Piotr Michałowski, Jacek Lachowicz, Filip Maciąg, Katarzyna Bielicka-Daszkiewicz

Modern application of programmable pharmaceuticals on target – multiple prodrugs against selective bioprecursors

 

2026-05-26

The subject of research. Prodrugs are defined as pharmacologically inactive chemical compounds that, upon administration to the body, undergo biotransformation, thereby releasing an active medicinal substance. The contemporary approach to their design is a tool that increases the efficacy and safety of pharmacotherapy, enabling improved bioavailability, solubility, permeability through biological barriers, and reduced toxicity. The extant literature distinguishes between three categories of prodrugs. Firstly, there are classic prodrugs associated with a carrier group. Secondly, there are enzymatically activated prodrugs. Thirdly, there are bioprecursors, which are compounds devoid of additional promoting groups, and which are activated under specific biological conditions. This study focuses on the utilization of prodrugs in the management of cancer, neurological, and chronic diseases.

The objective of the present study. The objective of this review was to discuss contemporary strategies for prodrug design, taking into account their classification, activation mechanisms, and clinical examples. Particular emphasis was placed on the role of bioprecursors, which exhibit latent structural activity and are activated only in the presence of specific enzymes in target tissues, thereby reducing adverse effects (e.g., valganciclovir, prasugrel, DHED). Moreover, the concept of multifunctional prodrugs and environmentally activated systems (e.g., under hypoxic conditions) was presented as an example of advanced therapeutic strategies in the treatment of cancer or neurodegenerative diseases.

Materials and methods. The review was based on an analysis of scientific literature from 2018 to 2025, including original articles, review papers, and FDA and EMA regulatory reports. In the course of the study, a number of factors were given full consideration, including, but not limited to, historical data relating to acetanilide and aspirin, the classification of compounds according to carrier type and activation mechanism, and a range of clinical and experimental examples. The pharmacokinetic properties, biological effects, and biotransformation mechanisms of selected classic, dual, and triple prodrugs and bioprecursors were evaluated.

Results. The analysis indicates that currently prodrugs account for approximately 10% of new pharmaceuticals entering the market, and their share is growing. Classic carrier-associated prodrugs (e.g., ester, amide) have been demonstrated to enhance the solubility and bioavailability of active substances. The utilization of enzymatically activated prodrugs facilitates the selective action of the pharmaceutical compound, while bioprecursors ensure activation is confined to target tissues, thereby reducing the incidence of adverse effects. The clinical significance of this approach is further substantiated by the utilization of medications such as valganciclovir, prasugrel and DHED. The use of double and triple prodrugs has been shown to improve control over the release of active substances and to enhance therapeutic efficiency under hypoxic conditions characteristic of cancer. The use of modern multifunctional systems and environmentally activated prodrugs has emerged as a key approach to advancing personalized medicine.

Conclusions. Prodrugs represent a rapidly expanding group of pharmaceuticals, which are gaining increasing clinical significance. The utilization of these agents has been demonstrated to enhance the efficacy of therapeutic interventions, reduce toxicity, and facilitate precise targeting, thereby contributing to improved patient outcomes. The significance of bioprecursors and conditionally activated smart systems is increasingly recognized, with the potential to inform targeted and personalized therapeutic approaches in the future.

Keywords: prodrugs, double prodrugs, tripartite prodrugs, bioprecursors, targeted pharmaceuticals.

© Farm Pol, 2025, 81(10): 585–596