RESUMO
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
Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in singleagent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Topotecan/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Glioblastoma/patologia , Humanos , Masculino , Ratos , Ratos Nus , Ratos Sprague-Dawley , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/análogos & derivados , Doxorrubicina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Convecção , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Sinergismo Farmacológico , Meia-Vida , Humanos , Irinotecano , Lipossomos , Masculino , Nanopartículas , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
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
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
Direct delivery of therapeutic agents to the human central nervous system remains an inadequately studied field. Our group has extensively studied and refined a powerful method for distributing various macromolecules and nanoparticles into the parenchyma by means of a procedure called convection-enhanced delivery (CED). First, we developed an improved design of infusion cannula that greatly decreased the likelihood of reflux of infusate up the outside of the cannula. Second, we began to use liposomes loaded with the MRI contrast reagent, Gadoteridol (Gd), to track infusions into brain parenchyma in real time. This innovation generated a wealth of quantitative and qualitative data that in turn drove further improvements in CED. In this chapter, we review many of the recently devised methods needed to ensure controlled distribution of therapeutic agents in the brain.
Assuntos
Encéfalo/metabolismo , Compostos Heterocíclicos/administração & dosagem , Lipossomos , Compostos Organometálicos/administração & dosagem , Animais , Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética , PrimatasRESUMO
Convection-enhanced delivery (CED) is gaining popularity in direct brain infusions. Our group has pioneered the use of liposomes loaded with the MRI contrast reagent as a means to track and quantitate CED in the primate brain through real-time MRI. When co-infused with therapeutic nanoparticles, these tracking liposomes provide us with unprecedented precision in the management of infusions into discrete brain regions. In order to translate real-time CED into clinical application, several important parameters must be defined. In this study, we have analyzed all our cumulative animal data to answer a number of questions as to whether real-time CED in primates depends on concentration of infusate, is reproducible, allows prediction of distribution in a given anatomic structure, and whether it has long term pathological consequences. Our retrospective analysis indicates that real-time CED is highly predictable; repeated procedures yielded identical results, and no long-term brain pathologies were found. We conclude that introduction of our technique to clinical application would enhance accuracy and patient safety when compared to current non-monitored delivery trials.
Assuntos
Encéfalo/metabolismo , Convecção , Sistemas de Liberação de Medicamentos , Lipossomos/metabolismo , Macaca fascicularis/anatomia & histologia , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Gadolínio/administração & dosagem , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos RetrospectivosRESUMO
The surgical delivery of therapeutic agents into the parenchyma of the brain is problematic because it has been virtually impossible to know with any certainty where infused material is going, and how much to infuse. We have started to use liposomes loaded with Gadoteridol (GDL) as a tracer that allows us to follow infusions in real-time on magnetic resonance imaging (MRI). MRI allows precise tracking and measurement of liposomes loaded with markers and therapeutics. This review provides an overview of real-time delivery of liposomes to the central nervous system (CNS), and discusses the technical aspects of delivery, liposomes as colloidal systems of delivery, real-time distribution of liposomes in CNS, and quantification of liposome distribution. Our data suggests that real-time monitoring of liposomal drug infusion is likely to improve outcomes of clinical trials where convection-enhanced delivery (CED) is being used to target drugs to specific brain structures through limitation of systemic toxicity and reduction of side effects. This review is a summary of work done by our group over the past four years.
Assuntos
Encéfalo/metabolismo , Convecção , Sistemas de Liberação de Medicamentos , Lipossomos/metabolismo , Animais , Barreira Hematoencefálica , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Fluorescência , Gadolínio/administração & dosagem , Humanos , Irinotecano , Imageamento por Ressonância MagnéticaRESUMO
Convection-enhanced delivery has recently entered the clinic and represents a promising new therapeutic option in the field of neurodegenerative diseases and treatment of brain tumors. Understanding of the principles governing delivery and flow of macromolecules within the CNS is still poorly understood and requires more investigation of the microanatomy and fluid dynamics of the brain. Our previously established, reflux-free convection-enhanced delivery (CED) technique and real-time imaging MR method for monitoring CED delivery of liposomes in primate CNS allowed us to closely monitor infusions of putamen. Our findings indicate that CED in putamen is associated with perivascular transport of liposomes, throughout CNS arteries. The results may explain side effects seen in current clinical trials using CED. In addition, they clearly show the necessity for a monitoring technique for future direct delivery of therapeutic agents to the human central nervous system. Based on these findings, we believe that the physiological concept that the perivascular space serves as a conduit for distribution of endogenous molecules within the CNS also applies to interstitially infused agents.
Assuntos
Convecção , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Putamen/irrigação sanguínea , Animais , Angiografia por Ressonância Magnética , Primatas , 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.