title: Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics.
abstract: Ovarian cancers are the leading cause for mortality among gynecologic malignancies with five-year survival rate less than 30%. The purpose of this study is to develop a redox and pH-sensitive self-assembling hyaluronic acid nanoparticle with active targeting peptide for anticancer drug delivery. Anti-cancer drug is grafted onto hyaluronic acid (HA) via cis-aconityl linkage and disulfide bond to possess pH sensitivity and redox property, respectively. This conjugate is amphiphilic and can self-assemble into nanoparticle (NP) in aqueous solution. The results show that the nanoconjugate is successfully developed and the grafting ratio of cystamine (cys) is 17.8% with drug loading amount about 6.2% calculated by (1)H NMR spectra. The particle size is approximately 229.0 nm using dynamic light scatting measurement, and the morphology of nanoparticles is observed as spherical shape by transmission electron microscope. The pH and redox sensitivities are evaluated by changing either pH value or concentration of dithiothreitol in the medium. It is proved that the drug carrier is capable of achieving sustained controlled release of anti-cancer drug to 95% within 150 h. The intracellular uptake is observed by fluorescent microscope and the images show that conjugating luteinizing hormone-releasing hormone (LHRH) peptide can enhance specific uptake of nanoparticles by OVCAR-3 cancer cells; thus, resulting in inhibitory cell growth to less than 20% in 72 h in vitro. Orthotopic ovarian tumor model is also established to evaluate the therapeutic and diagnostic efficacy using non-invasive in vivo imaging system. The representative results demonstrate that LHRH-conjugated NPs possess a preferable tumor imaging capability and an excellent antitumor ability to almost 30% of original size in 20 days.
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chun-Jui
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Department of Plastic Surgery, National Taiwan University Hospital, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Kuan
authors.affiliation: Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Wang
authors.affiliation: Department of Material Engineering, Tatung University, Taipei, Taiwan.
authors.forename: Hsi-Chin
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chien-Wen
authors.initials: CW
authors.lastname: Chang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Rih-Yang
authors.initials: RY
authors.lastname: Huang
authors.affiliation: Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: twwang@mx.nthu.edu.tw.
authors.forename: Tzu-Wei
authors.initials: TW
authors.lastname: Wang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003538:Cystamine / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D058726:Nanoconjugates / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry; D000068936:Theranostic Nanomedicine
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D058726:Nanoconjugates; D010455:Peptides; D004317:Doxorubicin; D006820:Hyaluronic Acid; D003538:Cystamine
keywords: Active targeting; Cancer therapy; Drug delivery; Dual responsive; Orthotopic model; Self-assembling