Halloysite Nanotube Vehicles for Drug Delivery Through a Model Blood–Brain Barrier

Abstract

Epilepsy treatment requires anti-seizure medical formulations; available medications have various painful side effects and penetrate the brain–blood barrier poorly. A promising method is the use of natural clay nanocontainers for drug delivery through this membrane barrier. Halloysites (Hly) are biocompatible, 50-nm diameter tubes with a positively charged, hollow inner lumen and negatively charged outer shell and are available naturally. These characteristics enable them to be versatile as drug loaded ‘nano-torpedoes’ effectively penetrating cell membranes. The endothelial cells are a major cell type in the blood–brain barrier that provides for the selective permeability separating the circulating blood and allowing only the passage of glucose, water, and amino acids, but not traditional drug formulations. Nanotubes encapsulating rhodamine isothiocyanate and ionomycin penetration through the rat-brain microvascular endothelial cells followed by a prolonged 24-h drug release was demonstrated. A model membrane was set up across 0.4-μm-pore polystyrene transwell supports covered by seeding endothelial and astrocyte cells to mimic the blood–brain barrier in vivo. This barrier demonstrated a dual permeation mechanism (inter-cell accumulation and through-passing) for loaded Hlys, exploiting the potential of this nanoclay in the trans-membrane delivery of drugs. Use of Hly nanotubes as drug carriers to penetrate the brain microvascular endothelial barrier and to deliver the payload displayed a new approach for the treatment of brain diseases such as epilepsy.

Recent Advances of Halloysite Nanotubes in Biomedical Applications

“…Notably, the harnessing of HNTs has proffered a novel modality, envisaged as a "nano torpedo" mechanism, ingeniously transgressing endothelial cellular barriers, thereby culminating in the adept and protracted dispensation of encapsulated moieties (Table 6). [152] Zeraatpishe's, Malakinezhad's, and Abdouss's group embarked upon investigations concerning the tailored modification of HNTs as carriers for phenytoin sodium, with a focus on the potential for controlled release and enhanced loading efficacy. Phenytoin, a widely employed anti-epileptic agent, is associated with an array of commonplace adverse effects encompassing nausea, abdominal discomfort, anorexia, diminished coordination, hypertrichosis, and gingival hypertrophy.…”

“…Notably, the harnessing of HNTs has proffered a novel modality, envisaged as a “nano torpedo” mechanism, ingeniously transgressing endothelial cellular barriers, thereby culminating in the adept and protracted dispensation of encapsulated moieties ( Table 6 ). [ 152 ]…”

Architectural design of core–shell nanotube systems based on aluminosilicate clay

“…We introduced the term “nano-torpedo” for such halloysite intracellular penetration assuming easier penetration of the loaded nanotubes through cell membranes and skin in a perpendicular position, when the efficient halloysite cross-section may be compared with 50 nm diameter spherical nanoparticles. 55 Practically, for medical skin applications this may be performed by halloysite-cream massaging.…”

Nanoclays in medicine: a new frontier of an ancient medical practice

“…139 In a recent work, Lvov and co-workers employed HNTs as drug transporters to cross the brain microvascular endothelial barriers and prolong incremental payload release. 140,141 HNTs can significantly improve the efficiency of bioactive molecules that have low solubility in water. For instance, HNTs were also successfully loaded with resveratrol, a drug with limited water solubility known for antineoplastic and antioxidant properties.…”