title: Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex.
abstract: Treatment of glioblastoma (GBM) remains to be the most formidable challenge because of the hindrance of the blood-brain barrier (BBB) along with the poor drug penetration into the glioma parenchyma. Nanoparticulate drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting ligand to target the glioma-associated transferrin receptor (TfR) had met the problem of loss of specificity in biological environment due to the high level of endogenous Tf. Here we conjugated CRT peptide, an iron-mimicry moiety targeting the whole complex of Tf/TfR, to poly(ethylene glycol)-poly(l-lactic-co-glycolic acid) nanoparticles (CRT-NP), to open a new route to overcome such obstacle. High cellular associations, advanced transport ability through the BBB model, and penetration in 3-dimensional C6 glioma spheroids in vitro had preliminarily proved the advantages of CRT-NP over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP, and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior antiproliferation effect on C6 glioma cells and stronger inhibitory effect on glioma spheroids. Favored pharmacokinetics behavior and enhanced accumulation in glioma foci was observed, together with a much deeper distribution pattern in glioma parenchyma compared with unmodified nanoparticles and Tf-NP. Eventually, mice treated with CRT-NP-PTX showed a remarkably prolonged median survival compared to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification of CRT to nanoparticles holds great promise for enhancement of antiglioma therapy.
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Mengyin
authors.initials: M
authors.lastname: Jiang
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Xingye
authors.initials: X
authors.lastname: Feng
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Yao
authors.affiliation: §Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, P. R. China.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.affiliation: §Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, P. R. China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: §Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, P. R. China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.affiliation: †Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage; D010446:Peptide Fragments / Q000494:pharmacology*; D056951:Photoelectron Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution; D014168:Transferrin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D010446:Peptide Fragments; D011990:Receptors, Transferrin; D014168:Transferrin; D011092:Polyethylene Glycols; D007501:Iron; D017239:Paclitaxel
keywords: CRT peptide; blood−brain barrier; glioblastoma therapy; nanoparticles; penetration