Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics
Journal
Biomaterials
Journal Volume
90
Pages
12-26
Date Issued
2016
Author(s)
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 1H 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. ? 2016 Elsevier Ltd.
SDGs
Other Subjects
Covalent bonds; Diagnosis; Drug delivery; Fish; Grafting (chemical); Hyaluronic acid; Nanoparticles; Nuclear magnetic resonance spectroscopy; Organic acids; Particle size; Peptides; pH sensors; Solutions; Transmission electron microscopy; Tumors; Active targeting; Cancer therapy; Dual responsive; Orthotopic; Self-assembling; Diseases; cystamine; dithiothreitol; doxorubicin; glutathione; gonadorelin; hyaluronic acid; nanoconjugate; antineoplastic antibiotic; delayed release formulation; doxorubicin; nanoconjugate; peptide; animal cell; animal experiment; antineoplastic activity; Article; controlled release formulation; controlled study; drug delivery system; drug uptake; female; human; human cell; in vitro study; light scattering; mouse; nonhuman; ovarian cancer cell line; ovary cancer; pH; priority journal; proton nuclear magnetic resonance; ring opening; synthesis; theranostic nanomedicine; tissue section; transmission electron microscopy; animal; chemistry; delayed release formulation; drug delivery system; drug effects; Ovarian Neoplasms; ovary; oxidation reduction reaction; pathology; procedures; theranostic nanomedicine; tumor cell line; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cystamine; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Female; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Mice; Nanoconjugates; Ovarian Neoplasms; Ovary; Oxidation-Reduction; Peptides; Theranostic Nanomedicine
Publisher
Elsevier Ltd
Type
journal article