Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

Parodi, Alessandro; Rudzińska, Magdalena; Deviatkin, Andrei A.; Soond, Surinder M.; Baldin, Alexey V.; Zamyatnin, Andrey A.

doi:10.3390/pharmaceutics11050245

Cited by 58 publications

(34 citation statements)

References 153 publications

(173 reference statements)

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“…First, the traditional approach consists of the injection of a hyperosmotic solution before the administration of the therapeutics that induce endothelial cell shrinkage and increased vascular leakage in the brain parenchyma. 81,82 Second, focused ultrasound allows for a substantial increase in BBB permeability via the application of fine-tuned acoustic pressure to the brain that could be utilized for therapeutic delivery. Focused ultrasound produced more desirable results in breaching the BBB when used in combination with microbubbles.…”

Section: Role Of Tgf-bmentioning

confidence: 99%

“…This application is beneficial in delivering large molecules and nanoparticles, but it is limited to a small area of the brain. 81,86,87 Lastly, the convection-enhanced delivery approach (CED) allows for intratumoral local drug injection via a catheter. Despite the invasive nature of the approach, CED has documented efficacy and safety with several therapeutic agents.…”

Section: Role Of Tgf-bmentioning

confidence: 99%

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Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Al‐kharboosh

Lara-Velazquez

Grewal

et al. 2020

Mayo Clinic Proceedings: Innovations, Quality & Outcomes

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Glioblastoma is the most aggressive malignant primary brain tumor, with a dismal prognosis and a devastating overall survival. Despite aggressive surgical resection and adjuvant treatment, average survival remains approximately 14.6 months. The brain tumor microenvironment is heterogeneous, comprising multiple populations of tumor, stromal, and immune cells. Tumor cells evade the immune system by suppressing several immune functions to enable survival. Gliomas release immunosuppressive and tumorsupportive soluble factors into the microenvironment, leading to accelerated cancer proliferation, invasion, and immune escape. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, or umbilical cord are a promising tool for cell-based therapies. One crucial mechanism mediating the therapeutic outcomes often seen in MSC application is their tropism to sites of injury. Furthermore, MSCs interact with host immune cells to regulate the inflammatory response, and data points to the possibility of using MSCs to achieve immunomodulation in solid tumors. Interleukin 1b, interleukin 6, tumor necrosis factor a, transforming growth factor b, and stromal cellederived factor 1 are notably up-regulated in glioblastoma and dually promote immune and MSC trafficking. Mesenchymal stem cells have widely been regarded as hypoimmunogenic, enabling this cell-based administration across major histocompatibility barriers. In this review, we will highlight (1) the bidirectional communication of glioma cells and tumorassociated immune cells, (2) the inflammatory mediators enabling leukocytes and transplantable MSC migration, and (3) review preclinical and human clinical trials using MSCs as delivery vehicles. Mesenchymal stem cells possess innate abilities to migrate great distances, cross the blood-brain barrier, and communicate with surrounding cells, all of which make them desirable "Trojan horses" for brain cancer therapy.

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Section: Role Of Tgf-bmentioning

confidence: 99%

Section: Role Of Tgf-bmentioning

confidence: 99%

Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Al‐kharboosh

Lara-Velazquez

Grewal

et al. 2020

Mayo Clinic Proceedings: Innovations, Quality & Outcomes

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“…This natural strategy exploits the various transporters and receptors expressed at the BBB, as well as the physiological properties of the BBB (e.g., charge and lipid composition) ( Figure 2) [41][42][43]. These translocation mechanisms are fundamental for the uptake of essential substances to maintain brain homeostasis.…”

Section: Physiological Approachmentioning

confidence: 99%

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

et al. 2020

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The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

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“…to reach the brain parenchyma at an efficient dose [12,[16][17][18]. Indeed, the cytochrome P450 (CYP) enzymes are involved in the metabolism of many endogenous (e.g.…”

Section: Introductionmentioning

confidence: 99%

Development of a human in vitro blood–brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance

Deligne

Hachani

Duban-Deweer

et al. 2020

Fluids Barriers CNS

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Background: Pediatric diffuse intrinsic pontine glioma (DIPG) represents one of the most devastating and lethal brain tumors in children with a median survival of 12 months. The high mortality rate can be explained by the ineligibility of patients to surgical resection due to the diffuse growth pattern and midline localization of the tumor. While the therapeutic strategies are unfortunately palliative, the blood-brain barrier (BBB) is suspected to be responsible for the treatment inefficiency. Located at the brain capillary endothelial cells (ECs), the BBB has specific properties to tightly control and restrict the access of molecules to the brain parenchyma including chemotherapeutic compounds. However, these BBB specific properties can be modified in a pathological environment, thus modulating brain exposure to therapeutic drugs. Hence, this study aimed at developing a syngeneic human blood-brain tumor barrier model to understand how the presence of DIPG impacts the structure and function of brain capillary ECs. Methods: A human syngeneic in vitro BBB model consisting of a triple culture of human (ECs) (differentiated from CD34 +-stem cells), pericytes and astrocytes was developed. Once validated in terms of BBB phenotype, this model was adapted to develop a blood-brain tumor barrier (BBTB) model specific to pediatric DIPG by replacing the astrocytes by DIPG-007,-013 and-014 cells. The physical and metabolic properties of the BBTB ECs were analyzed and compared to the BBB ECs. The permeability of both models to chemotherapeutic compounds was evaluated. Results: In line with clinical observation, the integrity of the BBTB ECs remained intact until 7 days of incubation. Both transcriptional expression and activity of efflux transporters were not strongly modified by the presence of DIPG. The permeability of ECs to the chemotherapeutic drugs temozolomide and panobinostat was not affected by the DIPG environment. Conclusions: This original human BBTB model allows a better understanding of the influence of DIPG on the BBTB ECs phenotype. Our data reveal that the chemoresistance described for DIPG does not come from the development of a "super BBB". These results, validated by the absence of modification of drug transport through the BBTB ECs, point

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Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

Cited by 58 publications

References 153 publications

Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Inflammatory Mediators in Glioma Microenvironment Play a Dual Role in Gliomagenesis and Mesenchymal Stem Cell Homing: Implication for Cellular Therapy

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

Development of a human in vitro blood–brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance

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