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Lung cancer chemo-interception by sulfasalazine and disulfiram codelivered using a nano self-emulsifying drug
Fekadu Kassie1,2, Kevin Wang3, Katherine Bang4
1College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, United States.
Abstract:
Although preclinical studies consistently indicate that sulfasalazine (SAS) and disulfiram (DSF) are promising agents for the prevention and treatment of lung cancer, their clinical efficacy is limited. This discrepancy is attributed to the poor bioavailability of the drugs. Therefore, in the present study, we explored whether delivery of lower doses of SAS and DSF in nano self-emulsifying drug delivery systems (Nano-SEDDS) improves their potency and efficacy in suppressing malignant progression of lung tumors. Mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and once lung adenoma developed, high doses of free SAS (250 mg/kg) + DSF (100 mg/kg) or SEDDS formulations containing lower doses of SAS + DSF (40 mg/kg SAS + 8, 16 or 40 mg/kg DSF) were administered by oral gavage, every other day, for 10 weeks. Although the doses of SAS and DSF contained in SAS + DSF-SEDDS were about 6-fold and 3-15-fold lower, respectively, than the doses of the respective free drugs, SAS + DSF-SEDDS was more effective than free SAS + DSF in reducing the multiplicity of bigger lung tumors (≥1 mm). These effects were paralleled by significant reductions in the multiplicity of adenoma with progression and adenocarcinoma histopathological lesions. Also, lung tumors from mice treated with SAS + DSF-SEDDS exhibited an increase in the level of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), lipid peroxidation products. Overall, our results show that the Nano-SEDDS formulation of SAS + DSF is a promising approach to enhance the potency and efficacy of the drugs for lung cancer chemo-interception and treatment.
Insights
Nano self-emulsifying drug delivery systems (Nano-SEDDS) enhance the efficacy of sulfasalazine (SAS) and disulfiram (DSF) for lung cancer treatment. Lower doses of SAS and DSF in Nano-SEDDS formulations were more effective than higher free drug doses in reducing tumor progression.
Area of Science:
- Pharmacology
- Oncology
- Drug Delivery Systems
Background:
- Preclinical studies show sulfasalazine (SAS) and disulfiram (DSF) are promising for lung cancer prevention and treatment.
- Clinical efficacy of SAS and DSF is limited by poor bioavailability.
- Novel drug delivery systems are needed to improve lung cancer therapeutic outcomes.
Purpose of the Study:
- To investigate if nano self-emulsifying drug delivery systems (Nano-SEDDS) improve the potency and efficacy of lower doses of SAS and DSF.
- To evaluate the effect of SAS + DSF-SEDDS on lung tumor progression and histopathological lesions.
- To assess lipid peroxidation markers in lung tumors treated with SAS + DSF-SEDDS.
Main Methods:
- Mice were induced with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to develop lung adenoma.
- Treatments included high-dose free SAS + DSF or lower-dose SAS + DSF in SEDDS formulations via oral gavage for 10 weeks.
- Tumor multiplicity, histopathological progression, and levels of lipid peroxidation products (4-HNE, MDA) were analyzed.
Main Results:
- SAS + DSF-SEDDS significantly reduced the multiplicity of larger lung tumors (≥1 mm) compared to free SAS + DSF.
- A notable decrease in adenoma progression and adenocarcinoma lesions was observed with SAS + DSF-SEDDS.
- Increased levels of lipid peroxidation products (4-HNE, MDA) were found in lung tumors treated with SAS + DSF-SEDDS.
Conclusions:
- Nano-SEDDS formulation of SAS + DSF enhances drug potency and efficacy for lung cancer chemo-interception.
- This approach offers a promising strategy to overcome bioavailability limitations of SAS and DSF.
- The findings support the potential of Nano-SEDDS for improved lung cancer treatment and prevention.
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