Mechanisms of the increase in the permeability of the blood-tumor barrier obtained by combining low-frequency ultrasound irradiation with small-dose bradykinin.
The research was conducted to study the characteristics of the noninvasive, reversible, targeted opening of the blood-brain barrier (BBB) by use of low-frequency ultrasound (LFU) irradiation and the selective opening of the blood-tumor barrier (BTB) by intracarotid infusion of bradykinin (BK) in small-dose, with the objective of exploring maximum opening of the BTB by combining LFU irradiation with BK infusion. Thus, it provides new therapeutic strategies for targeted transport of macromolecular or granular drugs to the brain. By using the rat C6 glioma model it was shown that extravasation of Evans blue (EB) through the BTB was significantly increased by combining LFU irradiation (frequency = 1.0 MHz, power = 12 mW, duration = 20 s) with intracarotid small-dose BK infusion, compared with utilizing the two methods separately. By transmission electron microscopy (TEM) we observed that this combination significantly increased the number of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) in the BTB. An even more significant increase was observed by using RT-PCR, western blot, immunohistochemistry, and immunofluorescence to detect mRNA and changes of expression of the caveolae structure proteins caveolin-1 and caveolin-2 of BMECs. In summary, this research concludes that LFU irradiation and small-dose BK together selectively enhance the permeability of the BTB and increase the number of pinocytic vesicles of BMECs to a maximum. Significant up-regulation of the level of expression of caveolae structure proteins caveolin-1 and caveolin-2 might be the molecular mechanism of the co-enhanced endocytotic transport by BMECs. Thus, this research provides new therapeutic strategies for targeted transport of macromolecular drugs and the design of drugs.
Xia
Chun-yi
CY
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Zhang
Zhen
Z
Xue
Yi-xue
YX
Wang
Ping
P
Liu
Yun-hui
YH
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D001920:Bradykinin / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D051243:Caveolin 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D046529:Microscopy, Electron, Transmission / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D014464:Ultrasonic Therapy; D014665:Vasodilator Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D051242:Caveolin 1; D051243:Caveolin 2; D014665:Vasodilator Agents; D001920:Bradykinin