Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma

Abstract

Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

“…Indeed scientific literature has previously highlighted the therapeutic potential of Tf‐based NP transport across the BBB. [ 22,26–28 ] Tf can also be expressed by brain microcapillaries and other ECs [ 47 ] such as those of liver capillaries and might play an important role for NP transport across liver‐specific microvessels. Further studies can involve the surface‐functionalization of NPs with other brain‐specific ligands, which can further validate and optimize the BBB model for preclinical screening of nanotherapeutics.…”

“…[ 12,24,25 ] Notably, TfR‐targeting NPs have been found to improve drug delivery into brain tissue. [ 22,26–28 ] Despite evidence suggesting that NPs with specific size and surface composition can accumulate in the brain, the clinical translation of such approaches has not been achieved successfully.…”

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review

“…Vijayakumar et al [127] reported that the biological half-life, passive brain targeting, and antiglioma cytotoxicity of RES were significantly enhanced by using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated liposomes (RES-TPGS-Lipo). Guo et al [128] modified the surface of RES-loaded polyethylene glycol-polylactic acid nanoparticles with transferrin moieties (Tf-NP-RES), which led to increased intracellular uptake, higher cytotoxicity, and apoptosis of rat C6 and human U-87 MG GBM cell lines in vitro compared to free RES and nanoparticles without transferrin. Since transferrin receptors are exclusively expressed in brain capillaries [129], the accumulation of Tf-NP-RES in tumor tissue, decreased tumor volume, and prolonged survival were shown in rats bearing C6 orthotopic glioma.…”

Peptide based drug delivery systems to the brain

“…Rassu et al (2017) reported that a positive surface charge on NPs ensures their mucoadhesion [183]. On the other hand, NP formulations have been reported for brain delivery with zeta potentials between −1 and −45 mV [184][185][186]. Different shapes of NPs are shown in figure 5.…”