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Acid‐Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery
Author(s) -
Ruan Shaobo,
Qin Lin,
Xiao Wei,
Hu Chuan,
Zhou Yang,
Wang Ranran,
Sun Xing,
Yu Wenqi,
He Qin,
Gao Huile
Publication year - 2018
Publication title -
advanced functional materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.069
H-Index - 322
eISSN - 1616-3028
pISSN - 1616-301X
DOI - 10.1002/adfm.201802227
Subject(s) - transcytosis , blood–brain barrier , endocytosis , biophysics , glioma , parenchyma , transferrin receptor , drug delivery to the brain , microbiology and biotechnology , receptor , endothelium , chemistry , biochemistry , biology , cancer research , endocrinology , botany , central nervous system
Receptor mediated transcytosis (RMT) is a common mechanism used for nanotherapeutics to traverse the blood–brain barrier (BBB). However, the transcytosis of ligand modified nanoparticles via RMT is likely to be trapped within brain capillary endothelial cells due to the high binding affinity of ligand with receptors, which greatly reduces the amount of nanoparticles across BBB. Here, P‐aminophenyl‐α‐D‐mannopyranoside (MAN) decorated doxorubicin‐loaded dendrigraft poly‐l‐lysine with acid‐cleavable transferrin (Tf) coating outside (DD‐MCT) is proposed. The DD‐MCT is engineered to specifically recognize the Tf receptor (TfR) on the luminal side of BBB endothelium. Then the DD‐MCT undergoes an acid‐responsive cleavage of Tf, leading to the separation of MAN‐decorated DGL‐DOX (DD‐M) from the Tf–TfR complex in endo/lysosomes. The detached DD‐M is more prone to escape from endo/lysosomes and can further be exocytosed into brain parenchyma via the mediation of glucose transporter located on the abluminal endothelial membrane. Moreover, the DD‐M in brain parenchyma can target glioma cells. Significantly, the DD‐MCT enters into brain parenchyma in greater amounts, resulting in enhanced accumulation at glioma site and thus improved antiglioma therapeutic outcome. This strategy pioneers a new path for reducing the trapping of nanotherapeutics within BBB endothelium but increasing their transcytosis into brain parenchyma.