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Innovative agents for actinic keratosis and nanocarriers enhancing skin penetration
M Schäfer-Korting1, M Höltje, H C Korting
1Institut für Pharmazie (Pharmakologie und Toxikologie) der Freien Universität Berlin, Berlin, Deutschland. msk@zedat.fu-berlin.de
Abstract:
Actinic keratosis and cutaneous squamous cell carcinoma are of increasing importance with aging and increased ultraviolet light exposure in Western societies. Efficient and well-tolerated therapy is still a matter of concern. As with tumours of other organs, new target sites and innovative drugs selectively addressing them are widely looked for. Due to the relevance for DNA synthesis and thus cell proliferation, human DNA polymerase alpha should be such a target, the more so as the three-dimensional structure of the active site has been proposed based on the application of molecular modelling methods and molecular dynamics simulations. The modelled structure of the active site was used for docking nucleotide analogues in order to design selective inhibitors. Consequently, well-fitting thymidine and guanosine analogues were synthesized and tested in vitro for their influence on normal and transformed human keratinocytes. In fact, the combination of modelling studies and in vitro tests allowed us to design antiproliferative and cytotoxic agents which are new drug candidates for the therapy of skin tumours, given the agents are no relevant substrates of nucleotide transporters (MRP-4, MRP-5) expressed by skin cancer cells. Essential kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogues. Due to the rather high molecular weight and poor solubility, however, skin penetration should be poor and thus topical therapy may require carriers to improve the uptake. This becomes feasible by lipidic and non-lipidic nanoparticles which can enhance the uptake of lipophilic agents up to 13-fold.
Insights
New drug candidates targeting human DNA polymerase alpha show promise for treating skin tumors like actinic keratosis. Nanoparticle delivery enhances uptake of these novel antiproliferative and cytotoxic agents.
Area of Science:
- Dermatology
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Actinic keratosis and cutaneous squamous cell carcinoma are rising health concerns due to aging populations and increased UV exposure.
- Current therapies for these skin cancers lack efficiency and optimal tolerability, necessitating novel therapeutic strategies.
- Identifying new molecular targets and developing innovative drugs are crucial for effective skin cancer treatment.
Purpose of the Study:
- To identify and validate human DNA polymerase alpha as a therapeutic target for skin tumors.
- To design and synthesize novel nucleotide analogues as selective inhibitors of DNA polymerase alpha.
- To evaluate the antiproliferative and cytotoxic potential of these analogues against human keratinocytes.
Main Methods:
- Utilized molecular modeling and dynamics simulations to determine the 3D structure of the DNA polymerase alpha active site.
- Employed molecular docking to design and identify potential nucleotide analogue inhibitors.
- Synthesized thymidine and guanosine analogues and tested their in vitro effects on normal and transformed human keratinocytes.
- Assessed the role of nucleotide transporters (MRP-4, MRP-5) and essential kinases in nucleoside activation.
Main Results:
- Successfully designed and synthesized novel thymidine and guanosine analogues with antiproliferative and cytotoxic effects.
- Demonstrated that these agents are not substrates for MRP-4 and MRP-5, suggesting selective action on cancer cells.
- Identified key kinases involved in nucleoside activation, correlating with observed analogue effects.
- Confirmed that lipidic and non-lipidic nanoparticles can enhance the skin penetration and uptake of these agents by up to 13-fold.
Conclusions:
- Developed promising drug candidates for skin tumor therapy by targeting human DNA polymerase alpha.
- The combination of computational modeling and in vitro studies proved effective in designing novel anti-skin cancer agents.
- Nanoparticle-based drug delivery systems offer a viable strategy to overcome poor skin penetration and enhance therapeutic efficacy.
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