title: Dual-targeting hybrid nanoparticles for the delivery of SN38 to Her2 and CD44 overexpressed human gastric cancer.
abstract: Gastric cancer (GC), particularly of the type with high expression of both human epidermal growth factor receptor 2 (Her2) and cluster determinant 44 (CD44), is one of the most malignant human tumors which causes a high mortality rate due to rapid tumor growth and metastasis. To develop effective therapeutic treatments, a dual-targeting hybrid nanoparticle (NP) system was designed and constructed to deliver the SN38 agent specifically to human solid gastric tumors bearing excessive Her2 and CD44. The hybrid NPs consist of a particle core made of the biodegradable polymer PLGA and a lipoid shell prepared by conjugating the AHNP peptides and n-hexadecylamine (HDA) to the carboxyl groups of hyaluronic acid (HA). Upon encapsulation of the SN38 agent in the NPs, the AHNP peptides and HA on the NP surface allow preferential delivery of the drug to gastric cancer cells (e.g., HGC27 cells) by targeting Her2 and CD44. Cellular uptake and in vivo biodistribution experiments verified the active targeting and prolonged in vivo circulation properties of the dual-targeting hybrid NPs, leading to enhanced accumulation of the drug in tumors. Furthermore, the anti-proliferation mechanism studies revealed that the inhibition of the growth and invasive activity of HGC27 cells was not only attributed to the enhanced cellular uptake of dual-targeting NPs, but also benefited from the suppression of CD44 and Her2 expression by HA and AHNP moieties. Finally, intravenous administration of the SN38-loaded dual-targeting hybrid NPs induced significant growth inhibition of HGC27 tumor xenografted in nude mice compared with a clinical antitumor agent, Irinotecan (CPT-11), and the other NP formulations. These results demonstrate that the designed dual-targeting hybrid NPs are promising for targeted anti-cancer drug delivery to treat human gastric tumors over-expressing Her2 and CD44.
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn and Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Guangzhou, Guangdong 510060, China. xurh@sysucc.org.cn.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Ya
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Yingqin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Guangzhou, Guangdong 510060, China. xurh@sysucc.org.cn.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. liujie56@mail.sysu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D002166:Camptothecin; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D000077146:Irinotecan; D018719:Erb-b2 Receptor Tyrosine Kinases; C497483:CD44 protein, human; C508053:ERBB2 protein, human