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A novel and versatile family of enzymaticallyand reductively degradableα-amino acid-based poly(ester amide)s (SS-PEAs) were developedfrom solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-l-phenylalaninediesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate(NA) in N,N-dimethylformamide (DMF).SS-PEAs with Mnranging from 16.6 to 23.6kg/mol were obtained, depending on NA/SS-Phe-2TsOH molar ratios. Thechemical structures of SS-PEAs were confirmed by 1H NMRand FTIR spectra. Thermal analyses showed that the obtained SS-PEAswere amorphous with a glass transition temperature (Tg) in the range of 35.2–39.5 °C. The in vitrodegradation studies of SS-PEA films revealed that SS-PEAs underwentsurface erosion in the presence of 0.1 mg/mL α-chymotrypsinand bulk degradation under a reductive environment containing 10 mMdithiothreitol (DTT). The preliminary cell culture studies displayedthat SS-PEA films could well support adhesion and proliferation ofL929 fibroblast cells, indicating that SS-PEAs have excellent cellcompatibility. The nanoparticles prepared from SS-PEA with PVA asa surfactant had an average size of 167 nm in phosphate buffer (PB,10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiologicalenvironment undergo rapid disintegration under an enzymatic or reductivecondition. The in vitro drug release studies showed that DOX releasewas accelerated in the presence of 0.1 mg/mL α-chymotrypsinor 10 mM DTT. Confocal microscopy observation displayed that SS-PEAnanoparticles effectively transported DOX into both drug-sensitiveand -resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEAnanoparticles had a high antitumor activity approaching that of freeDOX in drug-sensitive MCF-7 cells, while more than 10 times higherthan free DOX in drug-resistant MCF-7/ADR cells. These enzymaticallyand reductively degradable α-amino acid-based poly(ester amide)shave provided an appealing platform for biomedical technology in particularcontrolled drug delivery applications. [ABSTRACT FROM AUTHOR]