title: Extracellular matrix remodeling in vivo for enhancing tumor-targeting efficiency of nanoparticle drug carriers using the pulsed high intensity focused ultrasound.
abstract: 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 (20W/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.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Wonkwang University, 460 Iksandae-ro, Iksan, Jeonbuk 54538, Republic of Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemical and Biomolecular Engineering, Sogang University, Shinsu-dong, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Hyounkoo
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Heebeom
authors.initials: H
authors.lastname: Koo
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Na
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Hong Yeol
authors.initials: HY
authors.lastname: Yoon
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.
authors.forename: Hyukjin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Chemical and Biomolecular Engineering, Sogang University, Shinsu-dong, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Hyuncheol
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 1 Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea. Electronic address: kim@kist.re.kr.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002232:Carbocyanines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage; D004337:Drug Carriers / Q000008:administration & dosage*; D005109:Extracellular Matrix; D005456:Fluorescent Dyes / Q000008:administration & dosage; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000628:therapy*
chemical_list: C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D004337:Drug Carriers; D005456:Fluorescent Dyes; C118638:glycol-chitosan; D048271:Chitosan
keywords: Collagen; Extracellular matrix; HIFU; Nanoparticles; Tumor-targeting