期刊
ACS APPLIED MATERIALS & INTERFACES
卷 9, 期 10, 页码 8569-8580出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.6b16669
关键词
Doxorubicin-conjugated gold nanoparticles; drug location; two-step drug release; lysosomal escape; treatment efficacy improvement
资金
- Natural Science Foundation of China [31470916, 31500769]
- Fundamental Research Funds for the Central Universities [2015PT036, 2016PT014]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance [DQCP2015MS01]
Drug-conjugated gold nanoparticles (GNPs), which are generally constructed with many molecules of thiol-terminated polyethylene glycol (PEG) drug decorated on their surfaces via a thiol-Au covalent bond, are promising and efficient nanoprodrugs. However, because of the exposure of the hydrophobic drug molecules on the surface of the conjugate, in vivo stability, opsonization, and subsequent inefficient therapy become the main issues of this system. To solve these problems without complicating the structures of gold conjugates, herein we propose a method to change the relative position of PEG and the drug. A novel gold conjugate (GNP-NHN=Dox-mPEG) with doxorubicin (Dox) shielded by PEGylation on the surface of GNPs is designed. It demonstrates improved solubility, stability, and dispersion and achieves a two-step stimulus-responsive drug release in response to an acidic environment in lysosomes and then esterase in the cytoplasm. This unique manner of release enables the cytoplasm to act as a reservoir for sustained drug delivery into the nucleus to improve antitumor efficacy in vivo. The intratumoral drug concentrations of the conjugate reach 14.4 +/- 1.4 mu g/g at 8 h, a two-fold increase in the drug concentration compared with that of the doxorubicin hydrochloride group. This molecular design and regulation approach is facile but important in modulating the in vivo performance of nanovehicles and demonstrates its vital potential in developing effective nanoparticle-based drug delivery agents.
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