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There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system CNS combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS.

Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling.

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Patients with the most common and deadly form, glioblastoma GBM rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies.

New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we 1 discuss the history and evolution of treatments for GBM, 2 define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and 3 identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.

Brain cancer includes a diverse set of intracranial neoplasms and is the leading cause of cancer-related deaths in patients younger than 35 years 12. Half of all primary brain tumors arise from cells within the brain intrinsic lesions while the remainder originate in the meninges or nerves extrinsic lesions.

Interestingly, MG is locally aggressive within the central nervous system CNSbut very rarely metastasizes to other locations. The invasive tumor cells can be found far from the main tumor mass even in the more histologically benign forms 3. Understanding the critical importance of residual invasive tumor cells, a neurosurgeon named Walter Dandy began removing the entire involved cerebral hemisphere in patients with suspected glioma 5. However, even with this aggressive surgical approach, his patients went on to succumb to tumor recurrence.

Hence, even with advanced surgical technologies, including stereotactic localization, intra-operative and functional MRI, real-time brain mapping, and fluorescence-guided surgery, the vexing problem of residual invasive cells within functional brain tissue still remains — surgery alone is unlikely to cure this disease.

The history of post-operative adjuvant therapies for glioma is one filled with attempts to deliver drugs to invading cancer cells while sparing the adjacent brain tissue. Figure 1. Emerging insights into barriers to effective brain therapeutics. Given the crucial role of the CNS in overall body function and health, the NVU has evolved to tightly regulate the exchange of most substances, including microbial, cellular, and metabolic elements.

The NVU consists of a continuous layer of specialized endothelial cells linked together by tight junctions; this layer is supported by adhesions and interactions with basement membranes, brain pericytes, astrocytes, and neurons Figure 1. In one study exploring drugs used in the treatment of CNS diseases, the Comprehensive Medicinal Chemistry database of over available pharmaceuticals was queried and it was found that few of these drugs effectively cross the BBB 7.

In addition to size and physico-chemical restrictions, numerous active transporters exist to either increase or decrease the flux of substances across the BBB interface Examples include glucose transporters i. Active molecular transporters add an additional complexity to the BBB on top of the stringent requirements for passive diffusion.

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In certain disease processes, such as tumors, inflammation, and infection, the structure of the BBB is altered, leading to extravasation of a more varied group of substances into the associated brain tissue 11 — In addition, the enhanced permeability and retention EPR effect 14 has been described for nanoparticulate delivery systems, where nanoparticle NP accumulation in neoplastic tissue is increased, likely due to increased movement of particles through wider fenestrations in the immature or malformed blood vessels, and NP clearance is decreased due to incomplete pseudo-lymphatic drainage pathways 15 While the BBB is compromised in many gliomas, BBB breakdown is often heterogeneous throughout the tumor and generally remains intact in brain regions where infiltrating cells are found Therefore, the BBB remains a key hurdle in the treatment of infiltrating gliomas.

The ECS in brain tissue represents the major pathway for movement of many aling molecules and metabolites, as well as therapeutic and diagnostic substances Movement in the ECS is governed by diffusion and bulk flow. Diffusion is the passive, random movement of substances that can occur either in relation to a concentration gradient, where there is a positive net flux of the substance within a medium toward regions of lower concentration, or without a concentration gradient where there is no net flux.

Bulk flow is the movement of substances due to an energy or pressure gradient driving the motion of fluid and material through a space. Critical to the discussion of intrinsic brain tumors are the interstitial pressure gradients commonly found within these tumors. Abnormally permeable tumor vasculature le to fluid leakage from the intravascular space into the ECS, leading to the higher interstitial pressures found within tumors compared to the surrounding brain 23 — The eventual distribution and retention of a given material in the brain is, therefore, related to its movement via diffusion and bulk flow, in combination with the relative rates of clearance, including degradation and partitioning into other spaces.

The brain ECS contains a complex network of lipids, polysaccharides, and proteins with electro-statically charged as well as hydrophobic regions. ECS volume shifts with changes in cerebral metabolic activity and blood flow 20 Importantly, the ECS may be ificantly altered in and around brain tumors, further increasing the challenge of movement within the ECS 27 Their study suggests that, contrary to the common conception of MG as a mainly hypercellular lesion, higher grade glial tumors also have a larger, more complex extra-cellular component, which is likely to contribute ificantly to the patho-physiology of the disease.

This idea is supported by numerous studies describing the link between the extra-cellular matrix structure and tumor invasion, recurrence, and patient survival 29 — Interestingly, tenascin proteins have been shown to enhance tumor cell proliferation and migration, and promote angiogenesis in gliomas 32 — Sontheimer et al. The physico-chemical properties, including mesh spacing, of the brain extra-cellular matrix are keys factors in the movement of materials within the brain. studies have detailed the complex nature of the brain ECS, including electro-statically charged and hydrophobic areas, channel and dead space regions, and a virtual briar patch of matrix components including proteoglycans, glycosaminoglycans, and hyaluronic acid structures 2036 — More closely defining the size limits and surface property characteristics required for movement within the brain ECS has greatly aided the establishment of de criteria for therapeutic and diagnostic delivery systems aimed at movement within the brain ECS Regardless of how the drug is delivered oral, intravascular, CSF-mediated, or direct interstitial deliverypenetration of therapeutic agents to distant residual cells is crucial to the eventual efficacy of a treatment.

When detailing the critical physiologic and anatomic considerations for therapeutic delivery to infiltrating brain tumors, it becomes important to consider the complex, moving target these tumors represent. Moreover, recent work has detailed the heterogeneity that exists within the tumors individual patients. Specifically, large-scale multi-platform profiling studies have revealed that there are roughly four subtypes of MG that are defined by differences in transcriptional atures 41 — Additionally, complementary copy analysis and next generation sequencing approaches have pointed to the distinct molecular features that define each of these subtypes The genetic subgroups include the classical [epidermal growth factor receptor EGFR -driven], proneural [platelet derived growth factor PDGF -driven], mesenchymal [neurofibromatous type I NF1 -driven], and neural.

With the proneural group, extensive work over the last 5 years has demonstrated that IDH1 -mutant tumors exhibit strikingly distinct biological and clinical features 45 — Thus, these studies have begun to describe the heterogeneity that exists within the MG histopathologic umbrella. It is also likely that ificant complexity exists within each individual tumor. Stommel et al. A subset of this intratumoral complexity can be explained by clonal RTK genomic co-amplification. These data point to the idea that each tumor may be comprised of an admixture of distinct diseases and underline the challenges of targeting specificity.

An increasing of studies have detailed the diverse gene expression profiles found in human gliomas and the numerous pathologic mechanisms involved, including immune escape, angiogenesis, hyperproliferation, invasion, and drug resistance Figure 1 29414344464752 — Most of these studies compare the transcriptome or chromosomal changes found in different grades of glial tumors, which has led to an emerging genetic classification scheme 44 In addition to genetic diversity, it is becoming clear that when selective pressure is placed on MG, the high propensity for genetic mutation and redundant pathogenic mechanisms enable the rapid emergence of clones that are resistant to the applied pressure Genetic instability and pathogenic redundancy are evidenced by the numerous DNA repair and methylation mechanisms that are commonly mutated in primary brain cancers, including the well-studied genes encoding p53 and O6-methylguanine methyltransferase MGMT 465258 — Together the unique genetic sub-classifications and the inherent genetic instability of MG cells create the potential for vast clonal diversity.

In addition, studies suggest there are also loco-regional differences in the cellular genetics, likely related to environmental changes experienced by the tumor cells in distinct tumor regions This has led some to suggest that glioma cells may be viewed as two regional subtypes: 1 stationary proliferative cells generally found within the main tumor mass, and 2 migratory invasive cells located in more distant brain parenchyma. Importantly, these two cell populations have been shown to have quite different genetic profiles and active cellular pathways, and therefore may require distinct therapeutic targets and approaches In other cancers where genetic diversity and instability contribute ificantly to disease pathogenesis, treatments that offer continuous, combined effects have proven to produce the most durable benefits 64 — Sporadic or episodic treatments have been shown to allow the evolution of treatment resistance and lead to earlier disease progression when compared to sustained treatment strategies 69 — Although MG has undergone some of the most extensive molecular classification across all cancer types, we have not yet been able to target particular driver mutations with the same level of success as has been observed in other settings such as in BRAF -mutant melanoma, EGFR -mutant lung cancer, or HER2 -amplified breast cancer.

A greater understanding of intratumoral genomic heterogeneity and instability potential will be critical to harnessing our molecular understanding of these diseases. Clinical research in treatments for MG has a rich history, with reports of hundreds of clinical trials of various types and approaches being published 72 The vast of research studies exploring treatment modalities for MG makes review and interpretation complex.

However, insights can be gained by examining the evolution of the standard of care, with an emphasis on some of the key successes and failures over this time Figure 2.

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Numerous early studies, including those dating back to the s, were well-deed with appropriate controls, providing sound, evidence-based guidelines. Figure 2. Improvements in median survival over time for patients undergoing various treatments for malignant glioma. Since the s when corticosteroids were introduced for tumor-associated brain edema, there has been more than a quadrupling of the median survival for these patients.

More recently, combination chemotherapy regimens have been suggested to increase this median survival upwards of 20 months. One of the first key discoveries came from the University of Minnesota in by Drs. Galicich, French, and Melby, who described the use of systemic corticosteroids dexamethasone to reduce peri-tumoral cerebral edema in patients with brain tumors While this treatment was not evaluated on the basis of halting tumor progression or improving patient survival, it improved many of the neurological symptoms weakness, aphasia, headache, and others attributed to MG both before and after surgery However, the profound improvements seen with this anti-inflammatory therapy continue to place corticosteroids in a central role in the management of tumor-associated edema for patients with MG.

Not to be overlooked, the immunosuppressive and BBB modulating effects of dexamethasone 76 — 78 are also important in considering systemically administered or immunologic treatment strategies for MG patients in need of anti-edema therapy. Also during the s, radiation therapy RT in the form of whole-brain radiation began to emerge as an efficacious adjuvant therapy for MG As with other cancers, the non-specific targeting of rapidly dividing cells by RT increased survival for many patients with MG 5859 ; RT typically doubled survival from about 6 to approximately 12 months.

Whole-brain RT WBRT soon became the standard of care and characterized the control arm for future treatment studies However, the maximum WBRT dose prescribed is limited by the radiation tolerance of critical CNS structures, such as the frontal lobes, optic apparatus, and brainstem. Alternative fractionation schemes and techniques, including dose escalation, hyper- and hypo-fractionation, brachytherapy, charged particles, and radiosensitizing drugs, have been explored, but none have consistently demonstrated improvement in survival.

Eventually a regional, fractionated radiation approach was found to be as effective as WBRT, providing a high dose to a more focused region while minimizing toxicity 61 Currently, most patients with MG receive intensity modulated radiation therapy IMRT fractionated in daily doses of 2 Gy given 5 days per week for 6 weeks, for a total radiation dose of 60 Gy 5.

With the roles of steroids and RT firmly in place, studies of chemotherapeutic drugs known as alkylating agents dominated the major clinical trials through the s. In particular, carmustine BCNU and more recently, temozolomide TMZ, oral formulation: Temodarhave been the focus of many chemotherapy studies for gliomas. A meta-analysis suggested that systemic administration of nitrosoureas, like BCNU, added approximately 2 months to the median survival for patients with high grade glioma Despite this modest improvement, systemically administered BCNU was adopted into the standard of care at many centers through the mids.

These drug-loaded interstitial wafers were deed to line the surgical resection cavity and deliver chemotherapy directly to residual tumor cells following MG surgery. Interstitial chemotherapy IC treatment consists of up to eight dime-size wafers made of a poly-anhydride biodegradable polymer impregnated with BCNU, providing sustained release of the drug over a 2—3-week period. IC therapy has shown the potential for local delivery to improve efficacy while reducing systemic side-effects, such as pulmonary fibrosis and myelosuppression, in the case of BCNU 81 This FDA approval marked a transition toward incorporating unique delivery strategies for MG and a broader recognition of the importance of mitigating the BBB in successful MG treatment approaches.

Since then, numerous studies and trials have explored local delivery approaches to take advantage of the unique drug delivery opportunity at the time of surgery. These have included regional and antibody-targeted brachytherapy, drug-loaded polymer and formulation strategies, and catheter-based infusions, with and without convection enhancement.

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Emerging insights into barriers to effective brain tumor therapeutics