title: Development and characterisation of disulfiram-loaded PLGA nanoparticles for the treatment of non-small cell lung cancer.
abstract: Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer in both men and women. A recent phase IIb study demonstrated that disulfiram (DSF) in combination with cisplatin and vinorelbine was well tolerated and prolonged the survival of patients with newly diagnosed NSCLC. However, DSF is rapidly (4min) metabolised in the bloodstream and it is this issue which is limiting its anticancer application in the clinic. We have recently demonstrated that a low dose of DSF-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles supplemented with oral Cu inhibited tumour growth and reduced metastasis in a xenograft mouse lung cancer model. Here we demonstrate the influence of PLGA polymer, stabilizer loading and molecular weight as well as sonication time on the characteristics, including DSF release and the cytotoxicity of 10% w/w DSF-loaded PLGA nanoparticles. The paper demonstrates that the choice of PLGA as no significance on the characteristics of the nanoparticles apart from their DSF release, which is due to the differing degradation rates of the polymers. However, increasing the loading and molecular weight of the stabilizer as well as the sonication time reduced the size of the nanoparticles, reduced their ability to protect the DSF from reacting with Cu and degrading in serum, while increasing their DSF release rate and cytotoxicity. Additionally, increasing the sonication time resulted in the premature degradation of the PLGA, which increased the permeability of the nanoparticles further decreasing their ability to protect DSF from reacting with Cu and degrading in serum, while increasing their DSF release rate and cytotoxicity.
authors.affiliation: Department, Medicine and Healthcare Science, Faculty of Medical Science, Anglia Ruskin University, Chelmsford, Essex CM1 1SQ, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Najlah
authors.affiliation: School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK.
authors.forename: Zahima
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK.
authors.forename: Patrica
authors.initials: P
authors.lastname: Tawari
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfrana Street, Wolverhampton WV1 1LY, UK.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston B15 2TT, UK. Electronic address: C.Mcconville.2@bham.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: McConville
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004221:Disulfiram / Q000008:administration & dosage*; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004221:Disulfiram
keywords: Disulfiram; Lung cancer; Nanoparticles; PLGA