title: Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer.
abstract: Hypoxia-inducible factor 1α (HIF1α) has emerged as a promising new target for pancreatic cancer treatment over the past decade. High expression of HIF-1α increases the drug resistance of the current first line chemotherapeutic drug, gemcitabine (Gem). Here we employed biocompatible lipid-polymer hybrid nanoparticles to co-deliver HIF1α siRNA (si-HIF1α) and Gem for pancreatic cancer treatment in subcutaneous and orthotopic tumor models. The cationic ε-polylysine co-polymer (ENPs) can effectively absorb negatively charged si-HIF1α on the surface and encapsulate Gem to the hydrophilic core. Further coating of ENPs with PEGylated lipid bilayer resulted formation of LENPs, with reversed surface charge. The lipid bilayer of LENPs prevented nanoparticle aggregation and si-HIF1α degradation in serum, as well as Gem leakage. Those characteristics endow LENPs encapsulating drug prolonged lifetime in bloodstream and improved drug release via the enhanced tumor vasculature effect in tumor tissues. LENPs can co-deliver Gem and si-HIF1α (LENP-Gem-si-HIF1α) into tumor cells and effectively suppress the HIF1α expression both in vitro and in vivo. LENP-Gem-siHIF1α exhibited significant synergistic antitumor effects. Furthermore, LENP-Gem-si-HIF1α showed excellent capability to inhibit tumor metastasis in orthotopic tumor model.
authors: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors: Xiao
authors: X
authors: Zhao
authors: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors: Feng
authors: F
authors: Li
authors: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors: Yiye
authors: Y
authors: Li
authors: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors: Hai
authors: H
authors: Wang
authors: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors: He
authors: H
authors: Ren
authors: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors: Jing
authors: J
authors: Chen
authors: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China. Electronic address: niegj@nanoctr.cn.
authors: Guangjun
authors: G
authors: Nie
authors: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: haojihui@tjmuch.com.
authors: Jihui
authors: J
authors: Hao
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016898:Interferon-alpha / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000737:chemistry*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D044967:Serum / Q000737:chemistry; D055672:Static Electricity; D000093542:Gemcitabine
chemical_list: D001672:Biocompatible Materials; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016898:Interferon-alpha; D015850:Interleukin-6; D008055:Lipids; D011108:Polymers; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Combination therapy; Hypoxia-inducible factor 1α; Lipid-polymer hybrid nanoparticles; Orthotopic tumor model; Pancreatic cancer; siRNA delivery