title: Performance of Doxorubicin-Conjugated Gold Nanoparticles: Regulation of Drug Location.
abstract: Drug-conjugated gold nanoparticles (GNPs), which are generally constructed with many molecules of thiol-terminated polyethylene glycol (PEG)-drug decorated on their surfaces via a thiol-Au covalent bond, are promising and efficient nanoprodrugs. However, because of the exposure of the hydrophobic drug molecules on the surface of the conjugate, in vivo stability, opsonization, and subsequent inefficient therapy become the main issues of this system. To solve these problems without complicating the structures of gold conjugates, herein we propose a method to change the relative position of PEG and the drug. A novel gold conjugate (GNP-NHN═Dox-mPEG) with doxorubicin (Dox) shielded by PEGylation on the surface of GNPs is designed. It demonstrates improved solubility, stability, and dispersion and achieves a two-step stimulus-responsive drug release in response to an acidic environment in lysosomes and then esterase in the cytoplasm. This unique manner of release enables the cytoplasm to act as a reservoir for sustained drug delivery into the nucleus to improve antitumor efficacy in vivo. The intratumoral drug concentrations of the conjugate reach 14.4 ± 1.4 μg/g at 8 h, a two-fold increase in the drug concentration compared with that of the doxorubicin hydrochloride group. This molecular design and regulation approach is facile but important in modulating the in vivo performance of nanovehicles and demonstrates its vital potential in developing effective nanoparticle-based drug delivery agents.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Hai
authors.identifier: http://orcid.org/0000-0002-3827-0992
authors.initials: H
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutical Analysis, ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, and §Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Ya
authors.identifier: http://orcid.org/0000-0001-6214-5641
authors.initials: Y
authors.lastname: Ding
mesh_terms: D045744:Cell Line, Tumor; D004317:Doxorubicin; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006046:Gold; D006801:Humans; D053768:Metal Nanoparticles; D011092:Polyethylene Glycols
chemical_list: D011092:Polyethylene Glycols; D006046:Gold; D004317:Doxorubicin
keywords: Doxorubicin-conjugated gold nanoparticles; drug location; lysosomal escape; treatment efficacy improvement; two-step drug release