期刊
JOURNAL OF CONTROLLED RELEASE
卷 279, 期 -, 页码 147-156出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.04.016
关键词
Reversibly activatable cell-penetrating peptides; Polymer micelles; Nanoparticles; pH-sensitive; Tumor-specific cytoplasm targeting
资金
- National Natural Science Foundation of China [81501579]
- Natural Science Foundation of Jiangsu Province [BK20150702]
- Ministry of Science and Technology of the People's Republic of China [2017ZX09101001]
- Chinese Pharmacopeia Commission [ZG2017-5-01]
- Fundamental Research Funds for the Central Universities [2632018ZD13]
- Six Talents Summit Program of Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Cell-penetrating peptides (CPPs) have become a novel drug delivery system due to their distinct advantages, including high cell transmembrane potency and ability to carry cargo molecules inside cells. However, owing to their cationic charge and non-specificity characteristics, the clinical application of CPPs is limited. In the current study, we engineered a reversibly activatable cell-penetrating peptide (RACPP), containing oligoarginine fused to a pH-sensitive masking sequence via a polyglycine linker ((HE)(10)G(5)R(6) or HE-CPP) with ultra-pH-sensitivity. The HE-CPP sequence was coupled to the surface of polyethyleneglycol-polylactic acid (PEG-PLA) polymer micelles (PMs-HE-CPP) to realize improve specificity and targeted delivery of encapsulated paclitaxel (PTX). PTX/PMs-HE-CPP showed the satisfactory encapsulated efficiency, loading capacity, size distribution as well as reversible charge-conversion in response to the surrounding pH. The zeta potential of PMs-HE-CPP was negative at pH 7.5, moderately positive at pH 6.5, and even more positive at a lower pH. Coumarin 6-loaded PMs-HE-CPP (C6/PMs-HE-CPP) showed enhanced tumor cellular uptake at a mildly acidic tumor microenvironment (pH 6.5) via energy-dependent and clathrin-mediated endocytosis. Furthermore, PTX/PMs-HE-CPP had significantly higher cytotoxicity toward mice breast cancer (4T1) cells at pH 6.5 versus at pH 7.4. In vivo imaging studies in 4T1-BALB/c tumor xenograft models confirmed the tumor-targeting characteristic of PMs-HE-CPP. PTX/PMsHE-CPP also exhibited improved anti-tumor efficacy against unmodified polymer micelles and Taxol (R) in this tumor model. Accordingly, not only do RACPPs show the great potential to endow CPPs with specificity and reversible net-charge converting characteristic, they are also able to improve the targeting effect of nanoparticles.
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