Advancements in drug delivery methods for the treatment of brain disease

Abstract

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.

Breaking barriers: exploring mechanisms behind opening the blood–brain barrier

“…Cellular response varies depending on the strength of the applied electric field. Irreversible electroporation uses high electric fields (> 500 V/cm) leading to irreversible membrane permeabilisation and subsequent cell death, a common method in Glioblastoma tumour ablation [ 118 , 119 ]. Here, an intracranial needle electrode is placed in the target tissue and the outer surface electrode placed on the skin or skull.…”

“…4 b), leading to enhanced electroporation in the surrounding tissue (Fig. 4 c) [ 119 ] . The strongest electric field is found surrounding the electrode region, causing irreversible electroporation.…”

“…b Schematic needle insertion in HFIRE induced BBB disruption and c post-contrast MRI images after gadolinium enhancement surrounding tumour area after treatment. Figures taken from Partridge et al [ 119 ]. d MRI analysis of control brains in electroporation treatment with visible needle path (white arrow) obtained 30 min post treatment and e Histopathology of brain region with minimal bleeding along electrode insertion path.…”

Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia

“…A significant obstacle to pharmaceutical stroke treatments, however, is the presence of the blood–brain barrier (BBB), which limits drug access to the central nervous system (CNS) [ 39 , 40 ]. Only small, lipid-soluble molecules with a molecular weight < 400 Da can passively diffuse through the BBB via the transcellular lipophilic pathway without expending metabolic energy [ 41 ].…”

Enhancing Nose- To- Brain Delivery of Piribedil: Development of a Nanosuspension Dispersed in Nasal in-Situ Gelling System

“…Poor penetration of the BBB remains a substantial obstacle to the approval of over 90% of drugs targeting the CNS [1,2]. Various methods have been explored to improve brain drug delivery, including invasive procedures like injecting drugs directly into the brain's ventricles or using implanted devices, each with its effectiveness and risks [3,4]. Hence, there is a requirement for innovative drug delivery strategies capable of crossing the BBB without causing harm to brain cells, and this is where nanomedicine comes into play.…”