TY - JOUR
T1 - Extracellular matrix remodeling in vivo for enhancing tumor-targeting efficiency of nanoparticle drug carriers using the pulsed high intensity focused ultrasound
AU - Lee, Sangmin
AU - Han, Hyounkoo
AU - Koo, Heebeom
AU - Na, Jin Hee
AU - Yoon, Hong Yeol
AU - Lee, Kyung Eun
AU - Lee, Hyukjin
AU - Kim, Hyuncheol
AU - Kwon, Ick Chan
AU - Kim, Kwangmeyung
N1 - Funding Information:
This work was supported by the GRL project (NRF-2013K1A1A2A02050115) and the Intramural Research Program (CATS) of KIST.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/10/10
Y1 - 2017/10/10
N2 - Dense and stiff extracellular matrix (ECM) in heterogeneous tumor tissues can inhibit deep penetration of nanoparticle drug carriers and decreases their therapeutic efficacy. Herein, we suggest the ECM remodeling strategy by the pulsed high intensity focused ultrasound (Pulsed-HIFU) technology for enhanced tumor-targeting of nanoparticles. First, we clearly observed that the tumor-targeting efficacy and tissue penetration of intravenously injected Cy5.5-labled glycol chitosan nanoparticles (Cy5.5-CNPs) were greatly inhibited in tumor tissue containing high collagen and hyaluronan contents in ECM-rich A549 tumor-bearing mice, compared to in ECM-less SCC7. When collagenase or hyaluronidase was treated by intra-tumoral injection, the amount of collagen and hyaluronan decreased in ECM-rich A549 tumor tissues and more Cy5.5-CNPs penetrated inside the tumor tissue, confirmed using non-invasive optical imaging. Finally, in order to break down the stiff ECM structure, ECM-rich A549 tumor tissues were treated with the relatively low power of Pulse-HIFU (20 W/cm2), wherein acute tissue damage was not observed. As we expected, the A549 tumor tissues showed the remodeling of ECM structure after non-invasive Pulsed-HIFU exposure, which resulted in the increased blood flow, decreased collagen contents, and enhanced penetration of CNPS. Importantly, the tumor targeting efficiency in Pulsed-HIFU-treated A549 tumor tissues was 2.5 times higher than that of untreated tumor tissues. These overall results demonstrate that ECM remodeling and disruption of collagen structure by Pulse-HIFU is promising strategy to enhance the deep penetration and enhanced tumor targeting of nanoparticles in ECM-rich tumor tissues.
AB - Dense and stiff extracellular matrix (ECM) in heterogeneous tumor tissues can inhibit deep penetration of nanoparticle drug carriers and decreases their therapeutic efficacy. Herein, we suggest the ECM remodeling strategy by the pulsed high intensity focused ultrasound (Pulsed-HIFU) technology for enhanced tumor-targeting of nanoparticles. First, we clearly observed that the tumor-targeting efficacy and tissue penetration of intravenously injected Cy5.5-labled glycol chitosan nanoparticles (Cy5.5-CNPs) were greatly inhibited in tumor tissue containing high collagen and hyaluronan contents in ECM-rich A549 tumor-bearing mice, compared to in ECM-less SCC7. When collagenase or hyaluronidase was treated by intra-tumoral injection, the amount of collagen and hyaluronan decreased in ECM-rich A549 tumor tissues and more Cy5.5-CNPs penetrated inside the tumor tissue, confirmed using non-invasive optical imaging. Finally, in order to break down the stiff ECM structure, ECM-rich A549 tumor tissues were treated with the relatively low power of Pulse-HIFU (20 W/cm2), wherein acute tissue damage was not observed. As we expected, the A549 tumor tissues showed the remodeling of ECM structure after non-invasive Pulsed-HIFU exposure, which resulted in the increased blood flow, decreased collagen contents, and enhanced penetration of CNPS. Importantly, the tumor targeting efficiency in Pulsed-HIFU-treated A549 tumor tissues was 2.5 times higher than that of untreated tumor tissues. These overall results demonstrate that ECM remodeling and disruption of collagen structure by Pulse-HIFU is promising strategy to enhance the deep penetration and enhanced tumor targeting of nanoparticles in ECM-rich tumor tissues.
KW - Collagen
KW - Extracellular matrix
KW - HIFU
KW - Nanoparticles
KW - Tumor-targeting
UR - http://www.scopus.com/inward/record.url?scp=85014708657&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.02.035
DO - 10.1016/j.jconrel.2017.02.035
M3 - Article
C2 - 28257990
AN - SCOPUS:85014708657
SN - 0168-3659
VL - 263
SP - 68
EP - 78
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -