Zwitterionic nanocarriers have emerged as a new class of biocompatible nanomaterials with outstanding stealth capability in blood circulation. In this work, a novel biodegradable zwitterionic nanogel based on poly(sulfobetaine methacrylate) (PSBMA) was developed for reduction-responsive drug delivery to tumors. PSBMA nanogels were facilely fabricated by one-step reflux precipitation polymerization with the advantage of being surfactant-free and time-saving. The disulfide bond not only endowed the nanogels degradability in a reduction environment but also be modified with a fluorescent group after partial reduction. In vitro release experiments disclosed that doxorubicin (DOX)-loaded PSBMA nanogels could hold the drugs firmly in physiological conditions (only 7% release in 24 h) and release the drugs rapidly and sufficiently in 10 mM glutathione (85% in 8 h). More interestingly, PSBMA nanogels displayed long circulation in blood after intravenous injection, and small change was found in half-life of nanogels between the first (34.1 h) and the second injection (30.5 h), indicating that there was no accelerated blood clearance phenomenon for these nanogels. Meanwhile, no obvious immunogenic response was detected after PSBMA nanogels were injected into BALB/c mice. Furthermore, PSBMA nanogels showed a high accumulation of 9.5 and 10.7% of injected dose per gram of tissue in tumors at 24 and 48 h post intravenous injection, respectively. With outstanding long circulation time, high tumor accumulation, and sufficient drug release in a reduction environment, DOX-loaded PSBMA nanogels demonstrated the strongest tumor growth inhibition effect among all of the treatment groups in human hypopharyngeal carcinoma-bearing mouse models. Therefore, our study provided a facile drug delivery platform based on biodegradable zwitterionic nanogels and may have great potential in tumor drug delivery.

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