Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment.
Glioblastoma multiforme (GBM) is a highly malignant brain tumor. The blood-brain barrier (BBB) provides a major obstacle to chemotherapy since therapeutic doses cannot be achieved by traditional drug delivery without severe systemic cytotoxic effects. Recently, microbubble (MB)-enhanced focused ultrasound (FUS) was shown to temporally and locally disrupt the BBB thereby enhancing drug delivery into brain tumors. Here we propose the concept of smart, multifunctional MBs capable of facilitating FUS-induced BBB disruption while serving as drug-carrying vehicles and protecting drugs from rapid degradation. The designed MBs had a high loading capacity (efficiency of 68.01 ± 4.35%) for 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU). When combined with FUS (1-MHz), these BCNU-MBs facilitated local BBB disruption and simultaneously released BCNU at the target site, thus increasing local BCNU deposition. Encapsulation of BCNU in MBs prolonged its circulatory half-life by 5-fold, and accumulation of BCNU in the liver was reduced 5-fold due to the slow reticuloendothelial system uptake of BCNU-MBs. In tumor-bearing animals, BCNU-MBs with FUS controlled tumor progression (915.3%-39.6%) and improved median survival (29 days-32.5 days). This study provides a new approach for designing multifunctional MBs to facilitate FUS-mediated chemotherapy for brain tumor treatment.
Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
Chien-Yu
CY
Ting
Ching-Hsiang
CH
Fan
Hao-Li
HL
Liu
Chiung-Yin
CY
Huang
Han-Yi
HY
Hsieh
Tzu-Chen
TC
Yen
Kuo-Chen
KC
Wei
Chih-Kuang
CK
Yeh
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002330:Carmustine / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy*; D006207:Half-Life; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D009690:Nucleic Acid Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014464:Ultrasonic Therapy
D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine