Tumor microenvironment-responsive self-assembling polymeric prodrug-based nanomaterials for cancer therapy

Prodrug approach, involving the chemical modification of an active moiety, is one of the clinically proven strategies to overcome the unfavorable physicochemical and biopharmaceutical properties of potential therapeutic compounds. Despite many success stories, a number of small-molecule prodrugs face challenges in their druggability properties, thus limiting their clinical applications. Self-assembling prodrugs represent an emerging nanotherapeutic approach that possess the advantages of both prodrug design and nanotechnology. The selfassembling/formulating property of these prodrugs in aqueous media, by virtue of their amphiphilic character, constructs a wide variety of supramolecular nanostructures with numerous intrinsic advantages viz., high drug loading, minimal premature release, and improved pharmacodynamic and pharmacokinetic properties. Moreover, selection of suitable linker between the drug and promoiety, that selectively undergo cleavage at the target site, increases the selectivity of the delivery system, while decreasing the risk of off-targets effects. Although, majority of the self-assembling prodrug-based delivery systems have been developed for chemotherapeutic agents, a few examples of molecules belonging to other pharmacological classes can be found in the literature. In this review, we have comprehensively summarized the various self-assembling polymeric prodrugs of chemotherapeutic agents that have been developed for mono- and combination therapy. Responsiveness of linkers to the various endogenous stimuli of tumor microenvironment such as acidic pH, reactive oxygen species (ROS), redox, enzymes, and hypoxia is used to categorize these studies. This review is expected to be a unique document which along with providing the information hitherto available on this industrially relevant area, will provide guidance for the rational design of effective prodrug nanoassemblies that have clinical translational potential.