Brain Tumor Drug Research Articles

Temporary Disruption of the Blood–Brain Barrier by Use of Ultrasound and Microbubbles: Safety and Efficacy Evaluation in Rhesus Macaques

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

Issues in Developing Drugs for Primary Brain Tumors: Barriers and Toxicities

Drug development in neuro-oncology remains a challenge for neoplasms of the central nervous system (CNS). Drugs can be administered peripherally (i.e., oral or intravenous) or locally (into the tumor or the adjacent neuropil). Each of these routes has advantages and disadvantages. Like the treatment for non-CNS cancers, peripheral side effects are encountered (i.e., diarrhea, myelosuppression, rash); however, there also may be neural-specific side effects for patients that may be acute or delayed (i.e., seizures, somnolence, hearing loss). The nervous system is also a privileged site protected by the blood-brain barrier, so many agents developed for peripheral administration will not penetrate into the CNS due to issues of size, charge, or lack of lipid solubility. In addition, the abnormal vasculature, increased interstitial pressure, and inherent mechanisms of tumor resistance (methyl-guanine-methyl transferase [MGMT], P-glycoprotein, etc.) within brain neoplasms reduce the efficacy of many agents designed for neuro-oncologic indications. Each of these issues alone, and all of them in aggregate, are reasons for the limited success of therapeutic agents directed against CNS tumors despite promising data acquired using cell lines and animal models.

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3–4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration

This study aimed to examine the applicability of polyethyleneimine (PEI)-modified magnetic nanoparticles (GPEI) as a potential vascular drug/gene carrier to brain tumors. In vitro, GPEI exhibited high cell association and low cell toxicity – properties which are highly desirable for intracellular drug/gene delivery. In addition, a high saturation magnetization of 93 emu/g Fe was expected to facilitate magnetic targeting of GPEI to brain tumor lesions. However, following intravenous administration, GPEI could not be magnetically accumulated in tumors of rats harboring orthotopic 9L-gliosarcomas due to its poor pharmacokinetic properties, reflected by a negligibly low plasma AUC of 12 ± 3 μg Fe/ml min. To improve “passive” GPEI presentation to brain tumor vasculature for subsequent “active” magnetic capture, we examined the intra-carotid route as an alternative for nanoparticle administration. Intra-carotid administration in conjunction with magnetic targeting resulted in 30-fold ( p = 0.002) increase in tumor entrapment of GPEI compared to that seen with intravenous administration. In addition, magnetic accumulation of cationic GPEI (ζ-potential = + 37.2 mV) in tumor lesions was 5.2-fold higher ( p = 0.004) than that achieved with slightly anionic G100 (ζ-potential = −12 mV) following intra-carotid administration, while no significant accumulation difference was detected between the two types of nanoparticles in the contra-lateral brain ( p = 0.187). These promising results warrant further investigation of GPEI as a potential cell-permeable, magnetically-responsive platform for brain tumor delivery of drugs and genes.

New drugs for brain tumors? Insights from chemical probing of neural stem cells

The cancer stem cell hypothesis posits a direct relationship between normal neural stem cells (NSCs) and brain tumour stem cells (BTSCs). New insights into human brain tumour biology and treatment should thus emerge from the study of normal NSCs. These parallels have recently been exploited in a chemical genetic screen that identified a broad repertoire of neurotransmission modulators as inhibitors of both NSC and BTSC expansion in vitro. Prompted by these findings, we sought epidemiological support for effects of neuromodulation of brain tumours in vivo. We present observations from data collected from retrospective clinical studies suggesting that patients with a wide variety of neuropsychiatric disorders have decreased brain tumour incidence. We speculate that this reduction may derive from the use of drugs that collaterally affect the normal neural precursor compartment, and thereby limit a population that is suspected to give rise to brain tumours. Standard chronic neuropharmacological interventions in clinical neuropsychiatric care are thus candidates for redeployment as brain cancer therapeutics.

Combined magnetic resonance and fluorescence imaging of the living mouse brain reveals glioma response to chemotherapy

Fluorescent molecular tomographic (FMT) imaging can noninvasively monitor molecular function in living animals using specific fluorescent probes. However, macroscopic imaging methods such as FMT generally exhibit low anatomical details. To overcome this, we report a quantitative technique to image both structure and function by combining FMT and magnetic resonance (MR) imaging. We show that FMT-MR imaging can produce three-dimensional, multimodal images of living mouse brains allowing for serial monitoring of tumor morphology and protease activity. Combined FMT-MR tumor imaging provides a unique in vivo diagnostic parameter, protease activity concentration (PAC), which reflects histological changes in tumors and is significantly altered by systemic chemotherapy. Alterations in this diagnostic parameter are detectable early after chemotherapy and correlate with subsequent tumor growth, predicting tumor response to chemotherapy. Our results reveal that combined FMT-MR imaging of fluorescent molecular probes could be valuable for brain tumor drug development and other neurological and somatic imaging applications.

Increased Permeability of the Blood-Brain Barrier to Chemotherapy in Metastatic Brain Tumors: Establishing a Treatment Paradigm

There is no accepted standard of care for the chemotherapy treatment of metastatic brain tumors, which has been generally limited to lipophilic alkylators, which may not have efficacy against the tumor that metastasized to the brain. More than 50% of chemotherapy agents are natural product drugs, which are rarely used in the treatment of metastatic brain tumors because they are thought to not cross the blood-brain barrier (BBB). A major protein constituent in the BBB is P-glycoprotein (P-gp), which pumps natural product chemotherapy drugs and toxins out of the CNS. However, P-gp expression in the neovasculature of metastatic brain tumors is similar to the P-gp expression in the neovasculature of the primary, extracranial tumor. In contrast, gliomas have higher P-gp expression in their neovasculature, similar to the greater intrinsic expression of P-gp in normal brain vasculature. This decreased immunohistochemical expression of P-gp in the neovasculature of metastatic tumors, as well as our recent pharmacologic demonstration of increased tissue concentrations of paclitaxel in metastatic brain tumors compared with gliomas, support the idea that the choice of chemotherapy agents should be based on the histologic origin of the metastatic brain tumor and not on the lipophilicity of the drug. Our hypothesis is that metastatic brain tumors from tumors with intrinsically low P-gp expression (eg, lung, melanoma, and untreated breast) may be more permeable to natural product chemotherapy drugs than gliomas. This information could lead to a paradigm shift in the use of natural product drugs for metastatic brain tumors.

Drug delivery systems for brain tumor therapy.

Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.

Local anti-angiogenic brain tumor therapies.

The critical role of angiogenesis in the growth of solid tumors, including neoplasms of the central nervous system, has provided the impetus for research leading to the discovery of inhibitors of tumor neovascularization. The therapeutic potential of systemically administered antiangiogenic drugs for brain tumors, however, is limited by a variety of anatomic and physiologic barriers to drug delivery. Implantable controlled-release polymers for local drug administration directly into the tumor parenchyma have therefore been developed to achieve therapeutic concentrations of these drugs within the brain while minimizing systemic toxicity. With use of these polymers, successful antiangiogenic therapy for treatment of experimental intracranial malignancies has been achieved. This has been demonstrated with a variety of otherwise unrelated drugs -- including the angiostatic steroids, tetracycline derivatives, and amiloride -- which modulate collagenase activity, and thus, basement membrane and interstitial matrix metabolism. Controlled-release polymers provide a clinically practicable method of achieving sustained antiangiogenic therapy which can be readily used in combination with other treatment modalities such as cytoreductive surgery, radiation, and cytotoxic chemotherapy.

Fomiversen sodium approved to treat CMV retinitis.

Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.

Imaging ion and molecular transport at subcellular resolution by secondary ion mass spectrometry

The transport of K +, Na +, and Ca 2+ were imaged in individual cells with a Cameca IMS-3f ion microscope. Strict cryogenic frozen freeze-dry sample preparations were employed. Ion redistribution artifacts in conventional chemical preparations are discussed. Cryogenically prepared freeze-fractured freeze-dried cultured cells allowed the three-dimensional ion microscopic imaging of elements. As smaller structures in calcium images can be resolved with the 0.5 μm spatial resolution, correlative techniques are needed to confirm their identity. The potentials of reflected light microscopy, scanning electron microscopy and laser scanning confocal microscopy are discussed for microfeature recognition in freeze-fractured freeze-dried cells. The feasibility of using frozen freeze-dried cells for imaging molecular transport at subcellular resolution was tested. Ion microscopy successfully imaged the transport of the isotopically tagged ( 13C, 15N) amino acid, l-arginine. The labeled amino acid was imaged at mass 28 with a Cs + primary ion beam as the 28( 13C 15N) − species. After a 4 h exposure of LLC-PK 1 kidney cells to 4 mM labeled arginine, the amino acid was localized throughout the cell with a preferential incorporation into the nucleus and nucleolus. An example is also shown of the ion microscopic imaging of sodium borocaptate, an experimental therapeutic drug for brain tumors, in cryogenically prepared frozen freeze-dried Swiss 3T3 cells.

Adjuvant chemotherapy for brain tumor

Adjuvant systemic chemotherapy, in addition to surgical resection and cranial RT, modestly improves survival in children and adults with malignant astrocytoma or glioblastoma, and produces sustained major responses in patients with anaplastic oligodendroglioma. Chemotherapy alone can produce prolonged tumor control in children with optic pathway gliomas, delaying the need for RT. Adjuvant chemotherapy has also shown a clear benefit in the treatment of other tumors such as medulloblastoma, 53–55 pineal region germ-cell tumors, 56 and primary CNS lymphoma. 57 Although overall the gains to date have been modest, the development of new chemotherapeutic agents and combinations, and improvements in our knowledge of brain tumor biology and drug pharmacology should improve substantially the benefits of adjuvant chemotherapy for brain tumor in the future.

Chemotherapy of a rat brain tumor model by innoculation of ascites hepatoma cells--effects of ACNU and adriamycin, and their tissue concentrations (author's transl)

A rat brain tumor model was developed for chemotherapy by percutaneous innoculation of ascites hepatoma cells (AH-7974) through an optic canal. Using this in vivo model, efficacy of ACNU, one of the nitrosourea compounds, and adriamycin, an anthracycline derivative, was studied. The median survival time was significantly prolonged by a single injection of 10 mg/kg of ACNU on the 4th post-innoculation day and by double injections on the 4th and the 7th days when compared with the control group. No significant prolongation of life span was obtained by adriamycin except in the group given 5 mg/kg on the 7th day. The response of ascites hepatoma cells to these drugs was also studied using in vitro and subcutaneous tumor systems. The in vitro growth of the tumor cells was significantly suppressed by ACNU and adriamycin. The tissue concentrations of these drugs in both subcutaneous tumor and brain were equal. However, it was found that the tumor-brain ratio was different for these drugs because the normal brain was more permeable to ACNU than to adriamycin. This might be one reason why ACNU is a potent drug for brain tumors as well as for systemic tumors.