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 (4 minutes) 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 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 significant influence 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.

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment

“…To determine the total amount of DS in liposome formulation, 1 mL was diluted directly by 2 mL distilled water, and 0.5 mL of the resulting suspension was treated by methanol following the same steps described above. HPLC analysis reported by Najlah et al [14] was performed on an UltiMate 3000 UHPLC (Thermo Fisher Scientific UK, Loughborough, UK) with a Phenomenex Luna C18 4.6 × 150 mm column with a 5 μm particle size (Phenomenex, Torrance, CA, USA). The mobile phase comprised 80% HPLC grade methanol and 20% HPLC grade water.…”

“…The development of an efficient delivery system able to protect DS during its circulation into cancerous cells is essential. There has been a growing interest in developing nano-drug-delivery systems that are able to provide sufficient protection to DS, thus, enabling clinical trials [14].…”

“…For example, Wang et al have successfully encapsulated DS into liposome (Lipo-DS) and managed to mildly extend the half-life of DS in the bloodstream to approximately 20 min [3,19]. However, more development is required in this field, especially for enhancing the loading efficiency and extending the stability of DS [14]. For example, developing long-circulating drug delivery systems that might have a potential for translation to cancer therapy.…”

Hyaluronic Acid Decorated Naringenin Nanoparticles: Appraisal of Chemopreventive and Curative Potential for Lung Cancer

“…Poor prognosis, lack of early detection, development of resistance to chemotherapeutic agents and overall five-year survival rate of <15% are the foremost obstacles for effective LC treatment [ 5 ]. Currently, most opted treatment strategies include radiotherapy and chemotherapy which pose challenges to effective treatment of LC [ 6 ]. These conventional treatments have discouraging outcomes due to limitations, namely dose-dependent toxicity, low selectivity, resistance development and compromised delivery of chemotherapeutic agents to lung tissue due to high tumor interstitial pressure [ 7 ].…”

RPV‐modified epirubicin and dioscin co‐delivery liposomes suppress non‐small cell lung cancer growth by limiting nutrition supply

“…In the past decade, targeted therapy, immunotherapy, and similar approaches rapidly developed to become the new treatment modalities for NSCLC. Despite recent developments and improvements in diagnosis and treatment, prospects for patients with NSCLC are dismal and the 5‐year overall survival rate is only 15%‐18% . Rapid growth and metastasis are basic biological characteristics of malignant tumors, including NSCLC .…”