Dual-Stimulus-Responsive Fluorescent Supramolecular Prodrug for Antitumor Drug Delivery

To achieve higher bioavailability by taking advantage of the complex biological environment, the development of drug delivery systems (DDSs) keeps progressing. Through supramolecular technology, building blocks with different properties and functions could be combined in a controlled manner, realizing programmable drug delivery with high efficiency. In this study, we constructed a supramolecular DDS (SDDS) with charge-reversal polyanions and fluorescent polycations with reduction cleavable camptothecin (CPT) attached. During the supramolecular assembly process, the prodrug exhibited a morphological change from cubelike to rodlike and its fluorescence was significantly enhanced. Programmed drug delivery was achieved by a dual response of the extracellular acid and intracellular reductive environment. In vitro studies of the SDDS made it possible to visualize faster cellular uptake at pH 6.8 than at pH 7.4 because of the re exposure of cationic charges and subsequent successful delivery of CPT to the cell nucleus. In the in vivo studies, SDDS treatment through tail vein injection showed enhanced tumor suppression compared with that of the cationic prodrug and free CPT treatment at a low concentration (1.5 mg/kg of CPT equivalents). Altogether, we developed a novel fluorescent supramolecular system as a tumor microenvironment-responsive carrier of hydrophobic drugs for programmed drug delivery, which could be used in future cancer therapy.