title: Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery.
abstract: Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120 mg·g-1). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy.
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University; Laboratory of Biophysics, Faculty of Medicine, University of Turku, Turku, Finland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Prabhakar
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.
authors.forename: Jixi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University.
authors.forename: Diti
authors.initials: D
authors.lastname: Desai
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University.
authors.forename: Eudald
authors.initials: E
authors.lastname: Casals
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University.
authors.forename: Tina
authors.initials: T
authors.lastname: Gulin-Sarfraz
authors.affiliation: Laboratory of Biophysics, Faculty of Medicine, University of Turku, Turku, Finland; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Näreoja
authors.affiliation: Centre for Biotechnology, University of Turku and Åbo Akademi; Department of Pathology, University of Turku, Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rosenholm
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010084:Oxidation-Reduction; D011094:Polyethyleneimine / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D012822:Silicon Dioxide / Q000737:chemistry*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D012822:Silicon Dioxide; D011094:Polyethyleneimine
keywords: RNAi therapy; hybrid nanocarriers; mesoporous silica nanoparticles; siRNA delivery; stimuli-responsive drug release