title: Preparation of HIFU-triggered tumor-targeted hyaluronic acid micelles for controlled drug release and enhanced cellular uptake.
abstract: In this study, a novel type of high intensity focused ultrasound (HIFU)-triggered active tumor-targeting polymeric micelle was prepared and investigated for controlled drug release and enhanced cellular uptake. Amphiphilic hyaluronic acid (HA) conjugates were synthesized to form docetaxel loaded micelles in aqueous conditions with high encapsulation efficiencies of over 80%. The micelle sizes were limited to less than 150nm, and they varied slightly according to the encapsulated drug amount. Modifying the micellar surface modification with polyethylene glycol diamine successfully inhibited premature drug leakage at a certain level, and it can be expected to prolong the circulation time of the particles in blood. In addition, high-intensity focused ultrasound was introduced to control the release of docetaxel from micelles, to which the release behavior of a drug can be tuned. The in-vitro cell cytotoxicity of docetaxel-loaded micelles was verified against CT-26 and MDA-MB-231 cells. The IC50 values of drug-loaded micelles to CT-26 and MDA-MB-231 cells were 1230.2 and 870.9ng/mL, respectively. However, when exposed to HIFU, the values decreased significantly, to 181.9 and 114.3ng/mL, suggesting that HIFU can enhance cell cytotoxicity by triggering the release of a drug from the micelles. Furthermore, cellular uptake tests were conducted via the quantitative analysis of intracellular drug concentration within CT-26 (CD44 negative), MDA-MB-231 (CD44 positive), and MDA-MB-231 (CD44 blocked), and then imaged with coumarin-6 loaded micelles. The results verified that intracellular drug delivery can be enhanced efficiently via the CD44 receptor-mediated endocytosis of HA micelles. Moreover, HIFU enhanced the cellular uptake behavior by altering the permeability of the cell membrane. It was also able to aid with the extravasation of micelles into the interior of tumors, which will be explained in further research. Therefore, the present study demonstrates that the micelles prepared in this study can emerge as promising nanocarriers of chemotherapeutic agents for controlled drug release and tumor targeting in cancer treatment.
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Zheng
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jin
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Han
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Cho
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Van Du
authors.initials: VD
authors.lastname: Nguyen
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea.
authors.forename: Seong Young
authors.initials: SY
authors.lastname: Ko
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea. Electronic address: jop@jnu.ac.kr.
authors.forename: Jong-Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: School of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Gwangju 500 757, Republic of Korea. Electronic address: spark@jnu.ac.kr.
authors.forename: Sukho
authors.initials: S
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003374:Coumarins / Q000378:metabolism; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D004339:Drug Compounding; D016503:Drug Delivery Systems; D065546:Drug Liberation / Q000528:radiation effects; D004705:Endocytosis / Q000528:radiation effects; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D007700:Kinetics; D008823:Micelles; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D043823:Taxoids / Q000378:metabolism / Q000494:pharmacology; D000069453:Ultrasonic Waves
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D003374:Coumarins; D003692:Delayed-Action Preparations; D005456:Fluorescent Dyes; D018960:Hyaluronan Receptors; D008823:Micelles; D043823:Taxoids; D000077143:Docetaxel; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid; D017239:Paclitaxel
keywords: Active tumor targeting; Cellular uptake enhancement; Controlled release; HIFU; Hyaluronic acid; Polymeric micelles