RESUMO
One of the National Football League's (NFL) Head, Neck and Spine Committee's principal goals is to create a 'best practice' protocol for concussion diagnosis and management for its players. The science related to concussion diagnosis and management continues to evolve, thus the protocol has evolved contemporaneously. The Fifth International Conference on Concussion in Sport was held in Berlin in 2016, and guidelines for sports concussion diagnosis and management were revised and refined. The NFL Head, Neck and Spine Committee has synthesised the most recent empirical evidence for sports concussion diagnosis and management including the Berlin consensus statement and tailored it to the game played in the NFL. One of the goals of the Committee is to provide a standardised, reliable, efficient and evidence-based protocol for concussion diagnosis and management that can be applied in this professional sport during practice and game day. In this article, the end-of-season version of the 2017-18 NFL Concussion Diagnosis and Management Protocol is described along with its clinical rationale. Immediate actions for concussion programme enhancement and research are reviewed. It is the Committee's expectation that the protocol will undergo refinement and revision over time as the science and clinical practice related to concussion in sports crystallise.
Assuntos
Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/prevenção & controle , Concussão Encefálica/diagnóstico , Concussão Encefálica/prevenção & controle , Futebol/lesões , Medicina Esportiva/normas , Congressos como Assunto , Consenso , HumanosRESUMO
More than 200 million American adults and children participate in organized physical activity. Growing awareness has highlighted that concussion, especially when repeated, may be associated with prolonged neurological, cognitive, and/or neuropsychiatric sequelae. Objective diagnosis of concussion remains challenging. Although some concussion symptoms may be apparent even to nonmedical observers, diagnosis and removal from play for evaluation depend on validated assessment tools and trained, vigilant healthcare personnel. Over the past 2 decades, sideline concussion measures have undergone significant revision and augmentation to become more comprehensive batteries in order to detect a wide spectrum of symptomatology, eg, neurocognitive function, postconcussive symptoms, gait/balance, and saccadic eye movements. This review summarizes the current state-of-the-art concussion evaluation instruments, ranging from the Sports Concussion Assessment Tool (SCAT) and tools that may enhance concussion detection, to near-term blood-based biomarkers and emerging technology (eg, head impact sensors, vestibulo-ocular/eye-tracking, and mobile applications). Special focus is directed at feasibility, utility, generalizability, and challenges to implementation of each measure on-field and on the sidelines. This review finds that few instruments beyond the SCAT provide guidance for removal from play, and establishing thresholds for concussion detection and removal from play in qualification/validation of future instruments is of high importance. Integration of emerging sideline concussion evaluation tools should be supported by resources and education to athletes, caregivers, athletic staff, and medical professionals for standardized administration as well as triage, referral, and prevention strategies. It should be noted that concussion evaluation instruments are used to assist the clinician in sideline diagnosis, and no single test can diagnose concussion as a standalone investigation.
Assuntos
Traumatismos em Atletas/diagnóstico , Concussão Encefálica/diagnóstico , Exame Neurológico/métodos , Testes Imediatos/tendências , Medicina Esportiva/métodos , Adulto , Traumatismos em Atletas/complicações , Concussão Encefálica/etiologia , Criança , Feminino , Humanos , Masculino , Exame Neurológico/tendências , Medicina Esportiva/tendênciasRESUMO
OBJECT: The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage. METHODS: The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage. RESULTS: The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage. CONCLUSIONS: An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.
Assuntos
Encéfalo/fisiopatologia , Meios de Contraste/administração & dosagem , Convecção , Sistemas de Liberação de Medicamentos/métodos , Compostos Heterocíclicos/administração & dosagem , Compostos Organometálicos/administração & dosagem , Animais , Encéfalo/patologia , Meios de Contraste/farmacocinética , Cães , Gadolínio , Compostos Heterocíclicos/farmacocinética , Lipossomos/farmacocinética , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Modelos Animais , Compostos Organometálicos/farmacocinéticaRESUMO
OBJECT: Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery. METHODS: Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution. RESULTS: Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog. CONCLUSIONS: Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.
Assuntos
Camptotecina/análogos & derivados , Imageamento por Ressonância Magnética , Animais , Encéfalo/metabolismo , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/toxicidade , Cães , Monitoramento Ambiental , Feminino , Fluorescência , Gadolínio , Irinotecano , Lipossomos , NanopartículasRESUMO
We hypothesized that combining convection-enhanced delivery (CED) with a novel, highly stable nanoparticle/liposome containing CPT-11 (nanoliposomal CPT-11) would provide a dual drug delivery strategy for brain tumor treatment. Following CED in rat brains, tissue retention of nanoliposomal CPT-11 was greatly prolonged, with >20% injected dose remaining at 12 days for all doses. Tissue residence was dose dependent, with doses of 60 microg (3 mg/mL), 0.8 mg (40 mg/mL), and 1.6 mg (80 mg/mL) resulting in tissue half-life (t(1/2)) of 6.7, 10.7, and 19.7 days, respectively. In contrast, CED of free CPT-11 resulted in rapid drug clearance (tissue t(1/2) = 0.3 day). At equivalent CED doses, nanoliposomal CPT-11 increased area under the time-concentration curve by 25-fold and tissue t(1/2) by 22-fold over free CPT-11; CED in intracranial U87 glioma xenografts showed even longer tumor retention (tissue t(1/2) = 43 days). Plasma levels were undetectable following CED of nanoliposomal CPT-11. Importantly, prolonged exposure to nanoliposomal CPT-11 resulted in no measurable central nervous system (CNS) toxicity at any dose tested (0.06-1.6 mg/rat), whereas CED of free CPT-11 induced severe CNS toxicity at 0.4 mg/rat. In the intracranial U87 glioma xenograft model, a single CED infusion of nanoliposomal CPT-11 at 1.6 mg resulted in significantly improved median survival (>100 days) compared with CED of control liposomes (19.5 days; P = 4.9 x 10(-5)) or free drug (28.5 days; P = 0.011). We conclude that CED of nanoliposomal CPT-11 greatly prolonged tissue residence while also substantially reducing toxicity, resulting in a highly effective treatment strategy in preclinical brain tumor models.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Animais , Neoplasias Encefálicas/metabolismo , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/toxicidade , Linhagem Celular Tumoral , Convecção , Humanos , Irinotecano , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/farmacocinética , Lipossomos/toxicidade , Masculino , Nanoestruturas/química , Nanoestruturas/toxicidade , Fosfolipídeos/administração & dosagem , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/toxicidade , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECT: Before resective brain surgery, localization of the functional regions is necessary to minimize postoperative deficits. The face area has been relatively difficult to map noninvasively by using functional imaging techniques. Preoperative localization of face somatosensory cortex with magnetoencephalography (MEG) may allow the surgeon to predict the location of mouth motor areas. METHODS: The authors compared the location of face somatosensory cortex obtained with somatosensory evoked fields during preoperative MEG with the mouth motor areas identified during intraoperative electrocortical stimulation (ECS) mapping in 13 patients undergoing resection of brain tumor. RESULTS: In this group of patients, ECS mouth motor sites were usually anterior and lateral to MEG localizations of lip somatosensory cortex. The consistent quantitative relationship between results of these two mapping procedures allows the practitioner to predict the location of mouth motor cortex based on noninvasive preoperative MEG measurements. CONCLUSIONS: Based on this result, the authors suggest that somatosensory mapping using MEG can be used to guide intraoperative mapping and neurosurgical planning.
Assuntos
Mapeamento Encefálico/métodos , Neoplasias Encefálicas/fisiopatologia , Potenciais Somatossensoriais Evocados/fisiologia , Glioma/fisiopatologia , Magnetoencefalografia , Córtex Motor/fisiopatologia , Boca/fisiopatologia , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Feminino , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Treatment of malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle liposome containing topotecan. CED of this liposomal topotecan (Ls-TPT) resulted in extended brain tissue retention (t1/2 = 1.5 days), whereas free topotecan was rapidly cleared (t1/2 = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Convecção , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Topotecan/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioma/patologia , Humanos , Lipossomos , Masculino , Ratos , Ratos NusRESUMO
Convection-enhanced delivery (CED) is a recently developed technique for local delivery of agents to a large volume of tissue in the central nervous system (CNS). We have previously reported that this technique can be applied to CNS delivery of nanoparticles including viruses and liposomes. In this paper, we describe the impact of key physical and chemical properties of infused molecules on the extent of CED-mediated delivery. For simple infusates, CED distribution was significantly increased if the infusate was more hydrophilic or had less tissue affinity. Encapsulation of tissue-affinitive molecules by neutral liposomes significantly increased their tissue distribution. The poorer brain distribution observed with cationic liposomes, due to their greater tissue affinity, was completely overcome by PEGylation, which provides steric stabilization and reduced surface charge. Finally, liposomal encapsulation of doxorubicin reduced its tissue affinity and substantially increased its distribution within brain tumor tissue. Taken together, the physical and chemical properties of drugs, small molecules and macromolecular carriers determine the tissue affinity of the infusate and strongly affect the distribution of locally applied agents. Thus, an increased and more predictable tissue distribution can be achieved by reducing the tissue affinity of the infusate using appropriately engineered liposomes or other nanoparticles.
Assuntos
Encéfalo/fisiologia , Sistemas de Liberação de Medicamentos/instrumentação , Preparações Farmacêuticas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Química Farmacêutica , Convecção , Composição de Medicamentos , Eletroquímica , Excipientes , Lipossomos , Masculino , Nanoestruturas , Tamanho da Partícula , Veículos Farmacêuticos , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
Although liposomes have been used as a vehicle for delivery of therapeutic agents in oncology, their efficacy in targeting brain tumors has been limited due to poor penetration through the blood-brain barrier. Because convection-enhanced delivery (CED) of liposomes may improve the therapeutic index for targeting brain tumors, we conducted a three-stage study: stage 1 established the feasibility of using in vivo magnetic resonance imaging (MRI) to confirm adequate liposomal distribution within targeted regions in normal rat brain. Liposomes colabeled with gadolinium (Gd) and a fluorescent indicator, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-5,5'-disulfonic acid [DiI-DS; formally DiIC(18)(3)-DS], were administered by CED into striatal regions. The minimum concentration of Gd needed for monitoring, correlation of infused volume with distribution volume, clearance of infused liposome containing Gd and DiI-DS (Lip/Gd/DiI-DS), and potential local toxicity were evaluated. After determination of adequate conditions for MRI detection in normal brain, stage 2 evaluated the feasibility of in vivo MRI monitoring of liposomal distribution in C6 and 9L-2 rat glioma models. In both models, the distribution of Lip/Gd/DiI-DS covering the tumor mass was well defined and monitored with MRI. Stage 3 was designed to develop a clinically relevant treatment strategy in the 9L-2 model by infusing liposome containing Gd (Lip/Gd), prepared in the same size as Lip/Gd/DiI-DS, with Doxil, a liposomal drug of similar size used to treat several cancers. MRI detection of Lip/Gd coadministered with Doxil provided optimum CED parameters for complete coverage of 9L-2 tumors. By permitting in vivo monitoring of therapeutic distribution in brain tumors, this technique optimizes local drug delivery and may provide a basis for clinical applications in the treatment of malignant glioma.
Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Lipossomos/farmacocinética , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Carbocianinas/administração & dosagem , Carbocianinas/farmacologia , Convecção , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Gadolínio/administração & dosagem , Gadolínio/farmacocinética , Glioma/metabolismo , Gliossarcoma/metabolismo , Lipossomos/administração & dosagem , Lipossomos/toxicidade , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Obtenção de Tecidos e ÓrgãosRESUMO
Liposomes loaded with Gadoteridol, in combination with convection-enhanced delivery (CED), offer an excellent option to monitor CNS delivery of therapeutic compounds with MRI. In previous studies, we investigated possible clinical applications of liposomes to the treatment of brain tumors. In this study, up to 700 microl of Gadoteridol/rhodamine-loaded liposomes were distributed in putamen, corona radiata and brainstem of non-human primates. Distribution was monitored by real-time MRI throughout infusion procedures and allowed accurate calculation of volume of distribution within anatomical structures. We found that different regions of the brain gave various volumes of distribution when infused with the same volume of liposome. Based on these findings, distinct distribution pathways within infused structures can be predicted. This work underlines the importance of monitoring drug delivery to CNS and enables accurate delivery of drug-loaded liposomes to specific brain regions with a standard MRI procedure. Findings presented in this manuscript may allow for modeling of parameters used for direct delivery of therapeutics into various regions of the brain.
Assuntos
Encéfalo/fisiologia , Sistemas de Liberação de Medicamentos , Lipossomos , Imageamento por Ressonância Magnética/métodos , Animais , Encéfalo/anatomia & histologia , Meios de Contraste , Excipientes , Corantes Fluorescentes , Gadolínio , Compostos Heterocíclicos/administração & dosagem , Macaca fascicularis , Masculino , Compostos Organometálicos/administração & dosagem , RodaminasRESUMO
OBJECT: Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. METHODS: The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 microl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macacafascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-microl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. CONCLUSIONS: The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.
Assuntos
Encéfalo , Cateterismo/instrumentação , Sistemas de Liberação de Medicamentos/instrumentação , Animais , Carbocianinas/farmacocinética , Corantes/farmacocinética , Convecção , Corantes Fluorescentes/farmacocinética , Géis , Lipossomos/farmacocinética , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Sefarose , Azul Tripano/farmacocinéticaRESUMO
AIM: We sought to evaluate nanoliposomal irinotecan as an intravenous treatment in an orthotopic brain tumor model. MATERIALS & METHODS: Nanoliposomal irinotecan was administered intravenously in the intracranial U87MG brain tumor model in mice, and irinotecan and SN-38 levels were analyzed in malignant and normal tissues. Therapy studies were performed in comparison to free irinotecan and control treatments. RESULTS: Tissue analysis demonstrated favorable properties for nanoliposomal irinotecan, including a 10.9-fold increase in tumor AUC for drug compared with free irinotecan and 35-fold selectivity for tumor versus normal tissue exposure. As a therapy for orthotopic brain tumors, nanoliposomal irinotecan showed a mean survival time of 54.2 versus 29.5 days for free irinotecan. A total of 33% of the animals receiving nanoliposomal irinotecan showed no residual tumor by study end compared with no survivors in the other groups. CONCLUSION: Nanoliposomal irinotecan administered systemically provides significant pharmacologic advantages and may be an efficacious therapy for brain tumors.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Lipossomos , Nanoestruturas , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias Encefálicas/metabolismo , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Irinotecano , RatosRESUMO
BACKGROUND: Liposomal drug packaging is well established as an effective means for increasing drug half-life, sustaining drug activity, and increasing drug efficacy, whether administered locally or distally to the site of disease. However, information regarding the relative effectiveness of peripheral (distal) versus local administration of liposomal therapeutics is limited. This issue is of importance with respect to the treatment of central nervous system cancer, for which the blood-brain barrier presents a significant challenge in achieving sufficient drug concentration in tumors to provide treatment benefit for patients. METHODS: We compared the anti-tumor activity and efficacy of a nanoliposomal formulation of irinotecan when delivered peripherally by vascular route with intratumoral administration by convection-enhanced delivery (CED) for treating intracranial glioblastoma xenografts in athymic mice. RESULTS: Our results show significantly greater anti-tumor activity and survival benefit from CED of nanoliposomal irinotecan. In 2 of 3 efficacy experiments, there were animal subjects that experienced apparent cure of tumor from local administration of therapy, as indicated by a lack of detectable intracranial tumor through bioluminescence imaging and histopathologic analysis. Results from investigating the effectiveness of combination therapy with nanoliposomal irinotecan plus radiation revealed that CED administration of irinotecan plus radiation conferred greater survival benefit than did irinotecan or radiation monotherapy and also when compared with radiation plus vascularly administered irinotecan. CONCLUSIONS: Our results indicate that liposomal formulation plus direct intratumoral administration of therapeutic are important for maximizing the anti-tumor effects of irinotecan and support clinical trial evaluation of this therapeutic plus route of administration combination.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Lipossomos , Nanopartículas , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Camptotecina/administração & dosagem , Convecção , Vias de Administração de Medicamentos , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , História Antiga , Humanos , Técnicas Imunoenzimáticas , Injeções Intraperitoneais , Irinotecano , Camundongos , Camundongos Nus , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Liposomes have long been effective delivery vehicles for transport of toxins to peripheral cancers. The combination of convection-enhanced delivery (CED) with liposomal toxins was originally proposed to circumvent the limited delivery of intravascular liposomes to the central nervous system (CNS) due to the blood-brain-barrier (BBB). CED offers markedly improved distribution of infused therapeutics within the CNS compared to direct injection or via drug eluting polymers, both of which depend on diffusion for parenchymal distribution. This review examines the basis for improved delivery of liposomal toxins via CED within the CNS, and discusses preclinical and clinical experience with these therapeutic techniques. How CED and liposomal technologies may influence future neurooncologic treatments are also considered.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Convecção , HumanosRESUMO
Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Nanopartículas , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/veterinária , Camptotecina/administração & dosagem , Convecção , Modelos Animais de Doenças , Cães , Glioma/patologia , Glioma/veterinária , Irinotecano , Lipossomos , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: Our group has pioneered the use of gadoteridol-loaded liposomes (GDLs) in convection-enhanced delivery (CED) using real-time magnetic resonance imaging (MRI) to visualize the distribution of therapeutic agents in nonhuman primate and canine brains. We have shown that this procedure is highly predictable and safe. In the course of recent studies, however, we noted that infusion of large volumes caused local anatomic alterations, such as ventricular compression, to occur. This article reports our analysis of CED infusions into normal brains and those compromised by tumors and how monitoring the CED infusion with MRI may be helpful in preventing some complications. METHODS: A total of 54 CED infusions using GDLs were performed in 7 canines and 10 nonhuman primates and monitored using real-time MRI. The canines, having brain tumors, received infusions of GDLs as well as a chemotherapeutic agent via CED. The nonhuman primates were normal and received GDL infusions alone. Real-time analysis of the CED infusion was performed, looking for correct catheter position and infusion reflux, leakage, and mass effect. Retrospective analysis allowed assessment of CED volume of distribution versus volume of infusion. RESULTS: Approximately 10% of these infusions caused anatomic compression of the ventricles, especially in the canines with tumors. Reflux along the cannula and leakage of infusate into the ventricular cerebrospinal fluid or subarachnoid space were seen. Animal behavior, however, did not appear to be affected acutely or during the course of the study, and no ventricular compression was noted 2 weeks after the CED infusion on further brain imaging studies. CONCLUSION: These findings illustrate the value of being able to monitor infusions with real-time MRI to identify phenomena such as reflux along the cannula, leakage of infusate, and ventricular compression. Especially in tumor patients, the latter could be associated with morbidity.
Assuntos
Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/administração & dosagem , Animais , Força Compressiva/fisiologia , Cães , Gadolínio , Compostos Heterocíclicos , Macaca fascicularis , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Animais , Compostos Organometálicos , Fatores de Tempo , Distribuição TecidualRESUMO
Drug delivery to brain tumors has long posed a major challenge. Convection-enhanced delivery (CED) has been developed as a drug delivery strategy to overcome this difficulty. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain. We previously developed a magnetic resonance imaging (MRI)-based method to visualize the distribution of liposomal agents after CED in rodent brains. In the present study, CED of liposomes was further examined in the non-human primate brain (n = 6). Liposomes containing Gadoteridol, DiI-DS, and rhodamine were infused in corona radiata, putamen nucleus, and brain stem. Volume of distribution was analyzed for all delivery locations by histology and MR imaging. Real-time MRI monitoring of liposomes containing gadolinium allowed direct visualization of a robust distribution. MRI of liposomal gadolinium was highly accurate at determining tissue distribution, as confirmed by comparison with histological results from concomitant administration of fluorescent liposomes. Linear correlation for liposomal infusions between infusion volume and distribution volume was established in all targeted locations. We conclude that an integrated strategy combining liposome/nanoparticle technology, CED, and MRI may provide new opportunities for the treatment of brain tumors. Our ability to directly monitor and to control local delivery of liposomal drugs will most likely result in greater clinical efficacy when using CED in management of patients.
Assuntos
Encéfalo/metabolismo , Convecção , Sistemas de Liberação de Medicamentos , Gadolínio/administração & dosagem , Lipossomos/metabolismo , Imageamento por Ressonância Magnética , Animais , Processamento de Imagem Assistida por Computador/métodos , Macaca fascicularis , Masculino , Estatística como Assunto , Fatores de Tempo , Distribuição TecidualRESUMO
The combination of mapping functional cortical neurons by intraoperative cortical stimulation and axonal architecture by diffusion tensor MRI fiber tracking can be used to delineate the pathways between functional regions. In this study the authors investigated the feasibility of combining these techniques to yield connectivity associated with motor speech and naming. Diffusion tensor MRI fiber tracking provides maps of axonal bundles and was combined with intraoperative mapping of eloquent cortex for a patient undergoing brain tumor surgery. Tracks from eight stimulated sites in the inferior frontal cortex including mouth motor, speech arrest, and anomia were generated from the diffusion tensor MRI data. The regions connected by the fiber tracking were compared to foci from previous functional imaging reports on language tasks. Connections were found between speech arrest, mouth motor, and anomia sites and the SMA proper and cerebral peduncle. The speech arrest and a mouth motor site were also seen to connect to the putamen via the external capsule. This is the first demonstration of delineation of subcortical pathways using diffusion tensor MRI fiber tracking with intraoperative cortical stimulation. The combined techniques may provide improved preservation of eloquent regions during neurological surgery, and may provide access to direct connectivity information between functional regions of the brain.
Assuntos
Anomia/fisiopatologia , Encéfalo/fisiopatologia , Córtex Cerebral/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Idioma , Rede Nervosa/fisiopatologia , Adulto , Anomia/patologia , Anomia/cirurgia , Axônios/patologia , Axônios/fisiologia , Encéfalo/patologia , Mapeamento Encefálico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/cirurgia , Córtex Cerebral/patologia , Estimulação Elétrica , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Lobo Frontal/cirurgia , Glioma/patologia , Glioma/fisiopatologia , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Motor/patologia , Córtex Motor/fisiopatologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Rede Nervosa/patologia , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Putamen/patologia , Putamen/fisiopatologia , Tratos Piramidais/patologia , Tratos Piramidais/fisiopatologia , Córtex Somatossensorial/patologia , Córtex Somatossensorial/fisiopatologia , Lobo Temporal/patologia , Lobo Temporal/fisiopatologia , Lobo Temporal/cirurgiaRESUMO
Liposomes labeled with various markers were subjected to local-regional administration with either direct injection or convection-enhanced delivery (CED) into rodent brains and brain tumor models. Direct injection of liposomes containing attached or encapsulated fluorochromes and/or encapsulated gold particles indicated that tissue localization of liposomes could be sensitively and specifically detected in the central nervous system (CNS). When CED was applied, liposomes achieved extensive and efficient distribution within normal mouse brains. Co-infusion of mannitol further increased tissue penetration of liposomes. Liposomes were also loaded with gadodiamide to monitor their CNS distribution in rats by magnetic resonance imaging (MRI). CED-infused liposomes were readily seen on MRI scans as large regions of intense signal at 2 h, and more diffuse regions at 24 h. Finally, labeled liposomes were infused via CED into tumor tissue in glioma xenograft models in rodent hosts. In intracranial U-87 glioma xenografts, CED-infused liposomes had distributed throughout tumor tissue, including extension into surrounding normal tissue. Greater penetration was observed using 40 versus 90 nm liposomes, as well as with mannitol co-infusion. To our knowledge, this is the first report of CED infusion of liposomes into the CNS. We conclude that CED of liposomes in the CNS is a feasible approach, and offers a promising strategy for targeting therapeutic agents to brain tumors.