Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

Abstract

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…However, this is not the case for highly infiltrative tumors, like DIPG that use the existing brain vasculature with a largely intact BBB (107). Indeed, especially at diagnosis, DIPG shows limited to no contrast enhancement after intravenous delivery of gadolinium, as opposed to GBM tumors that harbor highly neovascular regions (108). Below, we describe therapies currently in clinical trials, as well as new agents still under pre-clinical evaluation that have the potential to target DIPG invasion and briefly discuss strategies for effective delivery across the BBB.…”

Ketogenic diet treatment in recurrent diffuse intrinsic pontine glioma in children: A safety and feasibility study

“…Chemotherapeutic strategies have been tested, but it proves to be difficult to get therapeutic agents across the blood–brain barrier (BBB) without major toxic side effects . Moreover, even after trespassing the BBB, the level of drug delivery may vary greatly due to inconsistent interstitial fluid pressure within the tumor …”

“…4 Moreover, even after trespassing the BBB, the level of drug delivery may vary greatly due to inconsistent interstitial fluid pressure within the tumor. 5,6 Abbreviations: CT, chemotherapy; DIPG, diffuse intrinsic pontine glioma; GI, gastrointestinal; GMFCS, gross motor functioning classification system; KD, ketogenic diet; LQ, liquid formula; MCT, medium chain triglycerides; OSR, overall survival rate; RT, fractionated radiotherapy; TMZ, temozolomide; VOOK, Ouders van een Overleden Kind This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Glioblastoma cells use glucose as their main source of energy, which is derived from the anaerobic glycolytic pathway.…”

Diffuse Intrinsic Pontine Glioma

“…In DIPG, local and distant metastases in the brain or spine are seen in 13-17% patients. Therefore, in situations where disseminated disease is present, CED therapy alone, directed toward the primary tumor site, will be inadequate and should be complemented with therapies for the secondaries [28,32].…”