Ester-Based Prodrugs: Rational Design, Mechanistic Insights, and Translational Applications in Neurology and Dermatology

The blood-brain barrier and the skin's stratum corneum restrict the access to target tissues for central nervous system (CNS) and dermatological drugs; systemic administration frequently causes side effects in other parts of the body. Imbalance of cutaneous neuroimmune signals is related to itching in atopic dermatitis and to peripheral sensitization in postherpetic neuralgia, indicating the necessity of drug delivery methods that integrate barrier penetration with local activation at the desired site. Ester prodrugs link the parent drug to a carrier through a reversible ester bond and are activated by esterase hydrolysis; they are extensively applied because of their structural flexibility and controllable activation. The main idea of their structure is to regulate the steric hindrance and electrical properties of the ester bond in order to achieve a good balance between systemic stability and efficacy in the target tissue. The expression of esterases and substrate specificity can lead to different activations in different places. For CNS delivery, esterification might enhance the permeability of the blood-brain barrier, while amino acid groups can facilitate uptake by LAT1; the release is dependent on the specific bioconversion pathway of the prodrug. In the skin, the local esterase activity supports in situ hydrolysis, but the responsible enzymes and their effects are influenced by the type of substrate and the model. This paper systematically discusses the design principles of ester prodrugs, mainly focusing on their translational applications in the fields of neurology and dermatology. In summary, the clinical application will involve solving the problems of esterase variability, premature hydrolysis, and the safety of leaving groups by using predictive models and specific activation strategies in different tissues.