Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment

Abstract

Convection-enhanced delivery (CED) is a technique designed to deliver drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the brain, has made it a promising drug delivery method for the treatment of primary brain tumors. A number of clinical trials utilizing CED of various therapeutic agents have been conducted to treat patients with supratentorial high-grade gliomas. Significant responses have been observed in certain patients in all of these trials. However, the insufficient ability to monitor drug distribution and pharmacokinetics hampers CED from achieving its potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma (DIPG) treatment is appealing because this tumor is compact and has no definitive treatment. The safety of brainstem CED has been established in small and large animals, and recently in early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG treatment will come from several directions including: choosing the right agents for infusion; developing better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence; and better understanding and control of drug distribution, clearance and time sequence. CED-based therapies for DIPG will continue to evolve with new understanding of the technique and the disease.

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

“…Notably, it plays an important role in promoting neuron regeneration in some neurodegenerative diseases, such as Alzheimer's disease and Parkinson's [11–13]. It could also improve memory and ameliorate depressive status [14, 15]. Moreover, it displayed a therapeutic efficacy in metabolic diseases on the basis of TrkB signaling to inhibit obesity [16].…”

Convection-Enhanced Delivery

“…Many of the promising therapeutics for central nervous system (CNS) diseases are large molecules, their size preventing their diffusion through the BBB and the brain interstitium [34]. Those therapies that are able to penetrate the CNS often cannot reach sufficiently high concentrations, as the required systemic concentrations are unacceptably toxic [11].…”

“…The most effective agents for CED are those that are not well transported across the BBB, as they will not travel from the interstitium back across the BBB into systemic circulation, thus minimizing systemic toxicity [18]. In addition, CED is less likely to cause toxicity to surrounding brain tissue, as the concentration fall off at the border is steep [11]. Fig.…”

“…Multiple port catheters provide an appealing delivery mechanism, as the multiple ports may provide better pressure output, thus improving the volume of distribution achieved [11]. However, an obstacle in the successful usage of multiport catheters CED is obtaining predictable flows from all of the ports.…”

“…Yet, a major challenge for the optimization of CED, and the investigation of whether or not efficacy of the treatments was limited by poor delivery, is the lack of ability to monitor and confirm adequate in vivo drug distribution [34]. This has led the possibility of discarding potentially beneficial agents as useless [11,60,120]. There is a need to monitor the tissue concentration of a given particle in vivo.…”