Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma
OBJECTIVE: The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs.
SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations.
METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier), which was developed and characterized.
RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss).
CONCLUSION: The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Drug development and industrial pharmacy - 49(2023), 5 vom: 08. Dez., Seite 377-391 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ardad, Rameshwar M [VerfasserIn] |
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| Links: |
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| Themen: |
15H5577CQD |
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| Anmerkungen: |
Date Completed 23.06.2023 Date Revised 23.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/03639045.2023.2216785 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357189582 |
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| 100 | 1 | |a Ardad, Rameshwar M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 23.06.2023 | ||
| 500 | |a Date Revised 23.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a OBJECTIVE: The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs | ||
| 520 | |a SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations | ||
| 520 | |a METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier), which was developed and characterized | ||
| 520 | |a RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss) | ||
| 520 | |a CONCLUSION: The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Drug repurposing | |
| 650 | 4 | |a anti-cancer activity | |
| 650 | 4 | |a hepatocarcinoma | |
| 650 | 4 | |a in vivo toxicity | |
| 650 | 4 | |a oral delivery | |
| 650 | 4 | |a self-emulsifying drug delivery | |
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| 650 | 7 | |a Docetaxel |2 NLM | |
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| 700 | 1 | |a Manjappa, Arehalli S |e verfasserin |4 aut | |
| 700 | 1 | |a Dhawale, Shashikant C |e verfasserin |4 aut | |
| 700 | 1 | |a Kumbhar, Popat S |e verfasserin |4 aut | |
| 700 | 1 | |a Pore, Yogesh V |e verfasserin |4 aut | |
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