We fabricated polymeric micelles containing 5-fluorouracil (5-FU) or fluorescein using the amphiphilic block copolymer, poly-4-vinylpyridine-b-6-O-methacryloyl galactopyranose. Although the polymeric micelles were stable at pH 7.4, they readily decomposed at pH 5, resulting in near complete release of 5-FU. Uptake of polymeric micelles containing fluorescein by HepG2 and HCT116 cells was also investigated. With both cell types, strong fluorescence was observed after a 12-h incubation, but the fluorescence weakened after 24 h of incubation. The fluorescein incorporated into the polymeric micelles was released into acidic organelles (endosome and/or lysosome), from which it diffused throughout the cell. The cytotoxicity of polymeric micelles containing 5-FU was evaluated against HepG2 cells using a CCK-8 assay. The results suggest that polymeric micelles containing 5-FU are more cytotoxic to HepG2 cells than free 5-FU.Key words pH responsiveness; polymeric micelle; mechanochemical solid-state polymerization; amphiphilic block copolymer Polymeric micelles formed from amphiphilic block copolymers (which consist of hydrophilic and hydrophobic blocks) have been extensively studied for their potential use as nanocarriers in aqueous solutions. Considerable attention has been paid to the use of polymeric micelles in drug delivery systems because of their ability to solubilize hydrophobic molecules and their nanoscale size, good thermodynamic stability in solution, capacity for extended release of various drugs, and their resistance to rapid clearance by the reticuloendothelial system. 1-9) Stimulus-responsive polymeric micelles have recently emerged as a novel controlled-release system in which drugs can be released by applying an appropriate stimulus, such as a specific temperature, pH, or ultrasound. A pHsensitive polymeric micelle would be particularly useful for targeting tumor tissues, endosomes, and lysosomes because these sites are more acidic than other parts of the body, such as the blood. Several reports describe the use of various types of pH-sensitive polymeric micelles for acidic pH-triggered drug release of drugs at tumor sites. [10][11][12][13] We previously reported the synthesis and drug release profiles of various polymeric prodrugs prepared by mechanochemical solid-state polymerization carried out through vibratory ball-milling of solid monomers in a metallic vessel under anaerobic conditions. 14-26) A series of studies revealed that this method is applicable to the preparation of a wide variety of vinyl monomers of important classes of bioactive compounds with different physicochemical properties. The method also provides a simple, novel means of synthesizing functionalized polymers in a totally dry process.19) The mechanochemical solid-state polymerization method we reported has several features: the resulting polymeric prodrugs have a narrow molecular weight distribution, represented by M w /M n , where M w represents the weight average molecular weight and M n the number average molecular weight; b...