Redox-responsive Polymeric Nanocarriers for Controlled Anticancer Drug Delivery: A Critical Appraisal of Trigger Biology, Design Evidence and Translational Constraints

Abstract

The difference in thiol concentration between the cytosol of tumour cells and the extracellular compartment has served for approximately two decades as the organising principle for a large family of polymeric nanocarriers designed to remain intact in circulation and to disassemble after cellular internalisation. Disulfide, diselenide and thioketal linkages have been placed in polymer backbones, at the junction between hydrophilic and hydrophobic blocks, within cross-linked cores and directly between carrier and cytotoxic agent, and the resulting micelles, polymersomes, nanogels and self-assembling prodrugs have been reported in several thousand preclinical studies. This review examines whether the accumulated evidence supports the confidence that is routinely expressed about the approach. Literature was identified through structured searching of biomedical, multidisciplinary and open-access scholarly indexes, supplemented by backward and forward citation searching, and appraised for design adequacy, comparator quality, transport plausibility and reporting completeness rather than for reported potency alone. Three findings recur. First, the biological premise is weaker than usually acknowledged: glutathione concentrations in human tumours are heterogeneous, overlap substantially with those of adjacent normal tissue, and are rarely measured in the same systems in which responsive carriers are tested. Second, the experimental evidence for redox-selective release is dominated by dissolution studies performed in strong reducing buffers that do not represent the intracellular environment, and matched non-responsive comparators are frequently absent, so the contribution of the trigger to any observed antitumour effect is often unidentifiable. Third, the quantity of drug that reaches tumour tissue is constrained by transport processes that operate upstream of any responsive chemistry, which limits the benefit that trigger optimisation alone can deliver. Redox-responsive architectures nevertheless offer a defensible route to improved carrier stability during circulation, and the strongest evidence supports this stabilising function rather than tumour-selective activation. Priorities include paired measurement of tumour redox status and carrier activation, mandatory non-responsive controls, reporting of released and encapsulated drug fractions, and evaluation in models that reproduce human tumour transport barriers.