A Noninvasive Gut‐to‐Brain Oral Drug Delivery System for Treating Brain Tumors

Abstract

head shaving, general anesthesia, installation of multielement extracranial systems, and others) that are needed for focused ultrasound treatments and their potential adverse thermal/mechanical effects on healthy tissues limit their clinical use. [3] Oral chemotherapy has the advantages of avoiding the pain and contamination that are frequently caused by injections and allows patients to take their drugs at home, favoring their quality of life. Unfortunately, most orally administered anticancer therapeutics fail to reach the intracerebral pathological regions because of two major biological barriers, the intestinal epithelial barrier (IEB) and the BBB, which are located between the gut and the brain. The IEB is an important physical barrier against pathogens and toxins in the digestive tract, whereas the BBB protects the brain from harmful substances in the bloodstream. [4] These two biological barriers together markedly limit the accumulation of therapeutic molecules at the brain tumor site when a drug is administered via the oral route, posing a great challenge to the use of conventional medications.Most orally administered drugs fail to reach the intracerebral regions because of the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), which are located between the gut and the brain. Herein, an oral prodrug delivery system that can overcome both the IEB and the BBB noninvasively is developed for treating gliomas. The prodrug is prepared by conjugating an anticancer drug on β-glucans using a disulfide-containing linker. Following oral administration in glioma-bearing mice, the as-prepared prodrug can specifically target intestinal M cells, transpass the IEB, and be phagocytosed/ hitchhiked by local macrophages (Mφ). The Mφ-hitchhiked prodrug is transported to the circulatory system via the lymphatic system, crossing the BBB. The tumor-overexpressed glutathione then cleaves the disulfide bond within the prodrug, releasing the active drug, improving its therapeutic efficacy. These findings reveal that the developed prodrug may serve as a gut-to-brain oral drug delivery platform for the well-targeted treatment of gliomas.

Advances in Nanomedicines for Interaction with the Intestinal Barrier

“…Reproduced with permission. [108] Copyright 2021, Wiley-VCH. [71] Copyright 2019, American Chemical Society.…”

“…Through these strategies, the amount of temozolomide measured in the brain tumor was around five times more than that detected in the free drug‐treated group ( Figure 9 ). [ 108 ] Finally, phospholipid‐based Labrasol/Pluronic F68‐modified nanomicelles have also been prepared for the safe delivery of flavonoids into the brain tumor microenvironment. [ 109 ]…”

“…After oral administration, the prodrug NPs cross the intestinal barrier through M cells, after which they are endocytosed by macrophages, and then transported into the brain where they provide anticancer therapy. Reproduced with permission [108]. Copyright 2021, Wiley-VCH.…”

The Role of Hitchhiking in Cancer Therapeutics—A Review

“…[18] The utilization of human circulatory cells in cellular hitchhiking magnifies the overall biological effect of therapeutic nanosystems (Figure 1). [19] Erythrocytes, [9,38,39] monocytes and macrophages, [40][41][42] and T cells [43] are the most widely exploited hitchhiked circulatory cells.…”

Effect of the disulfide bond and polyethylene glycol on the degradation and biophysicochemical properties of polyurethane micelles

“…35 This discrepancy provides an incentive to develop GSH-cleavable linkers to achieve precision therapy. 36–38 Many drug delivery vehicles containing disulfide bonds have been extensively explored recently for the precise spatiotemporal drug 39,40 and immunostimulatory agent release 41 or deplete GSH to amplify oxidative stress, 42 achieving cytoplasmic delivery, enhancing the exposure of therapeutic agents, and reducing systemic side effects. 43,44…”