Retro-inverso bradykinin opens the door of blood-brain tumor barrier for nanocarriers in glioma treatment.
The blood-brain barrier and the blood-brain tumor barrier (BBTB) prevent most drugs entering brain tumors. Complicated preparation procedures of drug delivery systems and damage to normal brain tissue have limited the application of many strategies for the treatment of brain tumor in clinical trials. We have designed a bradykinin analog, retro-inverso bradykinin (RI-BK), which is characterized by resistance to proteolysis and high binding activity with the bradykinin type 2 (B2) receptor. After systemic administration, RI-BK binds to B2 receptors and induces a change in zonula occluden-1 and depolymerization of F-actin to selectively open the BBTB. RI-BK increased the accumulation of drug-loaded nanocarriers in the glioma but not in normal brain. Co-administration with RI-BK enhanced the therapeutic efficiency of drug-loaded nanocarriers for glioma. These findings suggest that RI-BK could be translated into the clinic as an adjunctive treatment for malignant brain tumors.
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Zuoxu
Z
Xie
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Qing
Q
Shen
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Cao
C
Xie
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Weiyue
W
Lu
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Chunmei
C
Peng
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Xiaoli
X
Wei
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Xue
X
Li
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Bingxia
B
Su
Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200030, China.
Chunli
C
Gao
Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: liumin@shmu.edu.cn.
Min
M
Liu
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D002199:Capillary Permeability / Q000187:drug effects*; D003374:Coumarins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D021381:Protein Transport; D023041:Xenograft Model Antitumor Assays; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D003374:Coumarins; D004337:Drug Carriers; D008823:Micelles; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C000604477:retro-inverso bradykinin; C030123:coumarin; D001920:Bradykinin
Blood–brain tumor barrier; Glioma; Polymeric micelles; Retro-inverso bradykinin