title: A theranostic micelleplex co-delivering SN-38 and VEGF siRNA for colorectal cancer therapy.
abstract: The development of an efficient colorectal cancer therapy is currently a public health priority. In the present work, we proposed a multifunctional theranostic micellar drug delivery system utilizing cationic PDMA-block-poly(ε-caprolactone) (PDMA-b-PCL) micelles as nanocarriers of SN-38 (7-ethyl-10-hydroxycamptothecin), ultra-small superparamagnetic iron oxide nanoparticles (USPIO), and small interfering RNA (siRNA) that targets human vascular endothelial growth factor (VEGF). The VEGF siRNA was conjugated to polyethylene glycol (PEG) (siRNA-PEG) before complexation with the micelles in order to improve the siRNA's stability and to prolong its retention time in the blood circulation. To further improve the in vivo biosafety, we prepared mixed micelles using mPEG-PCL together with PDMA-b-PCL copolymer. The SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes passively targeted to tumor regions and synergistically facilitated VEGF silencing and chemotherapy, thus efficiently suppressing tumor growth via a multi-dose therapy regimen. Additionally, the SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes acted as a negative magnetic resonance imaging (MRI) contrast agent in T2-weighted imaging, resulting in a powerful tool for the diagnosis and for tracking of the therapeutic outcomes. In summary, we established a theranostic micellar drug and gene delivery system that not only synergistically combined gene silencing and chemotherapy but also served as a negative MRI contrast agent, which reveal its potential as a novel colorectal cancer therapy.
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan.
authors.forename: Shin-Yu
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan; Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan, 325, Taiwan.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Peng
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Wei
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan; Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ke-Cheng
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan; Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Yao
authors.affiliation: Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan; Department of Oncology, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan. Electronic address: soloman@ntu.edu.tw.
authors.forename: Ming-Jium
authors.initials: MJ
authors.lastname: Shieh
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D000077146:Irinotecan; D058185:Magnetite Nanoparticles / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D000067492:RNAi Therapeutics / Q000379:methods; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068936:Theranostic Nanomedicine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003911:Dextrans; D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D008689:Methacrylates; D008823:Micelles; D011091:Polyesters; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C097921:ferumoxtran-10; C016240:polycaprolactone; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin
keywords: Colorectal cancer; MRI; Micelleplex; Micelles; SN-38; VEGF siRNA