Targeted hypoxia-responsive small-molecule supramolecular carrier for tumor-selective doxorubicin delivery.

Abstract

Small-molecule supramolecular carriers provide structurally defined and highly tunable alternatives to conventional nanocarriers, but their limited passive tumor accumulation remains a major obstacle to effective drug delivery. Here, we developed an arginine-glycine-aspartic acid (RGD)-modified, hypoxia-responsive sulfonated azocalix[4]arene (pep-SAC4A) as an actively targeted supramolecular carrier for doxorubicin (DOX). DOX was incorporated through reversible noncovalent host-guest complexation, preserving the original drug structure while enabling stimulus-triggered release. The azo-containing supramolecular host underwent structural cleavage under hypoxic/reductive conditions, resulting in disruption of the host cavity and release of DOX. RGD modification enhanced integrin-mediated cellular uptake and promoted intracellular trafficking from lysosomes to the nucleus. Under hypoxic conditions, pep-SAC4A/DOX induced greater mitochondrial dysfunction and DNA damage than the non-targeted formulation. In tumor-bearing mice, pep-SAC4A/DOX exhibited enhanced tumor accumulation and produced the strongest inhibition of tumor growth, accompanied by increased apoptosis, reduced proliferation, and lower interindividual variability in serum alanine aminotransferase (ALT) levels. Collectively, these findings demonstrate that active targeting and hypoxia-responsive release can be integrated into a small-molecule supramolecular host, providing a compact strategy for improving tumor-selective chemotherapy.

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