Drug penetration in pediatric brain tumors: Challenges and opportunities

Abstract

Larger clinical trial enrollments and a greater understanding of biological heterogeneity have led to improved survival rates for children diagnosed with brain tumors in the last 50 years. However, reducing long‐term morbidities and improving survival rates of high‐risk tumors remain major challenges. Chemotherapy can reduce tumor burden, but effective drug penetration at the tumor site is limited by barriers in the route of drug administration and within the tumor microenvironment. Bioavailability of drugs is impeded by the blood‐brain barrier, plasma protein binding, and structural components by the tumor including the matrix and vasculature contributing to increased interstitial fluid pressure, hypoxia, and acidity. Designing drug delivery systems to circumvent these barriers could lead to improved drug penetration at the tumor site and reduce adverse systemic side effects. In this review, we expand on how systemic and local barriers limit drug penetration and present potential methods to enhance drug penetration in pediatric brain tumors.

Development of an In Vitro Test for the Optimization of Drug Diffusion in Pediatric Solid Tumors

“…Over the past century, we have made strides in developinng chemotheraputic drugs. However, there remains a gap in having the pre-clinical cytotoxic sucesses translate to patient survival [3, 19]. Through this pilot experiment compairing the distribution of DOX susposended in solution and DOX loaded into a a 10% starch hydrogel we have shown that this testing platform allows for the monitoring of diffusion.…”

“…Among childhood cancer survivors, 99% develop chronic conditions from the toxicity of the chemotherapy used to treat their initial malignancy [1][2][3][4]. These chronic conditions can be severe, disabling, or even life-threatening and can manifest years after completion of therapy.…”

“…However, due to the physiological limitations of systemically delivered drugs to CNS tumors there is a need to develop novel delivery methods [3]. To improve treatment efficacy and prevent longterm and late-effects in pediatric cancer patients, there are many groups working to develop novel local drug delivery systems to treat solid tumors [6].…”

“…Current standards for determining chemotherapy dosage to treat solid tumor malignancies of pediatric patients is based on several factors, including the patient’s surface area, age, and weight [5]. However, due to the physiological limitations of systemically delivered drugs to CNS tumors there is a need to develop novel delivery methods [3]. To improve treatment efficacy and prevent long-term and late-effects in pediatric cancer patients, there are many groups working to develop novel local drug delivery systems to treat solid tumors [6].…”

Establishing Novel Doxorubicin-Loaded Polysaccharide Hydrogel for Controlled Drug Delivery for Treatment of Pediatric Brain Tumors

“…Chemotherapies administered orally and intravenously are part of the standard of care treatment for most pediatric tumors, with pediatric patients diagnosed with medulloblastoma treated with mostly, if not only, chemotherapy [2][3][4]. Sadly, barriers to the systemic route of administration limit drug penetration in the tumor microenvironment and include but are not limited to plasma protein binding, the blood-brain barrier, and structural and mechanical components within the tumor microenvironment all hindering the potential of therapeutic effect on the cancer cells [5][6][7][8]. In treating brain tumors, nearly 98% of small molecules and 100% of large molecules do not cross the blood-brain barrier, defining the blood-brain barrier as the most significant physical obstacle to treating brain tumors [9,10].…”