Design, Classification, and Therapeutic Applications of Prodrugs in Modern Drug Development

Review Article

Abstract

Prodrugs represent chemically modified inactive derivatives of active drug molecules that undergo biotransformation to release the parent drug upon administration. The field of prodrug development has evolved significantly over the past decades, offering solutions to various pharmaceutical and pharmacokinetic limitations of existing drugs. The concept originated in 1958 has grown into a sophisticated drug design approach, addressing challenges like poor solubility, limited bioavailability, inadequate tissue targeting, and undesirable side effects. Recent developments in prodrug design have led to enhanced oral bioavailability and tumor-specific targeting through various mechanisms including enzyme-activated systems, carrier-linked modifications, and site-specific delivery approaches. Modern prodrug strategies incorporate advanced delivery systems such as antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT), enabling precise drug targeting and activation. Membrane transporters, particularly peptide transporters like PEPT1 and PEPT2, play crucial roles in prodrug absorption and distribution. The success of prodrugs in clinical applications is evident from various approved medications, including antiviral agents like sofosbuvir and baloxavir marboxil, demonstrating improved pharmacokinetic profiles and therapeutic outcomes. Recent advances in photodynamic therapy and enzyme-activated prodrugs have opened new avenues in cancer treatment, while carrier-linked and mutual prodrugs offer innovative solutions for various therapeutic challenges