Development of inhalable formulations of disulfiram metabolites for localised treatment of non-small cell lung cancer
Pulmonary drug delivery has gained a wide attention for targeted delivery in lung cancer treatment. Zinc Diethyldithiocarbamate (Zn(DDC)2) has a great potential for cancer treatment however, its low water solubility hinders its clinical application. Therefore, the aim of this study is enhancing the solubility of Zn(DDC)2 using cyclodextrins to form inclusion complexes, and to investigate the potential of pulmonary delivery of the developed complexes for pulmonary delivery in lung cancer treatment to help increasing drug accumulation at tumour site with lower doses and less systemic side effects which will benefit in reducing the cost of treatment and give more convenience therapeutic option to the patients.
Complexation of Zn(DDC)2 with cyclodextrin was investigated using hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-CD (SBE-β-CD). Using the direct method of saturated solution has increased the solubility of Zn(DDC)2 up to up to 3.92 ± 0.07 mg/ml and 4.46 ± 0.17 mg/ml for 20% w/w SBE-β-CD and HP-β-CD, respectively. Cyclodextrin complexes prevented the drug precipitation and provided better penetration to the cells that resulted in enhancing the cytotoxicity of Zn(DDC)2 by 10-folds compared to free drug. The IC50 of Zn(DDC)2 has decreased from 54.6 ± 1.59 μM for the free drug to 6.8 ± 0.57 μM and 4.9 ± 0.34 μM, for HP-Zn(DDC)2 and SBE-Zn(DDC) respectively. The nebulisation of the complexes was investigated using next generation impactor (NGI) and two stage twin impinger (TSI) using air-jet nebuliser only, the drug output reached up to 73.88 ± 9.27% with fine particle fraction (FPF) around 48.17 ± 3.74% and respiratory fraction of 80.57 ± 1.60 % indicating a good potential for pulmonary deposition of the complexes.
Dry powder formulations for Zn(DDC)2-CD complexes were produced using freeze-drying and spray-drying techniques for pulmonary delivery using dry powder inhaler. Spray-drying resulted in powders with desirable aerosolisation properties for inhalation compared to powders produced using freeze-drying. Therefore, spray-dried powders were investigated for further improvement using leucine, the incorporation of 10% leucine further improved the FPF percentage up to 76.77 ± 1.18% compared to 24.69 ± 1.84% for leucine free powders. The delivery of spray-dried powders of Zn(DDC)2-CD complexes with leucine using DPI exhibited better aerosolisation properties than their delivery via nebulisation using air-jet nebuliser. Hence, they have higher tendency to be deposited in the lungs and produce localised effect. Overall, cyclodextrin-based formulations for Zn(DDC)2 using dry powder inhalation showed a great potential for pulmonary delivery in the treatment of non-small cell lung cancer (NSCLC).
History
Institution
Anglia Ruskin UniversityFile version
- Published version
Thesis name
- PhD
Thesis type
- Doctoral
Affiliated with
- Faculty of Health, Medicine & Social Care Outputs