Overcoming the Blood-Brain Barrier in Chemotherapy Treatment of Pediatric Brain Tumors

Abstract

Pediatric brain tumors are most common cancers in childhood and among the leading causes of death in children. Chemotherapy has been used as adjuvant (i.e. after) or neoadjuvant (i.e. before) therapy to surgery and radiotherapy for the management of pediatric brain tumors for more than four decades and gained more attention in the recent two decades. Although chemotherapy has demonstrated its effectiveness in the management of some pediatric brain tumors, failure or inactiveness of chemotherapy is commonly met in the clinics and clinical trials. Some of these failures might be attributed to the blood-brain barrier (BBB), limiting the penetration of systemically administered chemotherapeutics into pediatric brain tumors. Therefore, various strategies have been developed and used to address this issue. Herein, we review different methods reported in the literature to circumvent the BBB for enhancing the present of chemotherapeutics in the brain to treat pediatric brain tumors.

Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death

“…Medulloblastoma is a significant cause of cancer-related morbidity and mortality in children [ 1 ]. Its standard-of-care consists of surgical resection, followed by radiotherapy and chemotherapy, which cause neurocognitive side effects [ 2 – 4 ]. Medulloblastoma molecular profiling delineated four subgroups, by consensus termed wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 [ 5 – 7 ].…”

Experimental Therapeutic Trial Design for Pediatric Brain Tumors

“…New mechanisms to overcome the blood brain barrier have been identified through research, with some being included in recent clinical trials. 57 One method of bypassing the blood brain barrier is through direct administration of the drug into the central nervous system, through intrathecal or intraommaya administration. Unfortunately, delivery of the medication directly into the central nervous system can lead to increased toxicity and uncertain drug distribution, and this has not improved treatment of intraparenchymal tumors.…”

“…Agents that disrupt the blood brain barrier through osmotic changes (mannitol) or vasoactive substances (ie, lobradimil) have been used to help improve delivery of therapeutic agents into the tumor, with variable success. 57 Finally, research into the utilization of very small carrier compounds (eg, nanoparticles) is ongoing and, although this is still being developed in adult patients, can soon provide a new method of drug delivery in pediatric patients. 58 Developmental Therapeutic Trial Design Pediatric brain tumor clinical trial development is complex and requires a team of collaborators, typically including personnel to oversee protocol coordination, statistical design, safety oversight, as well as the scientific study team.…”

Targeting tumor metastases: Drug delivery mechanisms and technologies

“…Thus, in colorectal carcinoma, the mesenteric circulation from the bowels and the permissiveness of the liver capillary sinusoids are thought to favor liver metastasis [79, 80]. However, to cross the blood-brain barrier (BBB) and metastasize to the brain, cancer cells require specialized mechanisms [81-85]. Thus, therapeutic agents could conceivably be designed to target these organ systems via mimicry of the mechanisms utilized by cancer cells during the metastatic process (Figure 2).…”