title: Reduction Responsive Self-Assembled Nanoparticles Based on Disulfide-Linked Drug-Drug Conjugate with High Drug Loading and Antitumor Efficacy.
abstract: Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 nm. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Song
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Yaoqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Song
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University , Beijing 100191, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D004317:Doxorubicin
keywords: antitumor efficiency; doxorubicin conjugates; high drug loading; reduction responsive; self-assembled nanoparticles