Journal
ADVANCED FUNCTIONAL MATERIALS
Volume 26, Issue 43, Pages 7775-7790Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201604206
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Funding
- Natural Science Foundation of China [21271002]
- National High-Level Personnel of Special Support Program
- National High Technology Research and Development Program of China [SS2014AA020538]
- Science Foundation for Distinguished Young Scholars of Guangdong Province [S2013050014667]
- YangFan Innovative & Entrepreneurial Research Team Project [201312H05]
- Guangdong Special Support Program and Guangdong Frontier
- Key Technological Innovation Special Funds [2014B050505012]
- Fundamental Research Funds for the Central Universities
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The rational design of cancer-targeted and bioresponsive drug delivery vehicles can enhance the anticancer efficacy of conventional chemotherapeutics and reduce their adverse side effects. However, the complexity of precise delivery and the ability to trigger drug release in specific tumor sites remain a challenging puzzle. Here, a sequentially triggered nanosystem composed of HER2 antibody with disulfide linkage as a surface decorator (HER2@NPs) is constructed for precise drug delivery and the simultaneous inhibition of cancer growth, migration, and invasion. The nanosystem actively accumulates in cancer cells, undergoes self-immolative cleavage in response to biological thiols, and is degraded to form small nanoparticles. After internalization by receptor-mediated endocytosis, the nanoparticles further disassemble under acidic conditions in the presence of lysozymes and cell lysates, leading to sequentially triggered drug release. The released payload triggers overproduction of reactive oxygen species and activates p53 and MAPKs pathways to induce cancer cell apoptosis. Moreover, HER2@NPs markedly suppress the migration and invasion of human bladder cancer cells at nontoxic concentrations. HER2@NPs demonstrate potent in vivo anticancer efficacy, but show no obvious histological damage to the major organs. Taken together, this study provides a valid tactic for the rational design of sequentially triggered nanosystems for precise drug delivery and cancer therapy.
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