title: Efficient nuclear drug translocation and improved drug efficacy mediated by acidity-responsive boronate-linked dextran/cholesterol nanoassembly.
abstract: The present study reported a lysosome-acidity-targeting bio-responsive nanovehicle self-assembled from dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA), aiming at the nucleus-tropic drug delivery. The prominent advantage of this assembled nanoconstruction arose from its susceptibility to acidity-labile dissociation concurrently accompanied with the fast liberation of encapsulated drugs, leading to efficient nuclear drug translocation and consequently favorable drug efficacy. By elaborately exploiting NH4Cl pretreatment to interfere with the cellular endosomal acidification progression, this study clearly evidenced at a cellular level the strong lysosomal-acidity dependency of nuclear drug uptake efficiency, which was shown to be the main factor influencing the drug efficacy. The boronate-linked nanoassembly displayed nearly no cytotoxicity and can remain structural stability under the simulated physiological conditions including 10% serum and the normal blood sugar concentration. The cellular exposure to cholesterol was found to bate the cellular uptake of nanoassembly in a dose-dependent manner, suggesting a cholesterol-associated mechanism of the intracellular internalization. The in vivo antitumor assessment in xenograft mouse models revealed the significant superiority of DOX-loaded Dex/Chol-PBA nanoassembly over the controls including free DOX and the DOX-loaded non-sensitive Dex-Chol, as reflected by the more effective tumor-growth inhibition and the better systematic safety. In terms of the convenient preparation, sensitive response to lysosomal acidity and efficient nuclear drug translocation, Dex/Chol-PBA nanoassembly derived from natural materials shows promising potentials as the nanovehicle for nucleus-tropic drug delivery especially for antitumor agents. More attractively, this study offers a deeper insight into the mechanism concerning the contribution of acidity-responsive delivery to the enhanced chemotherapy performance.
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Jia
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Qiu
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Xuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Ren-Xi
authors.initials: RX
authors.lastname: Zhuo
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China. Electronic address: fengjun@whu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Xian-Zheng
authors.initials: XZ
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001895:Boron / Q000737:chemistry*; D001897:Boronic Acids / Q000737:chemistry; D002219:Carbamates / Q000737:chemistry; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry*; D003593:Cytoplasm / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D010316:Particle Size
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D002219:Carbamates; D003911:Dextrans; D004337:Drug Carriers; D008823:Micelles; D002784:Cholesterol; C010686:benzeneboronic acid; D001895:Boron
keywords: Acidity-responsiveness; Boronate linking; Lysosomal acidity; Nanoassembly; Nuclear drug translocation; Tumor chemotherapy