**5.1. The blood–brain barrier**

The infiltrative nature of DIPG makes effective therapy extremely difficult and characterizes this tumor as one of the most, if not the most challenging childhood cancer. The successful and efficient delivery of effective therapy to the DIPG tumor is the major challenge that contrib‐ utes to the poor treatment options in children with this disease. For the effectiveness of a therapy, the agent needs to have certain important characteristics: (A) it has to be active and reach its molecular target in the tumor cell in adequate concentrations, (B) it has to reach the target for an adequate amount of time, and (C) the tumor cells need to be sensitive to the compound. Many factors can affect the level of a drug in the brain tumor site, including the concentration of this drug in the bloodstream, amount of protein to tissue binding, and the degree of central nervous system (CNS) penetration [8]. In DIPG, the BBB is often intact and has the ability to restrict the delivery of chemotherapeutic agents. Even for drugs that are capable of crossing the cerebral capillary bed, it is difficult to achieve optimal concentrations due to systemic toxicity.

Strategies have been used to overcome the BBB and to direct those agents to the specific anatomic region or tumor mass, reducing the disturbance of normal neurological functions. Among these strategies are the temporary disruption of the BBB, modification of drugs to enhance their ability to permeate the BBB, and local delivery methods such as the convec‐ tion-enhanced delivery (CED) to deliver drugs directly into the extracellular space [38,56].

Also known as interstitial infusion, CED is a technique designed to deliver high concentra‐ tions of drugs directly into the tumor, allowing intratumoral injection of novel therapeutic agents. The use of hydrostatic pressure allows the distribution of a homogeneous concentra‐ tion of molecules over large distances by displacing extracellular fluid with the infusate. Several clinical trials in patients with neurodegenerative disorders and malignant gliomas have been done with the use of CED, including ongoing phase I/II clinical trials in DIPG, and published studies have shown CED in DIPG to be feasible and safe [57–60]. The use of CED into murine brainstem had been well tolerated by mice with and without brainstem tumors, increasing median survival in preclinical models [38]. However, it is necessary to develop novel therapeutic agents for delivery via CED and also to improve the technique of CED in order to provide a better outcome and a new hope of treatment for children with DIPG.
