Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives
Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14191 |
| _version_ | 1797465129098412032 |
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| author | Kristian Kåber Pedersen Maria Helena Høyer-Hansen Thomas Litman Merete Hædersdal Uffe Høgh Olesen |
| author_facet | Kristian Kåber Pedersen Maria Helena Høyer-Hansen Thomas Litman Merete Hædersdal Uffe Høgh Olesen |
| author_sort | Kristian Kåber Pedersen |
| collection | DOAJ |
| description | Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed. |
| first_indexed | 2024-03-09T18:17:05Z |
| format | Article |
| id | doaj.art-d7dc4078a819479283a7a3bb556af1fa |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:17:05Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d7dc4078a819479283a7a3bb556af1fa2023-11-24T08:40:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221419110.3390/ijms232214191Topical Delivery of Hedgehog Inhibitors: Current Status and PerspectivesKristian Kåber Pedersen0Maria Helena Høyer-Hansen1Thomas Litman2Merete Hædersdal3Uffe Høgh Olesen4Department of Dermatology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, 2400 Copenhagen, DenmarkMolecular Biomedicine, LEO Pharma A/S, 2750 Ballerup, DenmarkMolecular Biomedicine, LEO Pharma A/S, 2750 Ballerup, DenmarkDepartment of Dermatology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, 2400 Copenhagen, DenmarkDepartment of Dermatology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, 2400 Copenhagen, DenmarkSystemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed.https://www.mdpi.com/1422-0067/23/22/14191keratinocyte carcinomabasal cell carcinomahedgehog inhibitorssmoothened inhibitorsvismodegibsonidegib |
| spellingShingle | Kristian Kåber Pedersen Maria Helena Høyer-Hansen Thomas Litman Merete Hædersdal Uffe Høgh Olesen Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives International Journal of Molecular Sciences keratinocyte carcinoma basal cell carcinoma hedgehog inhibitors smoothened inhibitors vismodegib sonidegib |
| title | Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives |
| title_full | Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives |
| title_fullStr | Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives |
| title_full_unstemmed | Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives |
| title_short | Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives |
| title_sort | topical delivery of hedgehog inhibitors current status and perspectives |
| topic | keratinocyte carcinoma basal cell carcinoma hedgehog inhibitors smoothened inhibitors vismodegib sonidegib |
| url | https://www.mdpi.com/1422-0067/23/22/14191 |
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