期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 90, 期 5, 页码 892-899出版社
WILEY
DOI: 10.1111/cbdd.13010
关键词
antibody-drug conjugate; drug delivery system; non-Hodgkin lymphoma; reduction-sensitive; rituximab
资金
- National Natural Science Foundation of China [81571828, 81402222, 81401355]
- Science and Technology Commission of Shanghai Municipality [14411963700]
In this study, a novel reduction-sensitive drug delivery system, the rituximab-doxorubicin (RTX-DOX) micellar nanoparticle (RDMN), was specially designed for targeted delivery and release of DOX in non-Hodgkin's lymphoma (NHL) cells. The RDMN was fabricated by self-assembling of amphiphilic RTX-DOX conjugates (RDCs), which were synthesized by conjugating the hydrophilic Fab fragments of RTX (an anti-CD20 monoclonal antibody) and hydrophobic DOXs by a reduction-responsive linker, 3-(2-Pyridyldithio) propionyl hydrazide (PDPH). The RDMNs were characterized via dynamic light scattering and transmission electron microscopy, both showed the sizes of approximately 94.1 +/- 14.5nm with a uniform size distribution. Polyplex dissociation, which was indicated by accelerated DOX release rate and increased particle size, was observed in the presence of 2.5mm 1,4-dithiothreitol due to the cleavage of disulfide bonds in PDPH linkers. In vitro transfection assays against human NHL cell line, JeKo-1, showed significantly increased uptake for RDMNs, as compared to RDCs and free RTX/DOX. Both in and ex vivo experiments demonstrated that RDMNs showed the highest therapeutic effect among all the experimental groups. These results suggested that this RDMN could be a potential, safe and efficient drug delivery vector, which deserves further investigation in the clinic.
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