Transferrin receptors-targeting nanocarriers for efficient targeted delivery and transcytosis of drugs into the brain tumors: a review of recent advancements and emerging trends

Abstract

Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood-brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.

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.…”

“…Additionally, it has been shown that surface modification of NPs with ligands for specific binding to BBB cells enhances NP accumulation in the brain through receptor‐mediated endocytosis. [ 17–20 ] Among these, [ 21,22 ] holo‐transferrin (Tf) has been widely studied as it binds to the Tf receptor (TfR), which is more abundantly expressed by brain ECs compared to ECs of other blood vessels, [ 21,23 ] and overexpressed by brain tumor vasculature. [ 12,24,25 ] Notably, TfR‐targeting NPs have been found to improve drug delivery into brain tissue.…”

“…[ 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.…”

Transferrin anchored solid lipid nanoparticles for brain cancer treatment

“…TR are selectively ) expressed on the luminal membrane of brain endothelial cells and also on the brain cancer cells ( Trowbridge Li et al, 2016, andOmary, 1981). Therefore, TfR were used to increase the uptake of SLN across the brain endothelial cells and also in brain tumor cells (Choudhury et al, 2018, Yang et al, 2008. SLN are the most promising carrier for the brain delivery of cytotoxic drugs due to its biocompatibility and biodegradability (Soni et al, 2017;Shankar et al, 2018).…”

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

“…With the increasing development of nanomaterials, receptor‐mediated transcytosis (RMT) has become one of the most promising protocols to overcome the BBB through receptors that are highly expressed on BBB endothelial cells, among which transferrin receptor (TfR) is a promising candidate . Moreover, TfR is also present in substantial quantities on GBM cells due to their high proliferation rate and iron demand . Correspondingly, transferrin (Tf), an important glycoprotein in the human body, has been extensively employed to traverse the BBB owing to its ability to combine with TfR to form the Tf‐TfR complex .…”