidade Capilar/efeitos da radiação , Edema , Células Endoteliais/patologia , Células Endoteliais/efeitos da radiação , Ratos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos da radiação , Vasodilatação/efeitos da radiaçãoRESUMO
Rationale: Delivery of therapeutic agents to the brain is limited by the presence of the blood-brain barrier (BBB). An emerging strategy to temporarily and locally increase the permeability of the BBB is the use of transcranial focused ultrasound (FUS) and systematically injected microbubbles (MBs). FUS+MB BBB treatments cause an acute inflammatory response, marked by a transient upregulation of pro-inflammatory genes; however, the cellular immune response remains unknown. Methods: FUS+MB BBB treatments were monitored in real-time using two-photon fluorescence microscopy and transgenic EGFP Wistar rats, which harbour several fluorescent cell types. Leukocyte identification and counts were confirmed using magnetic resonance imaging-guided FUS+MB BBB treatments. Participation of leukocytes in reducing ß-amyloid pathology following repeated FUS+MB BBB treatments was investigated in the TgCRND8 mouse model of Alzheimer's disease. Results: Intravascular leukocyte activity indicative of acute inflammation were identified, including transendothelial migration, formation of cell aggregates, and cell masses capable of perturbing blood flow. Leukocyte responses were only observed after the onset of sonication. Neutrophils were identified to be a key participating leukocyte. Significantly more neutrophils were detected in the sonicated hemisphere compared to the contralateral hemisphere, and to untreated controls. Three to five biweekly FUS+MB BBB treatments did not induce significantly more neutrophil recruitment, nor neutrophil phagocytosis of ß-amyloid plaques, in TgCRND8 mice compared to untreated controls. Conclusions: This study provides evidence that the cellular aspect of the peripheral immune response triggered by FUS+MB BBB treatments begins immediately after sonication, and emphasizes the importance for further investigations to be conducted to understand leukocyte dynamics and cerebral blood flow responses to FUS+MB BBB treatments.
Assuntos
Doença de Alzheimer/imunologia , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Leucócitos/imunologia , Microbolhas , Infiltração de Neutrófilos/imunologia , Sonicação/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/radioterapia , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Transporte Biológico , Barreira Hematoencefálica/efeitos da radiação , Feminino , Proteínas de Fluorescência Verde , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/radioterapia , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Ratos , Ratos WistarRESUMO
Focused ultrasound (FUS) is used to locally and transiently induce blood-brain barrier (BBB) permeability, allowing targeted drug delivery to the brain. The purpose of the current study is to evaluate the potential of Vasculotide to accelerate the recovery of the BBB following FUS disruption in the TgCRND8 mouse model of amyloidosis, characteristic of Alzheimer's disease (AD). Accelerating the restoration of the BBB post-FUS would represent an additional safety procedure, which could be beneficial for clinical applications. Methods: TgCRND8 mice and their non-transgenic littermates were treated with Vasculotide (250 ng, intraperitoneal) every 48 hours for 3 months. BBB permeability was induced using FUS, in presence of intravenously injected microbubbles, in TgCRND8 and non-transgenic mice, and confirmed at time 0 by MRI enhancement using the contrast agent gadolinium. BBB closure was assessed at 6, 12 and 20 hours by MRI. In a separate cohort of animals, BBB closure was assessed at 24-hours post-FUS using Evans blue injected intravenously and followed by histological evaluation. Results: Chronic Vasculotide administration significantly reduces the ultra-harmonic threshold required for FUS-induced BBB permeability in the TgCRND8 mice. In addition, Vasculotide treatment led to a faster restoration of the BBB following FUS in TgCRND8 mice. BBB closure after FUS is not significantly different between TgCRND8 and non-transgenic mice. BBB permeability was assessed by gadolinium up to 20-hours post-FUS, demonstrating 87% closure in Vasculotide treated TgCRND8 mice, as opposed to 52% in PBS treated TgCRND8 mice, 58% in PBS treated non-transgenic mice, and 74% in Vasculotide treated non-transgenic mice. In both TgCRND8 mice and non-transgenic littermates the BBB was impermeable to Evans blue dye at 24-hours post-FUS. Conclusion: Vasculotide reduces the pressure required for microbubble ultra-harmonic onset for FUS-induced BBB permeability and it accelerates BBB restoration in a mouse model of amyloidosis, suggesting its potential clinical utility to promote vascular health, plasticity and repair in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Ondas Ultrassônicas/efeitos adversos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/efeitos da radiação , Permeabilidade Capilar/efeitos da radiação , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intraperitoneais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , MicrobolhasRESUMO
Historically, the brain has been viewed as a specialized neurovascular inert organ with a distinctive immune privilege. Therefore, radiation-induced extracranial abscopal effects would be considered an unusual phenomenon due to the difficulty of the immunogenic signaling molecules to travel across the blood-brain barrier (BBB). However, it is now possible that localized central nervous system radiation has the ability to disrupt the structural integrity of the BBB and increase its endothelial permeability allowing the free passage of immunogenic responses between the intracranial and extracranial compartments. Thus, the nascent tumor-associated antigens produced by localized brain radiation can travel across the BBB into the rest of the body to modulate the immune system and induce extracranial abscopal effects. In clinical practice, localized brain radiation therapy-induced extracranial abscopal effects are a rarely seen phenomenon in metastatic melanoma and other advanced cancers. In this article, we provide a detailed overview of the current state of knowledge and clinical experience of central nervous system radiation-induced extracranial abscopal effects in patients with malignant melanoma. Emerging data from a small number of case reports and cohort studies of various malignancies has significantly altered our earlier understanding of this process by revealing that the brain is neither isolated nor passive in its interactions with the body's immune system. In addition, these studies provide clinical evidence that the brain is capable of interacting actively with the extracranial peripheral immune system. Thus, localized radiation treatment to 1 or more locations of brain metastases can induce extracranial abscopal responses. Collectively, these findings clearly demonstrate that localized brain radiation therapy-induced abscopal effects traverses the BBB and trigger tumor regression in the nonirradiated extracranial locations.
Assuntos
Barreira Hematoencefálica/efeitos da radiação , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Irradiação Craniana/métodos , Melanoma/patologia , Animais , Barreira Hematoencefálica/imunologia , Estudos de Coortes , Dano ao DNA , Humanos , Melanoma/radioterapia , Radiação Ionizante , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiaçãoRESUMO
The blood-brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.