title: Co-delivery of Se nanoparticles and pooled SiRNAs for overcoming drug resistance mediated by P-glycoprotein and class III β-tubulin in drug-resistant breast cancers.
abstract: Drug resistance mediated by P-glycoprotein (P-gp) and class III β-tubulin (β-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-β-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and β-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and β-tubulin III in drug-resistant breast cancers.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Qingchang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Taoyuan
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China; School of Pharmacy, Guangdong Medical University, Zhanjiang 524023, China.
authors.forename: Lanmei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. Electronic address: tliuliu@jnu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000737:chemistry; D061986:MCF-7 Cells; D053768:Metal Nanoparticles / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000737:chemistry; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D012643:Selenium / Q000008:administration & dosage* / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D008941:Spindle Apparatus; D014404:Tubulin / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017304:Annexin A5; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014404:Tubulin; D007770:L-Lactate Dehydrogenase; D012643:Selenium
keywords: Class III β-tubulin; Drug resistance; P-glycoprotein; Selenium; siRNA