Recent trends in bioresponsive linker technologies of Prodrug-Based Self-Assembling nanomaterials

Prodrugs are designed to improve pharmaceutical properties of potent compounds and represent a central approach in drug development. The success of the prodrug strategy relies on incorporation of a reversible linkage facilitating controlled release of the parent drug. While prodrug approaches enhance pharmacokinetic properties over their parent drug, they still face challenges in absorption, distribution, metabolism, elimination, and toxicity (ADMET). Conjugating a drug to a carrier molecule such as a polymer can create an amphiphile that self-assembles into nanoparticles. These nanoparticles display prolonged blood circulation and passive targeting ability. Furthermore, the drug release can be tailored using a variety of linkers between the parent drug and the carrier molecule. In this review, we introduce the concept of self-assembling prodrugs and summarize different approaches for controlling the drug release with a focus on the linker technology. We also summarize recent clinical trials, discuss the emerging challenges, and provide our perspective on the utility and future potential of this technology.