The Role of Blood–Brain Barrier in Brain Cancer: From Pathophysiology to Therapeutic Approaches

Abstract

Brain tumors remain among the most lethal cancers, in part due to the limited ability of therapeutic agents to reach malignant cells protected by the blood–brain barrier (BBB). This specialized vascular interface preserves neural homeostasis through several mechanisms and different elements. In brain malignancies, the barrier may be disrupted, remodeled, or remain largely intact depending on tumor type, leading to highly variable effects on different therapeutic approaches. These challenges have driven the development of innovative delivery strategies, including molecular engineering, nanocarriers, receptor-mediated transport systems, focused ultrasound, and direct regional administration. Understanding BBB biology and its tumor-specific alterations is essential for designing effective therapeutic approaches capable of improving outcomes in brain cancer. Recent studies showed promising results with different approaches, including pharmacological approaches, nanotechnology-based approaches, physical disruption techniques, biological and cellular approaches, and convection-enhanced delivery. This review summarizes the current understanding of the role of BBB in brain cancer, and reviews emerging strategies to overcome this barrier and enable effective brain cancer therapy.

Plain Language Summary

Brain tumors are among the deadliest cancers because many treatments cannot reach the tumor cells. This is largely due to the blood–brain barrier, a natural protective system that controls what substances can enter the brain to keep it healthy. In brain cancers, this barrier can behave differently: in some tumors it is damaged, in others it changes shape, and in some it stays mostly intact. Because of this, treatments that work for one brain tumor may not work for another. To overcome this problem, researchers are developing new ways to deliver drugs to the brain. These include designing drugs that can cross the barrier more easily, using nanoparticles, taking advantage of natural transport systems in blood vessels, applying focused ultrasound to temporarily open the barrier, and delivering treatments directly to the brain or tumor area. A better understanding of how the blood–brain barrier works—and how it changes in different brain tumors—is critical for creating more effective treatments. This review explains what is currently known about the blood–brain barrier in brain cancer and highlights new strategies aimed at improving drug delivery and patient outcomes.

Keywords

brain cancer blood-brain barrier drug properties therapeutic approaches

1. Introduction

Despite unprecedented decades of research and accelerated technological advancements, treating brain cancer remains one of the most profound and intractable challenges. This struggle is primarily dictated by the brain’s inherent vulnerability and the impenetrable fortress erected by the blood-brain barrier (BBB). The global landscape is grim; the incidence of brain and CNS neoplasms is surging, marked by a staggering 106% rise between 1990 and 2021, and a corresponding 63.67% escalation in mortality. This brutal trajectory underscores the deadly nature of these malignancies and the persistent failure to decisively improve treatment outcomes.¹ While breakthroughs in early detection and advanced therapies have marginally enhanced survival, this alarming increase is paralleled by unaddressed environmental and genetic risk factors, alongside the crucial disparity in access to advanced, costly neuro-oncological technologies across lower-income regions.¹ The sheer weight of this crisis is quantified by the Global Cancer Observatory (GLOBOCAN) 2020 estimates: brain and CNS cancers, though ranking 19th in frequency (1.9% of all cancers), stand as the 12th leading cause of cancer deaths globally (2.5% of all cancers).²

Brain neoplasms constitute a diverse spectrum. The most dominant histological category is glioma, encompasses the rapidly lethal, high-grade gliomas (e.g., glioblastomas) and the slower, but equally insidious, low-grade gliomas (e.g., astrocytomas and oligodendrogliomas). The remaining fraction comprises a complex mosaic of histology, including meningiomas, ependymomas, and CNS lymphomas. Reflecting the brain’s complexity, these tumors present a heterogeneous clinical picture, their symptoms ranging from non-specific, persistent headaches to catastrophic events like seizures, profound cognitive deficits, or paralysis.³

The continuous efforts of medical innovation have conducted a multidisciplinary approach against these malignant lesions. Techniques range from precise neuro-navigational surgery to advanced radio- and chemotherapy, supplemented by intensive rehabilitation.³ Yet, the Brain’s most essential filter, the BBB, tragically constitutes a remarkable enemy in this concern. This physiological barrier blocks therapeutic agents designed to penetrate the tumor and save the patient, culminating in the unfavorable prognoses that define neuro-oncology. Researchers are currently engaged in efforts to breach this physiological fortress, either by subtly modulating therapeutics to illicitly bypass the BBB or by employing mechanical means.⁴ The imperative for the future of neuro-oncological evolution is the unrelenting invention of treatments capable of rendering the BBB irrelevant.⁴

Considering the above-mentioned points, this narrative review, guided by the Scale for the Assessment of Narrative Review Articles (SANRA),⁵ embarks on a detailed exploration of this complex barrier, where it deconstructs the structure and function of the BBB, analyze its implications for drug delivery, and unravel the pathophysiology of the BBB specifically within the context of brain cancer. In addition, it spotlights the major brain cancer types most profoundly affected by the BBB’s defense, elaborating on pioneering strategies developed to conquer this barrier and revolutionize brain cancer treatment.

2. Anatomy, Histology, and Physiology of BBB

The BBB is a semipermeable, highly selective barrier formed by microvascular endothelial cells that prevents blood-borne agents from crossing the parenchyma into the central nervous system.⁶ The neurovascular unit (NVU) covering the brain is formed of different cellular components including endothelial cells, pericytes, astrocytic end-feet, neurons, and the basement membrane. The BBB plays a crucial role in maintaining brain homeostasis by regulating the influx and efflux of compounds.⁶

To successfully perform its function, the BBB has a specific physiology and anatomy designed to work synergistically with its role. In addition, the structural and functional integrity of the BBB arises from specialized intracellular and extracellular interactions.⁶

2.1. Endothelial Cells

Endothelial cells of the BBB originate form mesoderm-derived angioblasts.⁷ They exhibit a squamous, elongated, and thin morphology like endothelial cells in other tissues.⁸ However, they are non-fenestrated, a characteristic that contributes to the BBB’s restrictive permeability.^7,8 These endothelial cells form a continuous lining of the cerebral micro-vessels and possess distinct membrane transporter systems, such as P-gp and GLUT1, which regulate selective molecular exchange between the blood and the brain.^7,8

2.2. Tight Junctions (TJs)

The BBB restricts paracellular diffusion and regulates homeostasis of CNS by the presence of specialized types of cell-cell junctions known as tight junctions.⁹ TJs or zonula occludens seal intracellular gaps between endothelial cells, thus preventing paracellular diffusion of blood-borne particles. They maintain cell polarity by modulating the transport of lipids and proteins between apical and basolateral surfaces, and function as a signaling platform that adjusts and responds to environmental changes.^9,10 Occludin, claudins, and JAMs are special transmembrane and cytoplasmic proteins.⁹ Together, they maintain tight junctions’ integrity, which makes any dysfunction or downregulation of these proteins affect the BBB integrity.¹⁰

2.3. Astrocytes End-Feet (AEF)

AEF are star-shaped glial cells found abundantly in the central nervous system.⁷ By covering 90% of the BBB surface area, AEF provide structural support to neurons and play a crucial role in regulating the BBB. AEF have two major protein channels responsible for water and ion balance, expressed at the perivascular membrane domain facing the endothelial basement membrane.⁷ Aquaporin-4 (AQPA4) is responsible for regulating water homeostasis. However, Kir4.1 acts as an inwardly rectifying potassium channel that helps excrete excess K+ from the extracellular space, thus altering ionic concentration.^7,11

2.4. Pericytes

Pericytes are mural cells embedded between endothelial cells and the basement membrane providing mechanical stability to the BBB.^7,8 They regulate EC proliferation, tight junctions’ expression, and angiogenesis.¹² In addition, pericytes play an important role in regulating the development of BBB during maturation as well as maintaining its function during aging.¹² Dysfunction of these cells alters the permeability and role of the BBB.^7,12

2.5. Basement Membrane

Basement membrane is a thin, dense layer of extracellular matrix surrounding the endothelial cells. It works on providing mechanical support and anchorage between astrocytes-end feet and endothelial cells. The basement membrane contains multiple protein-based macromolecules. They include collagen IV which is responsible for mechanical strength, laminin that promotes cell adhesion and differentiation, fibronectin associated with cell attachment, migration, and wound repair, and heparan sulfate proteoglycans that regulate cell signaling, growth factor binding and molecular filtration. Together these proteins regulate the tightness and leakage of the BBB.⁸

3. Obstacles to Drug Penetration

For molecules circulating in the bloodstream to reach the brain parenchyma, they need to either slip through the BBB by passive diffusion or be pumped by active transport mechanisms.¹³ Knowing its important attribution in the medical field, scientists investigated various physicochemical characteristics for drugs used for both CNS and non-CNS disorders, aiming to link properties with therapeutic effectiveness in the brain.¹³ Figure 1 summarizes the factors affecting drug penetration into BBB.

Figure 1.

Factors affecting the penetration of drugs through the blood-brain barrier (BBB). Schematic representation of the neurovascular unit (NVU) illustrating the structural components of the BBB and key determinants of drug permeability. Drug penetration across this barrier is influenced by intrinsic drug properties, as well as active biological mechanisms including efflux transporters and metabolic enzymes expressed at the endothelial interface

Drug penetration into the brain is not determined by a single factor but rather by multiple defense mechanisms. The following sections discuss how physicochemical properties, efflux transporters and metabolic enzymes collectively restricts drug delivery across the BBB.

3.1. Drug Properties Affecting Passive Diffusion

Passive diffusion is the process by which drugs and molecular compounds move down their concentration gradient from the blood to the brain, crossing the BBB.¹⁴ Size of the molecule, lipophilicity, hydrogen bonding (polarity), and ionization state are the most important characteristics for successful diffusion.^14,15

3.1.1. Size of the Molecule

Under normal conditions, the physiological characteristics of the BBB prevent the leakage of molecules due to the presence of tight junctions and endothelial cells. Therefore, only small molecules (<400 Da) passively cross the BBB via paracellular transport.^8,16 However, in some brain tumor progression, the BBB is disrupted forming a leakier barrier known as blood-brain tumor barrier (BBTB).¹⁷ This altered barrier permits the transport of compounds through their pores with a molecular mass of approximately smaller than 11.7 to 11.9 nm.¹⁸

3.1.2. Lipophilicity

Low lipid-soluble molecules cannot enter the brain without being actively transported.¹⁹ Thus, for a compound to diffuse passively through the BBB, it should have a high lipophilicity and low polarity.¹⁷ However, studies showed that highly lipophilic compounds could be trapped within the lipid bilayer, leading to cellular toxicity, and reduced therapeutic effect.²⁰ Therefore, a balance between lipophilicity and hydrophilicity is essential, with an ideal log P value between 1.5 and 2.5 to reach a better therapeutic effect.²⁰

3.1.3. Hydrogen Bonding

Hydrogen bonding was identified as one of the major determinants limiting the entry of drugs across the BBB.^21,22 Hydrogen bonding capacity is inversely correlated with BBB permeability, thus an increase in hydrogen bond donors and acceptors-such as those found in peptides, reduces a drug’s ability to cross the BBB and therefore reducing passive diffusion.^21,22 In line with this, polar surface area (PSA) representing the surface area of a molecule that is occupied by polar atoms (primarily oxygen and nitrogen), is strongly associated with hydrogen bonding capacity.²² Studies showed that for drugs to penetrate the BBB, they should tend to have lower PSA with an upper limit of 90 Å².²²

3.1.4. Ionization State

Besides PSA and hydrogen bonding, the ionization state of a compound is a major factor of passive diffusion across the BBB. The BBB strongly restricts the passage of ionized or highly charged drugs, due to high polarity, and their inability to fuse with the lipid bilayer.^21,22 Drugs that are mainly unionized (pH ∼7.4) show a better CNS penetration, whereas ionized molecules rely on active transporters to bypass the BBB.²¹ For this reason, the pKa of a molecule, which determines its ionization state in bloodstream, is an important consideration in CNS drug design.²²

Improvement of therapeutic success is limited by defensive mechanisms in the BBB and BBTB.^4,10 Efflux pumps and metabolic enzymes form a double barrier present in the endothelial cells resulting in a low drug permeability into the brain.^23-25

3.2. Efflux Pumps

Efflux pumps are energy-dependent transporters that can actively pump out molecules from the brain back into circulation.^23,26 Two major types of active efflux pumps found in the brain are ABCB1 (P-glycoprotein), and ABCG2 (Breast Cancer Resistance Protein or BCRP).^26,27 During brain tumor progression, efflux transporters increase their expression, hence more strictly preventing the delivery of therapeutic agents.²⁶ While ABC transporters are in the endothelial cells of the BBB and BBTB, they were also found to be expressed at the tumor cells themselves.²⁷ For example, tumor cells exhibit efflux transports expressed on their cells, further restricting drug evasion of the tumor cells.^26,27

3.2.1. ABCB1 (P-Glycoprotein) Efflux Pumps

The discovery of P-glycoprotein in the 1970s was linked to MDR1 gene due to its high expression in the multidrug-resistance tumor cell lines. Structurally P-glycoprotein is a transmembrane protein, composed of two homologous halves, each containing six transmembrane helices and one ATP-binding domains.¹³ In addition to its expression in the BBB, ABCB1 is also found in multiple systems, such as gastrointestinal tract, liver canalicular membrane, kidney proximal tubules and placenta where it plays a role in regulating chemical agents’ penetration, distribution, and elimination. Recognizing the importance of P-glycoprotein in regulating the BBB, many studies were conducted, both in vitro and in vivo.¹³ Preclinical studies in mice showed better therapeutic effects upon the administration of ABCB1 inhibitors with chemotherapeutic agents that interfere with cell division and DNA integrity, such as Vincristine, Paclitaxel, and Daunorubicin.¹³ In brain cancer, particularly glioblastoma, co-administration of paclitaxel with P-glycoprotein inhibitor PSC 833 significantly increased drug accumulation in the brain compared to paclitaxel alone. These findings have been also supported in humans, where simultaneous administration of verapamil, a P-glycoprotein substrate, with a P-glycoprotein inhibitor resulted in increased drug penetration into the brain.¹³

3.2.2. ABCG2 (BCRP) Efflux Pumps

Alongside P-glycoprotein, ABCG2 is recognized as another major ABC transporter that restricts the penetration of anti-cancer drugs.^13,28,29 ABCG2 was discovered in 1998, where it was physiologically found in the BBB, intestines, liver, kidneys, and some tumors.²⁸ Numerous studies have linked the excessive presence of BCRP transporters at the luminal membrane of brain capillaries with drug penetration. Many drugs have been demonstrated to be ABCG2 substrates, including Imatinib, Mitoxantrone, Methotrexate, SN-38, Topotecan, Erlotinib, and Gefitinib. To overcome the efflux of these drugs including Imatinib, ABCG2 inhibitors such as GF120918 and Fumitremorgin C have been co-administered with chemotherapeutic agents resulting in an increased drug concentration inside the brain.²⁹

At the domain level, ABCG2 and P-glycoproteins are similar in having transporter building blocks, but they differ in the domain arrangement and how proteins are assembled to work together. ABCG2 is a homodimer which means “half-transporter”, that must dimerize to enable the transport process.^28,29

3.3. Metabolic Enzymes

Along with active efflux, metabolic enzymes chemically modify and detoxify drugs before reaching their target in the brain.³⁰ Conjugation, oxidation, and sulfonation are different metabolic mechanisms that help neutralize and excrete drugs, hence limiting therapeutic efficacy.²⁴ Enzymes involved in drug metabolism are divided into two main categories: phase 1 and phase 2 enzymes.

3.3.1. Phase 1 Enzymes

Phase 1 enzymes which involve cytochrome P450 enzymes, are responsible for the functionalization reaction. They introduce a functional group on drugs thereby increasing their polarity. Cytochrome P450 are a large family of heme-containing enzymes also known as CYP, present in the liver, gut, and various other organs, including the brain. Cytochrome P450 functions as an oxidative enzyme, altering the structure of drugs and xenobiotics, increasing their polarity, and contributing to their elimination.²⁴ CYP1B1, CYP3A4, CYP2C8/9, CYP2D6 are CYPs isoforms expressed at the tumor BBB (BBTB). Studies showed an upregulation of these CYPs in pathophysiological conditions (epilepsy, tumors, and inflammation), thus lowering the parent drug concentration inside the brain.²⁴

3.3.2. Phase 2 Enzymes

Beyond endothelial metabolism, glial cells-specifically astrocytes, and microglia- serve as an additional metabolic barrier.^24,30 They do not only provide physical support to the BBB, but also act as a second filter by expressing a range of phase 2 detoxification enzymes.^24,30 UDP-glucuronosyltransferases (UGTs), Glutathione S-transferases (GSTs), and Sulfotransferases (SULTs) together deactivate or alter the conformation of xenobiotics that bypass endothelial cells, slipping through the BBB.^25,31,32

1. UGTs increase water solubility of lipophilic agents by conjugation with glucuronic acid.³²

2. GSTs help in detoxifying electrophilic drugs by coupling to glutathione.²⁵

3. SULTs transfer sulfate groups to exogenous and endogenous compounds, increasing their solubility, hence facilitating excretion.³¹

Collectively, drugs that evade the protective mechanisms of the BBB may still be susceptible to degradation by metabolic enzymes, and the resulting metabolites can be subsequently transported out by efflux transporters. Together, metabolic enzymes and transport systems form a multilayer protective mechanism that limits drug penetration within the brain.

4. Altered Characteristics of BBB

4.1. BBB Alterations in Primary Brain Tumors

Primary brain tumors such as gliomas have profound alterations in BBB integrity through disruption of the normal vascular architecture.^17,33 Vascular endothelial growth factor (VEGF) signaling that is overexpressed promotes angiogenesis, but the newly formed vessels are immature and leaky with reduced pericyte coverage.^34,35 Tight junction proteins, such as claudin-5 and occludin, are downregulated, disrupting endothelial cohesion.^36-38 In parallel, matrix metalloproteinases (MMP-2 and MMP-9) degrade the basement membrane, further destabilizing endothelial integrity.^39,40 This is compounded by pro-inflammatory cytokines TNF-α and IL-6, which increase vascular permeability.⁴¹ Together, these interfere with the molecular and structural characteristics that maintain the integrity of the BBB in a healthy brain.^17,33

4.2. BBB Alterations in Metastatic Brain Tumors

Metastatic brain tumors, most frequently originating from breast, lung, and melanoma malignancies, result in partial disruption of BBB with substantial intact portions. Thus, vascular leakage occurs alongside limited drug delivery compared to peripheral tumors.^42-44 In these tumors, efflux transporters, such as P-glycoprotein (P-gp) and BCRP, continue to function, further limiting the buildup of drugs.^29,45 Therefore, some brain metastases have been shown to have unequal drug uptake, highlighting the ongoing challenge of achieving successful treatment in this context.^45-47

4.3. Molecular Changes

In some brain cancers, the BBB becomes a BTB, exhibiting aberrant angiogenesis, irregular permeability, and structural degradation.^17,48,49 The BTB is heterogeneously organized with regions of disordered leakiness interspersed with areas that maintain their restrictiveness, in contrast to the homogeneously protective barrier formed by the intact BBB.⁴³ Pathological remodeling can explain the incomplete and asymmetric delivery of therapeutic molecules into brain tumors.

The heterogeneity of barrier presence substantially reduces the effectiveness of treatment because most areas of the tumor still do not reach therapeutic levels of drugs despite the partial disruption of the barrier.⁴³ Several molecular changes contribute to this fact, including TJ proteins, transporters, and vascular permeability factors.

Tight junction proteins and efflux transporters usually control the BBB,^43,45,50,51 but structural remodeling and pathological permeability in brain tumors violate its integrity.^34,52,53 This heterogeneity of permeability is further worsened by pathological vascular structure caused by angiogenic signaling within tumors.¹⁷ By changing the tight junction proteins and enhancing paracellular permeability, inflammatory mediators like IL-6 have been reported to compromise the integrity of the BBB and enhance barrier dysfunction under tumor-associated conditions.^54,55

Tight junction proteins, such as occludin, claudin-3, claudin-5, and ZO-1/2/3, are usually of high resistance, limiting paracellular diffusion and enclosing the BBB endothelial cells.^56,57 VEGF-induced downregulation of tight junction proteins, in addition to angiogenesis under oxygen deficiency creates immature, permeable vessels.³⁶ Also, BBB integrity is compromised by MMP 2 and MMP 9 breakdown of the basement membrane of endothelium and disruption of tight junction proteins.^40,58,59 Because tumor severity and permeability are associated with each other in gliomas, these alterations lead to a heterogeneous BTB.⁶⁰ The implications are lost barrier integrity and varying drug delivery.⁴³

Beyond tight junction disruption and increased paracellular permeability, recent evidence indicates that transcellular transport pathways also contribute to BTB heterogeneity. Specifically, Wnt signaling regulates MFSD2A-dependent caveolae-mediated transcytosis, contributing to variability in drug delivery across brain tumors.⁶¹

As for efflux transporters, such as P-gp and BCRP, which are main factors in limiting drug accumulation across the BBB,⁶² their expression is dysregulated in specific locations by chronic upregulation that supports treatment resistance,^63,64 and in others where function is decreased, creating asymmetrical drug distribution.¹⁷ These heterogeneous transporters also contribute to structural abnormalities of the BTB and compromise uniform therapeutic delivery.^43,65

Regarding VEGF, which is overexpressed in the tumor microenvironment and known for stimulating angiogenesis with leaky, structurally immature vessels, it forms a major cause for vascular permeability in primary brain tumors.³⁶ Other mediators such as angiopoietins and PDGF play central roles in vascular stability. When dysregulated, like having excess Ang-2 or impaired PDGF-B/PDGFRβ signaling, they destabilize the vasculature and promote heterogeneous barrier permeability.⁶⁶ Additionally, the inflammatory cytokines TNF-α and IL-6 impair vascular function and destabilize endothelial integrity.^55,67,68 Another example is Pleiotrophin (PTN), a growth factor highly expressed in several tumors, activates anaplastic lymphoma kinase (ALK) receptors expressed on mural cells. PTN-ALK signaling alters mural cell behavior and impairs their interaction with endothelial cells, thereby weakening vascular support structures and increasing vascular permeability. Upon disruption of mural cells function, vessels become leaky contributing to heterogeneous permeability within the tumor vasculature and enhancing drug delivery to tumors.⁶⁹ When combined, these alterations create abnormal, leaky vessels that limit uniform drug delivery and promote BTB heterogeneity.^17,44,70,71

5. Major Brain Cancer Types Affected by BBB

Several brain cancer types form a more interesting field to assess the role of BBB in developing new therapeutic approaches. In brain metastasis (most common brain cancer) and glioblastoma (most common primary brain cancer in adults), the BBB is remodeled into a heterogeneous BTB with defense mechanism that hinder the drug delivery.^17,65,72,73 The role of BBB is also significant in other cases, such as diffuse midline gliomas, Primary CNS lymphoma (PCNSL) and SHH-medulloblastoma, where it is intact, inhibiting the access of the drug to the malignancies.^74-76 For this reason, a deep understanding of how different types of tumors can affect and are influenced by this barrier is important for better drug design.

5.1. Glioblastoma

One of the most aggressive primary brain tumors in adults is glioblastoma, despite the great efforts made with respect to treatment.^48,77,78 Due to its high ability to infiltrate, glioblastoma can recur at or few centimeters away from the site of initial presence. Glioblastoma remodels the BBB, extensively leading to a complex barrier representation.

The BBB visualized by Magnetic Resonance Imaging (MRI) shows multiple compromised regions in glioblastoma.^33,65,71 The compromised region is caused by reduced integrity and disorganized structures.^77,79

This phenomenon is affected by secretion of VEGF, which is an important factor for vessel formation.^49,78,79 However, endothelial cells in glioblastoma do not form a uniform population, and different endothelial phenotypes exist within the tumor microenvironment. This heterogeneity contributes to differences in efflux transporter expression, vascular stability, and variable permeability across different tumor regions.⁸⁰ Simultaneously, the tumor can break down the barrier by downregulating the tight junction proteins of endothelial cells, such as claudin-5 and ZO-1.^36,38 In addition, tumor cells invade the perivascular space and trigger the detachment of astrocytic end feet from the vasculature which disrupts the BBB.⁸¹ The affected regions of the BBB contain active efflux transporters such as the ATP biding cassette (ABC) family, and most importantly P-glycoprotein and BCRP. These transporters remain functional and limit the access of multiple therapeutic agents. This allows the tumor to evade the most potent therapy.¹⁷

Furthermore, BBB disruption in Glioblastoma is also driven by an extracellular matrix (ECM) remodeling around tumor vessels. In tumor environment, lysyl oxidase-like2 (LOXL2) is an enzyme that modifies collagen fibers, contributing to crosslink collagen and increases matrix stiffness around blood vessels. This remodeling contributes to abnormal vessel structure in glioblastoma, affecting permeability and facilitating tumor invasion along blood vessels.⁸²

The BBB is not equally affected in all glioblastoma patients, where some patients exhibit cancer regions where the BBB is intact.^71,72 This property is one obstacle for treatment because tumors infiltrate beyond the contrast-enhancing core into normal tissues where the BBB is intact hindering the entrance of the drug.^57,65,71,72 This makes the treatment of such region challenging but essential to achieve complete remission.⁷¹

Genetic variations make an important factor contributing to this heterogeneity in glioblastoma, especially differences in isocitrate dehydrogenase (IDH) mutant status. IDH-mutant tumors generally exhibit less aggressive vascular remodeling and more organized vasculature, whereas IDH-wildtype tumors show stronger angiogenic and more abnormal vascular proliferation. These differences influence angiogenesis, vascular structure, and possibly BBB characteristics in glioblastoma.⁸²

5.2. Primary Central Nervous System Lymphoma (PCNSL)

Primary central nervous system lymphoma is one of the rare tumors of extranodal non-Hodgkin lymphoma of the brain.^74,83 It is one of the most aggressive and poor prognosis tumors.⁷⁴

In most cases of PCNSL, the BBB remains intact or mildly disrupted, impending the delivery of necessary chemotherapy.^57,84 For this reason, most new therapies aim at disrupting this barrier.⁷⁴ An efficacy of 88% was noted in a Phase II trial investigating BBB immunochemotherapy, where the barrier was disrupted, then patients were treated with high-dose chemotherapy.⁷⁴

5.3. Brain Metastases

Metastatic tumors usually compromise the BBB, leading to a heterogeneous permeability depending on the size and anatomical location of the tumor.^17,43,79 This disruption was clearly seen on an MRI where a contrast enhancing region was related to the loss of perivascular normal astrocytic architectures. This disruption was positively correlated with the size of the tumor.⁷⁹ As for the region with no enhancement, the perivascular astrocytic architecture was normal.⁷⁹

The metastasis of cancer induces structural changes and neuronal death such as displacing the astrocyte end feet and altering pericytes of the BBB.^17,51 For example, metastatic breast cancer cells should express some specific factors to breach the BBB, such as RAC1, GEF, DOCK4.⁸⁵

5.4. Medulloblastoma

Medulloblastoma is one of the most common pediatric brain tumors, which have different BBB characteristics according to its molecular subtype.^75,77 SHH-Medulloblastoma is a subtype with an unfavorable prognosis, mainly due to the intact BBB hindering the access of chemotherapy.^75,77 However, WNT-Medulloblastoma is another subtype with favorable prognosis due to altered BBB by paracrine signals from mutant beta-catenin, which induces fenestrated vasculature and allows chemotherapy to reach the tumor.^75,77

5.5. Diffuse Midline Glioma

The challenge in treating diffuse midline glioma is the intact BBB which prevents many molecular therapies from reaching cancer cells in the brain parenchyma.⁷⁶ This is achieved by a non-angiogenic growth pattern, where they diffuse along an existing neural tract instead of forming new vessels and expressing pro-angiogenic signals to inhibit the formation of leaky vessels.⁷⁶

6. Radiotherapy Induced Modulation of the BBB

Radiation therapy has emerged as a cornerstone of treatment for brain tumors, including primary brain malignancies such as glioblastoma as well as brain metastases.⁸⁶

Besides its direct cytotoxic action on tumor cells, radiotherapy may also modulate the integrity and permeability of the BBB, thereby potentially affecting the delivery of therapeutic agents to brain tumors.⁸⁷ Radiation-induced disruption of the blood brain barrier can be explained by multiple plausible mechanisms. The endothelial layer of cerebral vasculature may be directly damaged by ionizing radiation, which disrupts major components that constitute the blood brain barrier, including claudins, occludins, and zonula occludens proteins that form tight junctions.⁸⁸ Additionally, ionizing radiation can activate inflammatory signaling pathways and induce oxidative stress within the NVU, leading to increased vascular permeability. Ionizing radiation can further compromise the BBB integrity by inducing endothelial apoptosis, and by activating brain microvascular endothelial cells and upregulate adhesion molecules such as ICAM-1 and VCAM-1, facilitating leukocyte recruitment and promoting neuroinflammation.⁸⁹ The severity and duration of BBB disruption following radiotherapy may vary depending on the physical characteristics of radiation exposure, such as radiation dose, fractionation schedule, and the timing after irradiation.⁸⁷

This modulation in BBB permeability can facilitate the penetration of chemotherapeutic agents and other therapeutic compounds into brain tissue. Therefore, radiotherapy may contribute not only to direct tumor cytotoxicity but also to improved therapeutic efficacy by enhancing drug delivery across the BBB.⁸⁷

7. Strategies to Overcome the BBB in Brain Cancer Therapy

The development of successful delivery strategies for several brain cancer types has focused on several mechanistic classes, including molecule-centric optimization to enable passive diffusion and/or carrier-mediated uptake, engagement of endogenous transport systems to achieve receptor-mediated transcytosis, controlled, transient modulation of BBB permeability, and anatomic bypass via regional administration.⁹⁰ Clinical development often features complex, multimodal combinations to achieve therapeutically adequate intratumoral concentrations with acceptable systemic tolerability. Figure 2 summarizes the approaches developed to overcome the BTB.

Figure 2.

Approaches enhancing drug delivery to overcome the blood-tumor barrier (BTB) in brain cancer. Schematic overview of strategies designed to improve therapeutic penetration across the blood–tumor barrier (BTB). Multiple strategies to enhance drug delivery are illustrated, including pharmacological modulation, nanotechnology-based carriers to facilitate transport, physical disruption techniques, biological and cellular approaches, and convection-enhanced delivery to bypass vascular limitations. These approaches aim to increase drug accumulation within tumor tissue and improve therapeutic efficacy in brain malignancies

7.1. Pharmacological Approaches

7.1.1. Lipid-Soluble Small Molecules

Favorable physicochemical properties of small molecules can improve the chances of brain distribution following systemic delivery.⁹¹ In the area of neuro-oncology, substances believed to be “BBB permeable” can exhibit uneven distribution within a brain tumor because of BTB permeability/perfusion heterogeneity in various regions of the tumor, including infiltrative regions with relatively preserved barrier properties.¹⁷ While optimization in pharmaceuticals can involve designing prodrugs, optimizing lipophilicity, or reducing efflux transporter liability, these changes can also affect the whole-body pharmacokinetics, including redistribution to peripheral tissues, thereby making optimal concentrations of free drug in the brain and tumor tissue difficult to achieve. Inhibition of efflux transporters also creates safety concerns, given that efflux transporters are also expressed extensively outside of the CNS; therefore, inhibiting those efflux transporters systemically increases off-target exposure. Hence, there has been a focus on developing BBB/BTB permeable agents with efficient target engagement in the CNS tumor microenvironment, as assessed by free drug concentration measures.⁹¹

7.1.2. Efflux Pump Inhibitors

Efflux transporters of the ATP-binding cassette (ABC) family present at the BBB/BTB contribute to lowering intracerebral concentrations of many xenobiotics and chemotherapy agents. However, because of their widespread expression and potential effect on overall drug clearance and drug-related toxicity, it is challenging to justify their systemic inhibition for improving intracerebral drug exposure. Thus, there are translational strategies to improve brain penetration that increasingly focus on drug design with knowledge about these transporters and measurement of CNS exposure using pharmacokinetic endpoints.^91,92

7.1.3. BBB Modulators

Regadenoson, an FDA-approved drug for pharmacologic cardiac stress testing in patients due to its properties as an adenosine A2A receptor agonist, has been explored for its possible uses in BBB modulation techniques. In a pilot human study, it was tested whether a standard dose of regadenoson would enable a transient increase in BBB permeability by determining brain penetration of imaging substances that would not normally pass through an intact BBB; however, there was no significant increase in penetration at standard dosing in human subjects, paving the way for further analysis with a different dosing pattern.⁹³ Human studies conducted on patients with gliomas have explored various doses with an emphasis on MR image measures of contrast enhancement and subtraction mapping, along with permeability parameters.⁹⁴

7.2. Nanotechnology-Based Delivery

Nanocarriers could facilitate the protection of the payload, prolong circulation time, reduce premature degradation, and perhaps enhance intracranial tumor delivery by exploiting properties of BTB leakiness, endothelial interactions, and receptor/carrier-mediated uptake. Nevertheless, the heterogeneity and partial disruption of the BTB can lead to variable levels of passive targeting, an incentive for targeting ligands or stimulus-responsive release strategies. Additionally, the relevance of nanotechnology for brain cancers is not directly the exploitation of a mechanism but its ability to offer a platform that could be tuned according to the constraints posed by BBB/BTB biology.^17,95

7.2.1. Liposomes, Polymeric Nanoparticles, Dendrimers

Liposomes have remained at the forefront of nanoplatforms due to their ability to entrap both hydrophilic and hydrophobic agents and their ease of functionalization with polyethylene glycol (PEG) and peptides for adjusting circulation half-life and targeting tumors. Ongoing nanotherapeutic strategies for glioblastoma include those based on peptides that target the BBB and tumor-associated receptors, in an effort to improve BBB/BTB transport and tumor penetration while maintaining an extended half-life. These nanocarriers include systems functionalized with peptides that can facilitate endocytosis while aiming to preserve acceptable pharmacokinetics.⁹⁶ In parallel, polymeric nanoparticles, ranging from micelles to biodegradable polymeric constructs, provide flexibility for controlled loading and release profiles, as well as multitasking such as the concurrent delivery of therapeutics and contrast agents. In glioblastoma, while enhancements in target-driven delivery by ligand conjugation and responsiveness to the tumoral milieu for nanocarriers have been shown, scale-up and limited definitive evidence from human studies following intravenous administration continue to hinder translation to the clinic.⁹⁷ Another widely studied nanocarrier class is dendrimers, which have highly branched morphologies with a programmable architecture presenting various functional groups for drug conjugation. In the area of central nervous system delivery, ongoing studies involving dendrimers highlight potential applications in improving CNS transport. Recently highlighted considerations in these studies include (i) size and surface charge characteristics, (ii) the specific ligand being used, (iii) interaction with the BBB, and brain concentration of exposure, as well as (iv) the need for studies examining potential toxicity.⁹⁸

7.2.2. Targeted Nanoparticles

Targeting nanoparticles typically involves targeting ligands (such as an antibody, peptide, or small molecule) that bind to BBB receptor sites and/or tumor cells to enhance the transport of nanoparticles across the BBB via receptor-mediated endocytosis and/or transcytosis, with subsequent accumulation within the tumor microenvironment. Receptors commonly targeted for interacting with BBB endothelial cells include the transferrin receptor, insulin receptor, and LRP1, depending on whether nanoparticles are designed to traverse the BBB, target tumor cells, or perform both functions.^17,95 One key consideration for nanoparticles targeting tumors and traversing the BBB is the variability of BBB receptor accessibility, and the potential inhibition of transcytosis with overly efficient binding affinity of these molecules to BBB receptors. It has been shown that the optimization of ligand affinity/avidity should ultimately be evaluated based on distribution within the target parenchyma rather than BBB receptor binding alone.^17,99

7.3. Physical Disruption Techniques

The objective of physical disruption methods is to temporarily enhance the BBB/BTB permeability in a controlled fashion, with the goal of enabling higher drug levels in the tumor while preserving the overall integrity of the barrier function.¹⁷ However, the risk of bleeding, edema, and neuroinflammation may increase with disruption; therefore, the use of image guidance and careful patient selection can be considered in many of these approaches.¹⁰⁰

7.3.1. Focused Ultrasound With Microbubbles

The BBB can be reversibly opened with intravenous microbubbles in combination with magnetic resonance-guided focused ultrasound (FUS). The safety and feasibility of opening the BBB in patients with primary brain tumors were evaluated in a clinical safety and feasibility study, which supported the safety of a non-invasive MR-guided FUS procedure in patients.¹⁰⁰ In addition to transient disruption protocols, a number of device-assisted strategies have emerged for repeated BBB disruption. For example, an implantable BBB device consisting of an ultrasonic emitter array has been investigated for the repeated disruption of the BBB during carboplatin chemotherapy for recurrent glioblastoma. Indeed, these strategies aim to coordinate BBBD treatments with chemotherapy cycles.¹⁰¹ More contemporary clinical research has assessed microbubble-enhanced transcranial FUS as a method to boost the delivery of temozolomide during the treatment of newly diagnosed high-grade glioma, predominantly glioblastoma.¹⁰²

7.3.2. Hyperosmotic BBB Disruption

Hyperosmotic disruption (classically using intra-arterial mannitol) has been shown to open the BBB by inducing transient endothelial cell shrinkage and loosening tight junctions, thereby increasing paracellular permeability. While this approach has been used for decades in brain tumor treatment, it has been hindered in broader clinical use because of its invasiveness as a procedure, inconsistencies in the intensity and regional extent of disruption, and the need to limit the degree/duration of BBB opening to reduce the risk of neurotoxicity.^17,103

7.3.3. Laser Interstitial Thermal Therapy (LITT)

Studies of LITT indicate that this technique can perform minimally invasive cytoreduction and also affect vascular permeability surrounding the ablation area. The permeability of the BBB/BTB can remain elevated for a period after the procedure. There is therefore potential for combining LITT with systemic therapy, timed to a delivery window after ablation.^104,105 The length of time and the area over which the BBB/BTB is disrupted following LITT have been described as variable, and the microenvironment in the peri-ablation region encompasses edema and inflammation that could potentially affect delivery and toxicity. Similar to other disruption methods, incorporating LITT into delivery approaches will likely require imaging confirmation of altered permeability and protocol development in relation to drug-delivery timing.^17,105

7.4. Biological and Cellular Approaches

Biological and cellular approaches aim to harness the power of endogenous and/or biologically engineered mechanisms to boost therapeutic distribution and activity in the brain, with the intent of targeting brain tumors. These methods often rely heavily on locoregional treatments to either bypass the BBB or optimize biological mechanisms that could overcome diffusion across an intact BBB.¹⁷

7.4.1. Cell-Penetrating Peptides

Cell-penetrating peptides (CPPs) are short peptides that facilitate cellular uptake of their conjugated cargoes, which include small molecules, peptides, proteins, and nucleic acids. In cancer therapy and fields related to cancer research, CPPs are often considered delivery tools that can be combined with motifs targeting tumors; in the context of the CNS, they can be regarded as elements in multistep delivery systems designed to cross the BBB and then penetrate tumors.^106,107 Translation into the clinic is demonstrated by peptide-conjugated drugs engineered for permeability across the BBB. These include ANG1005, a peptide-conjugated paclitaxel that targets glioblastoma patients with recurrent high-grade glioma.¹⁰⁸ These conjugated constructs would allow for higher levels of the drug concentration within the CNS compared to the free drug itself.¹⁰⁹ However, there are still challenges associated with off-target uptake and maintaining an acceptable safety profile.^106,108

7.4.2. Engineered Immune Cells

Adoptive cellular therapies, such as chimeric antigen receptor (CAR) T-cells, are also being evaluated for their potential against glioblastoma and are amenable to locoregional (intra-tumoral/intraventricular) administration to circumvent challenges in crossing the BBB. One of the earliest clinical publications discussed a case of successful regression of glioblastoma using IL13Rα2-targeted CAR T-cell immunotherapy; this not only underscored the viability of using engineered immunological components for targeting CNS tumors but also highlighted the utility of local routes of drug delivery.^17,110

7.4.3. Viral Vectors for Gene Therapy

Viral vectors can be used for local transgene delivery and, as oncolytic viruses, can directly infect and lyse cancer cells as well as trigger anti-tumor immunity. As a consequence of intratumoral delivery of multiple virus-based therapies, BBB related hurdles are bypassed; instead, delivery challenges emerge related to intratumoral distribution, immune neutralization, and/or toxicity.¹⁷ In a phase 1/2 trial of recurrent glioblastoma, the combination of oncolytic viral therapy DNX-2401 delivered directly into the tumor, followed by systemic pembrolizumab, demonstrates the integration of locoregional viral therapies with systemic biologics. Although the primary efficacy endpoint was not met (with a modest objective response rate), a subset of patients achieved durable benefit and long-term survival, supporting the potential value of biologically based platforms in combination approaches and the importance of patient selection.¹¹¹

7.5. Convection-Enhanced Delivery (CED)

One method that overcomes the BBB is CED. The BBB is overcome in that therapeutics are directly infused into the brain parenchyma via stereotactically implanted catheters using a liquid pressure gradient (positive pressure infusion). In this way, very large molecules can be delivered directly into a volume of tissue that would not be accessible via the systemic circulation.^112,113 The engineering and clinical problem in CED is the reliable delivery of a volume of distribution without reflux down the catheter tracts or unintended distribution into cerebrospinal fluid compartments. Consequently, current practice in CED focuses on catheter design and real-time imaging techniques, such as co-infused tracers.^112,113

Clinical trials continue to explore CED for glioblastoma, including immunomodulatory agents delivered directly to tumor-adjacent tissue. However, outcomes have been mixed, and key limitations include heterogeneous tissue properties, tumor infiltration beyond the infusion field, and practical complexity of repeated catheter-based treatments. These realities reinforce the need for careful agent selection (potency, stability), robust distribution monitoring, and combination strategies that address both local and diffuse disease.^113,114

8. Conclusion

The BBB and BTB remain central determinants of therapeutic failure in several primary and metastatic brain tumors. While the BBB serves a critical physiological role in maintaining central nervous system homeostasis, the BTB introduces an additional layer of complexity, leading to the failure of many systemically effective therapeutic approaches. Recent advances have substantially reshaped our understanding of BTB biology, leading to the development of innovative strategies to enhance drug penetration. Effective targeting of the BTB represents a pivotal frontier in neuro-oncology, where continued interdisciplinary efforts bridging vascular biology, drug engineering, imaging, and clinical trial design will be crucial to transform mechanistic insights into tangible improvements in outcomes for patients with brain tumors. Despite encouraging preclinical and early clinical data, significant challenges remain in translating these strategies into durable clinical benefit. Optimal patient selection, real-time assessment of BTB permeability, integration of advanced imaging and biomarker-guided approaches, and careful evaluation of neurotoxicity are essential for successful clinical implementation. Furthermore, future trial designs must integrate spatial multi-omics, mapping the transcriptomic and proteomic landscape of the BTB. This would further clarify the mechanism of the BTB in denying the treatment and therefore help develop appropriate approaches.

Supplemental Material

Supplemental Material - The Role of Blood–Brain Barrier in Brain Cancer: From Pathophysiology to Therapeutic Approaches

Supplemental Material for The Role of Blood–Brain Barrier in Brain Cancer: From Pathophysiology to Therapeutic Approaches by Diala El Masri, Maryam Tlayss, Lea El Masri, Hashem Shehade, Jana Al Achcar, Tarek Baroud, Tatiana Al Zakhem, Jad El Masri and Wassim Abou-Kheir in Cancer Control.

Footnotes

ORCID iDs

Jana Al Achcar

Jad El Masri

Author Contributions

Conceptualization: EMD, TM, EML, EMJ.; Writing – original draft: EMD, TM, EML, SH, AAJ, AZT, BT.; Writing – review and editing: EMJ, AKW.; Supervision: AKW.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

Appendix

References

Zhang

Zhong

Cheng

. Global, regional, and national burden of brain and central nervous system cancer: a systematic analysis of incidence, deaths, and DALYS with predictions to 2040. Int J Surg. 2025;111(6):4033-4038. doi:10.1097/JS9.0000000000002359.

Ilic

. International patterns and trends in the brain cancer incidence and mortality: An observational study based on the global burden of disease. Heliyon. 2023;9(7):e18222. doi:10.1016/j.heliyon.2023.e18222.

Kuang

Jiang

, et al. Global Disease Burden, Trends, and Inequalities of Brain and Central Nervous System Cancers, 1990-2021: A Population-Based Study with Projections to 2036. World Neurosurg. 2025;198:123970. doi:10.1016/j.wneu.2025.123970.

Upton

Ung

George

Tsoli

Kavallaris

Ziegler

. Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy. Theranostics. 2022;12(10):4734-4752. doi:10.7150/thno.69682.

Baethge

Goldbeck-Wood

Mertens

. SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4(1):5. doi:10.1186/s41073-019-0064-8.

Kadry

Noorani

Cucullo

. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020;17:69. doi:10.1186/s12987-020-00230-3.

Alahmari

. Blood-Brain Barrier Overview: Structural and Functional Correlation. Neural Plast. 2021;2021:6564585. doi:10.1155/2021/6564585.

Daneman

Prat

. The Blood–Brain Barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412. doi:10.1101/cshperspect.a020412.

Weidle

Niewöhner

Tiefenthaler

. The Blood–Brain Barrier Challenge for the Treatment of Brain Cancer, Secondary Brain Metastases, and Neurological Diseases. Cancer Genomics & Proteomics. 2015;12(4):167-177.

10.

Sminia

Westerman

. Blood–brain barrier crossing and breakthroughs in glioblastoma therapy. Br J Clin Pharmacol. 2016;81(6):1018-1020. doi:10.1111/bcp.12881.

11.

Warth

Mittelbronn

Wolburg

. Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol. 2005;109(4):418-426. doi:10.1007/s00401-005-0984-x.

12.

Wang

Chen

, et al. Blood–Brain Barrier (BBB) Dysfunction in CNS Diseases: Paying Attention to Pericytes. CNS Neurosci Ther. 2025;31(5):e70422. doi:10.1111/cns.70422.

13.

Deeken

Löscher

. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13(6):1663-1674. doi:10.1158/1078-0432.CCR-06-2854.

14.

Laquintana

Trapani

Denora

Wang

Gallo

Trapani

. New strategies to deliver anticancer drugs to brain tumors. Expert Opin Drug Deliv. 2009;6(10):1017-1032. doi:10.1517/17425240903167942.

15.

Ahmed

Canney

Carpentier

Idbaih

. Overcoming the blood brain barrier in glioblastoma: Status and future perspective. Revue Neurologique. 2023;179(5):430-436. doi:10.1016/j.neurol.2023.03.013.

16.

Dithmer

Blasig

Fraser

Qin

Haseloff

. The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies. International Journal of Molecular Sciences. 2024;25(11):5601. doi:10.3390/ijms25115601.

17.

Arvanitis

Ferraro

Jain

. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26-41. doi:10.1038/s41568-019-0205-x.

18.

Sarin

Kanevsky

, et al. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells. J Transl Med. 2008;6:80. doi:10.1186/1479-5876-6-80.

19.

Triarico

Maurizi

Mastrangelo

Attinà

Capozza

Ruggiero

. Improving the Brain Delivery of Chemotherapeutic Drugs in Childhood Brain Tumors. Cancers (Basel). 2019;11(6):824. doi:10.3390/cancers11060824.

20.

Mikitsh

Chacko

. Pathways for small molecule delivery to the central nervous system across the blood-brain barrier. Perspect Medicin Chem. 2014;6:11-24. doi:10.4137/PMC.S13384.

21.

Pajouhesh

Lenz

. Medicinal Chemical Properties of Successful Central Nervous System Drugs. NeuroRx. 2005;2(4):541-553. doi:10.1602/neurorx.2.4.541.

22.

Pardridge

. The Blood-Brain Barrier: Bottleneck in Brain Drug Development. NeuroRx. 2005;2(1):3-14. doi:10.1602/neurorx.2.1.3.

23.

Demeule

Régina

Jodoin

, et al. Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier. Vascular Pharmacology. 2002;38(6):339-348. doi:10.1016/S1537-1891(02)00201-X.

24.

Agúndez

JAG

Jiménez-Jiménez

Alonso-Navarro

García-Martín

. Drug and xenobiotic biotransformation in the blood–brain barrier: a neglected issue. Front Cell Neurosci. 2014;8:335. doi:10.3389/fncel.2014.00335.

25.

Kural

Kaya Kocdogan

Şimşek

, et al. Glutathione S-Transferases and Cytochrome P450 Enzyme Expression in Patients with Intracranial Tumors: Preliminary Report of 55 Patients. Med Princ Pract. 2018;28(1):56-62. doi:10.1159/000494496.

26.

Roy

Lemelin

Blanchette

Poirier

Aldakhil

Fortin

. Expression of ABCB1, ABCC1 and 3 and ABCG2 in glioblastoma and their relevance in relation to clinical survival surrogates. J Neurooncol. 2022;160(3):601-609. doi:10.1007/s11060-022-04179-1.

27.

van Tellingen

Yetkin-Arik

de Gooijer

Wesseling

Wurdinger

de Vries

. Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resistance Updates. 2015;19:1-12. doi:10.1016/j.drup.2015.02.002.

28.

Agarwal

Hartz

AMS

Elmquist

Bauer

. Breast Cancer Resistance Protein and P-glycoprotein in Brain Cancer: Two Gatekeepers Team Up. Curr Pharm Des. 2011;17(26):2793-2802. doi:10.2174/138161211797440186.

29.

Breedveld

Pluim

Cipriani

, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res. 2005;65(7):2577-2582. doi:10.1158/0008-5472.CAN-04-2416.

30.

Straehla

Reardon

Wen

Agar

NYR

. The Blood-Brain Barrier: Implications for Experimental Cancer Therapeutics. Annu Rev Cancer Biol. 2023;7:265-289. doi:10.1146/annurev-cancerbio-061421-040433.

31.

Teubner

Meinl

Florian

Kretzschmar

Glatt

. Identification and localization of soluble sulfotransferases in the human gastrointestinal tract. Biochem J. 2007;404(Pt 2):207-215. doi:10.1042/BJ20061431.

32.

Ouzzine

Gulberti

Ramalanjaona

Magdalou

Fournel-Gigleux

. The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication. Front Cell Neurosci. 2014;8:349. doi:10.3389/fncel.2014.00349.

33.

Dubois

Campanati

Righy

, et al. Gliomas and the vascular fragility of the blood brain barrier. Front Cell Neurosci. 2014;8:418. doi:10.3389/fncel.2014.00418.

34.

Jain

. ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA. Cancer Cell. 2014;26(5):605-622. doi:10.1016/j.ccell.2014.10.006.

35.

Winkler

Kozin

Tong

, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6(6):553-563. doi:10.1016/j.ccr.2004.10.011.

36.

Argaw

Gurfein

Zhang

Zameer

John

. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A. 2009;106(6):1977-1982. doi:10.1073/pnas.0808698106.

37.

Huber

Witt

Hom

Egleton

Mark

Davis

. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. American Journal of Physiology-Heart and Circulatory Physiology. 2001;280(3):H1241-H1248. doi:10.1152/ajpheart.2001.280.3.H1241.

38.

Liebner

Fischmann

Rascher

, et al. Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol. 2000;100(3):323-331. doi:10.1007/s004010000180.

39.

Liu

Hendren

Qin

Shen

Liu

. Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem. 2009;108(3):811-820. doi:10.1111/j.1471-4159.2008.05821.x.

40.

Lischper

Beuck

Thanabalasundaram

Pieper

Galla

. Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. Brain Research. 2010;1326:114-127. doi:10.1016/j.brainres.2010.02.054.

41.

Rochfort

Collins

Murphy

Cummins

. Downregulation of Blood-Brain Barrier Phenotype by Proinflammatory Cytokines Involves NADPH Oxidase-Dependent ROS Generation: Consequences for Interendothelial Adherens and Tight Junctions. PLoS One. 2014;9(7):e101815. doi:10.1371/journal.pone.0101815.

42.

Hasegawa

Ushio

Hayakawa

Yamada

Mogami

. Changes of the blood-brain barrier in experimental metastatic brain tumors. Journal of Neurosurgery. 1983;59(2):304-310. doi:10.3171/jns.1983.59.2.0304.

43.

Lockman

Mittapalli

Taskar

, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16(23):5664-5678. doi:10.1158/1078-0432.CCR-10-1564.

44.

Pitz

Desai

Grossman

Blakeley

. Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neurooncol. 2011;104(3):629-638. doi:10.1007/s11060-011-0564-y.

45.

Taskar

Rudraraju

Mittapalli

, et al. Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer. Pharm Res. 2012;29(3):770-781. doi:10.1007/s11095-011-0601-8.

46.

Saleem

Searle

Kenny

, et al. Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Research. 2015;5(1):30. doi:10.1186/s13550-015-0103-5.

47.

Morikawa

Peereboom

Thorsheim

, et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro Oncol. 2015;17(2):289-295. doi:10.1093/neuonc/nou141.

48.

Wen

Tan

Dai

, et al. VEGF-mediated tight junctions pathological fenestration enhances doxorubicin-loaded glycolipid-like nanoparticles traversing BBB for glioblastoma-targeting therapy. Drug Deliv. 2017;24(1):1843-1855. doi:10.1080/10717544.2017.1386731.

49.

Das

Marsden

. Angiogenesis in Glioblastoma. N Engl J Med. 2013;369(16):1561-1563. doi:10.1056/NEJMcibr1309402.

50.

Kabraji

Lin

Xie

Winer

Zhao

. Drug resistance in HER2-positive breast cancer brain metastases: blame the barrier or the brain? Clin Cancer Res. 2018;24(8):1795-1804. doi:10.1158/1078-0432.CCR-17-3351.

51.

Lyle

Lockman

Adkins

, et al. Alterations in Pericyte Subpopulations are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer. Clin Cancer Res. 2016;22(21):5287-5299. doi:10.1158/1078-0432.CCR-15-1836.

52.

Kodack

Askoxylakis

Ferraro

, et al. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation. Sci Transl Med. 2017;9(391):eaal4682. doi:10.1126/scitranslmed.aal4682.

53.

Askoxylakis

Ferraro

Kodack

, et al. Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment. J Natl Cancer Inst. 2015;108(2):djv313. doi:10.1093/jnci/djv313.

54.

Brückener

El Bayâ

Galla

Schmidt

. Permeabilization in a cerebral endothelial barrier model by pertussis toxin involves the PKC effector pathway and is abolished by elevated levels of cAMP. Journal of Cell Science. 2003;116(9):1837-1846. doi:10.1242/jcs.00378.

55.

Desai

Leeper

Hynes

Gewertz

. Interleukin-6 Causes Endothelial Barrier Dysfunction via the Protein Kinase C Pathway. Journal of Surgical Research. 2002;104(2):118-123. doi:10.1006/jsre.2002.6415.

56.

Abbott

. Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat. 2002;200(6):629-638. doi:10.1046/j.1469-7580.2002.00064.x.

57.

McDannold

Vykhodtseva

Hynynen

. Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity. Phys Med Biol. 2006;51(4):793-807. doi:10.1088/0031-9155/51/4/003.

58.

Feng

Cen

Huang

, et al. Matrix Metalloproteinase-2 and -9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins. PLoS One. 2011;6(8):e20599. doi:10.1371/journal.pone.0020599.

59.

Rodríguez

Morrison

Overall

. Matrix metalloproteinases: What do they not do? New substrates and biological roles identified by murine models and proteomics. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2010;1803(1):39-54. doi:10.1016/j.bbamcr.2009.09.015.

60.

Zhu

Kang

, et al. Glioma grading by microvascular permeability parameters derived from dynamic contrast-enhanced MRI and intratumoral susceptibility signal on susceptibility weighted imaging. Cancer Imaging. 2015;15(1):4. doi:10.1186/s40644-015-0039-z.

61.

Xie

Zhang

, et al. Wnt signaling regulates MFSD2A-dependent drug delivery through endothelial transcytosis in glioma. Neuro Oncol. 2023;25(6):1073-1084. doi:10.1093/neuonc/noac288.

62.

Löscher

Potschka

. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family. NeuroRx. 2005;2(1):86-98. doi:10.1602/neurorx.2.1.86.

63.

Xia

Shen

Verma

. NF-κB, an active player in human cancers. Cancer Immunol Res. 2014;2(9):823-830. doi:10.1158/2326-6066.CIR-14-0112.

64.

Smith

Shimamura

Barbera

Bejcek

. NF-κB controls growth of glioblastomas/astrocytomas. Mol Cell Biochem. 2008;307(1):141-147. doi:10.1007/s11010-007-9593-4.

65.

Griffith

Sarkaria

Elmquist

. Efflux Limits Tumor Drug Delivery Despite Disrupted BBB. Trends Pharmacol Sci. 2021;42(6):426-428. doi:10.1016/j.tips.2021.03.001.

66.

Armulik

Genové

Betsholtz

. Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises. Developmental Cell. 2011;21(2):193-215. doi:10.1016/j.devcel.2011.07.001.

67.

Schwaninger

Sallmann

Petersen

, et al. Bradykinin Induces Interleukin-6 Expression in Astrocytes Through Activation of Nuclear Factor-κB. Journal of Neurochemistry. 1999;73(4):1461-1466. doi:10.1046/j.1471-4159.1999.0731461.x.

68.

Deli

Descamps

Dehouck

, et al. Exposure of tumor necrosis factor-α to luminal membrane of bovine brain capillary endothelial cells cocultured with astrocytes induces a delayed increase of permeability and cytoplasmic stress fiber formation of actin. Journal of Neuroscience Research. 1995;41(6):717-726. doi:10.1002/jnr.490410602.

69.

Zhang

Kundu

Feenstra

, et al. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas. Science Signaling. 2015;8(406):ra125. doi:10.1126/scisignal.aaa1690.

70.

Hobbs

Monsky

Yuan

, et al. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc Natl Acad Sci U S A. 1998;95(8):4607-4612. doi:10.1073/pnas.95.8.4607.

71.

Sarkaria

Parney

, et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018;20(2):184-191. doi:10.1093/neuonc/nox175.

72.

Oberoi

Parrish

Sio

Mittapalli

Elmquist

Sarkaria

. Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro Oncol. 2016;18(1):27-36. doi:10.1093/neuonc/nov164.

73.

Harmalkar

Sivaraman

Nada

, et al. Natural products as IL-6 inhibitors for inflammatory diseases: Synthetic and SAR perspective. Medicinal Research Reviews. 2024;44(4):1683-1726. doi:10.1002/med.22022.

74.

Kuitunen

Rönkä

ALK

Sonkajärvi

, et al. Blood-Brain Barrier Disruption (BBBD)-Based Immunochemotherapy for Primary Central Nervous System Lymphoma (PCNSL), Early Results of a Phase II Study. Cancers (Basel). 2023;15(4):1341. doi:10.3390/cancers15041341.

75.

Phoenix

Patmore

Boop

, et al. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell. 2016;29(4):508-522. doi:10.1016/j.ccell.2016.03.002.

76.

Martinez

Green

Borden

. Targeting diffuse midline gliomas: The promise of focused ultrasound-mediated blood-brain barrier opening. J Control Release. 2024;365:412-421. doi:10.1016/j.jconrel.2023.11.037.

77.

Quail

Joyce

. The Microenvironmental Landscape of Brain Tumors. Cancer Cell. 2017;31(3):326-341. doi:10.1016/j.ccell.2017.02.009.

78.

Jain

di Tomaso

Duda

Loeffler

Sorensen

Batchelor

. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8(8):610-622. doi:10.1038/nrn2175.

79.

Nduom

Yang

Merrill

Zhuang

Lonser

. Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms. J Neurosurg. 2013;119(2):427-433. doi:10.3171/2013.3.JNS122226.

80.

Xie

Lugano

, et al. Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing. JCI Insight. 2021;6(15):e150861. doi:10.1172/jci.insight.150861.

81.

Watkins

Robel

Kimbrough

Robert

Ellis-Davies

Sontheimer

. Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells. Nat Commun. 2014;5(1):4196. doi:10.1038/ncomms5196.

82.

Xie

Yang

, et al. Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier. Neuron. 2024;112(18):3089-3105.e7. doi:10.1016/j.neuron.2024.07.026.

83.

Jahnke

Doolittle

Muldoon

Neuwelt

. Implications of the blood-brain barrier in primary central nervous system lymphoma. Neurosurg Focus. 2006;21(5):E11. doi:10.3171/foc.2006.21.5.12.

84.

Calimeri

Marcucci

Corti

. Overcoming the blood-brain barrier in primary central nervous system lymphoma: a review on new strategies to solve an old problem. Annals of Lymphoma. 2021;5(0):20. doi:10.21037/aol-20-54.

85.

Galloni

Egnuni

Zahed Mohajerani

, et al. Brain endothelial cells promote breast cancer cell extravasation to the brain via EGFR-DOCK4-RAC1 signalling. Commun Biol. 2024;7(1):602. doi:10.1038/s42003-024-06200-x.

86.

McTyre

Scott

Chinnaiyan

. Whole brain radiotherapy for brain metastasis. Surg Neurol Int. 2013;4(Suppl 4):S236-S244. doi:10.4103/2152-7806.111301.

87.

Hart

Odé

Derieppe

MPP

, et al. Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies. Clin Transl Radiat Oncol. 2022;35:44-55. doi:10.1016/j.ctro.2022.04.013.

88.

Allen

Limoli

. Breaking barriers: Neurodegenerative repercussions of radiotherapy induced damage on the blood-brain and blood-tumor barrier. Free Radic Biol Med. 2022;178:189-201. doi:10.1016/j.freeradbiomed.2021.12.002.

89.

Lumniczky

Szatmári

Sáfrány

. Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain. Front Immunol. 2017;8:517. doi:10.3389/fimmu.2017.00517.

90.

Tournier

Langer

. Imaging the Activity of Efflux Transporters at the Blood-Brain Barrier in Neurologic Diseases: Radiotracer Selection Criteria. J Nucl Med. 2025;66(5):676-680. doi:10.2967/jnumed.124.269322.

91.

Ronaldson

Davis

. Blood-brain barrier transporters: a translational consideration for CNS delivery of neurotherapeutics. Expert Opin Drug Deliv. 2024;21(1):71-89. doi:10.1080/17425247.2024.2306138.

92.

Löscher

Potschka

. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005;6(8):591-602. doi:10.1038/nrn1728.

93.

Jackson

George

Lodge

, et al. The effect of regadenoson on the integrity of the human blood-brain barrier, a pilot study. J Neurooncol. 2017;132(3):513-519. doi:10.1007/s11060-017-2404-1.

94.

Grossman

Romo

, et al. Assessing the dose of regadenoson required to transiently alter blood-brain barrier integrity in patients with infiltrating gliomas. Neurooncol Adv. 2025;7(1):vdaf041. doi:10.1093/noajnl/vdaf041.

95.

Lim

Yee

Khang

. Nanoparticle-Based Combinational Strategies for Overcoming the Blood-Brain Barrier and Blood-Tumor Barrier. Int J Nanomedicine. 2024;19:2529-2552. doi:10.2147/IJN.S450853.

96.

Jourdain

Eyer

. Recent advances in liposomes and peptide-based therapeutics for glioblastoma treatment. J Control Release. 2024;376:732-752. doi:10.1016/j.jconrel.2024.10.037.

97.

Liu

Tan

Wang

. Applications of polymeric nanoparticles in drug delivery for glioblastoma. Front Pharmacol. 2024;15:1519479. doi:10.3389/fphar.2024.1519479.

98.

Bharadwaj

Roullin

Chain

. Crossing the blood–brain barrier: advances in dendrimer-based nanocarriers for central nervous system delivery. Nanoscale. 2025;17(40):23202-23227. doi:10.1039/D5NR02548F.

99.

Zhang

Kenrick

, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011;3(84):84ra44. doi:10.1126/scitranslmed.3002230.

100.

Mainprize

Lipsman

Huang

, et al. Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study. Sci Rep. 2019;9(1):321. doi:10.1038/s41598-018-36340-0.

101.

Carpentier

Stupp

Sonabend

, et al. Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial. Nat Commun. 2024;15(1):1650. doi:10.1038/s41467-024-45818-7.

102.

Woodworth

Anastasiadis

Ozair

, et al. Microbubble-enhanced transcranial focused ultrasound with temozolomide for patients with high-grade glioma (BT008NA): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology. 2025;26(12):1651-1664. doi:10.1016/S1470-2045(25)00492-9.

103.

Chu

Jablonska

Gao

, et al. Hyperosmolar blood-brain barrier opening using intra-arterial injection of hyperosmotic mannitol in mice under real-time MRI guidance. Nat Protoc. 2022;17(1):76-94. doi:10.1038/s41596-021-00634-x.

104.

Bartlett

Nagaraja

Griffith

, et al. Persistent Peri-Ablation Blood-Brain Barrier Opening After Laser Interstitial Thermal Therapy for Brain Tumors. Cureus. 2023;15(4):e37397. doi:10.7759/cureus.37397.

105.

Nielsen

Skjøth-Rasmussen

Larsen

, et al. Blood-brain barrier disruption following MR-guided laser interstitial thermal therapy. Neuro Oncol Adv. 2025;7(1):vdaf148. doi:10.1093/noajnl/vdaf148.

106.

Bottens

Yamada

. Cell-Penetrating Peptides (CPPs) as Therapeutic and Diagnostic Agents for Cancer. Cancers (Basel). 2022;14(22):5546. doi:10.3390/cancers14225546.

107.

Ghorai

Deep

Magoo

Gupta

. Cell-Penetrating and Targeted Peptides Delivery Systems as Potential Pharmaceutical Carriers for Enhanced Delivery across the Blood-Brain Barrier (BBB). Pharmaceutics. 2023;15(7):1999. doi:10.3390/pharmaceutics15071999.

108.

Dmello

Brenner

Piccioni

, et al. Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma. Neurooncol Adv. 2024;6(1):vdae186. doi:10.1093/noajnl/vdae186.

109.

Régina

Demeule

Ché

, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol. 2008;155(2):185-197. doi:10.1038/bjp.2008.260.

110.

Brown

Alizadeh

Starr

, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. New England Journal of Medicine. 2016;375(26):2561-2569. doi:10.1056/NEJMoa1610497.

111.

Nassiri

Patil

Yefet

, et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat Med. 2023;29(6):1370-1378. doi:10.1038/s41591-023-02347-y.

112.

Mehta

Sonabend

Bruce

. Convection-Enhanced Delivery. Neurotherapeutics. 2017;14(2):358-371. doi:10.1007/s13311-017-0520-4.

113.

Rolfe

Dadario

Canoll

Bruce

. A Review of Therapeutic Agents Given by Convection-Enhanced Delivery for Adult Glioblastoma. Pharmaceuticals (Basel). 2024;17(8):973. doi:10.3390/ph17080973.

114.

Sperring

Argenziano

Savage

, et al. Convection-enhanced delivery of immunomodulatory therapy for high-grade glioma. Neurooncol Adv. 2023;5(1):vdad044. doi:10.1093/noajnl/vdad044.