This study plans to develop a nanoparticle technology that can assemble different polymeric “building blocks” with various desired functionalities into one nanosystem in a pH-dependent manner. For this purpose, polymeric building blocks were specifically designed with hyperbranched architectures, and orthogonal pH-reversible phenylboronic acid-diols were taken as “joints” to integrate them together. To verify the idea, a corona-core dual-polymer nanoassembly was prepared as the vehicle for lysosomotropic gene/drug co-delivery. Phenylboronic acid modified hyperbranched oligoethylenimine (OEI-PBA) was arranged to cluster around the hydrophobic core composed of hyperbranched polyglycerol, just by mixing two polymers in an appropriate ratio at neutral conditions. Compared with the parent OEI-PBA, this nanoassembly demonstrated better capture of plasmid DNA, highly enhanced activity for cellular transport and gene transfection (up to 100 fold), the ability to further load hydrophobic drugs, lysosome acidity-targeting pH-dependent release of both carried cargoes, and improved cell-biocompatibility. To evaluate its potential for combinational gene/drug therapy, in vitro experiments using the therapeutic p53 gene and antitumor doxorubicin as models were carried out. This intracellular co-delivery led to apparently synergetic anti-cancer effects in cultured cancer cells. This dynamic paradigm shows interesting features including easy manipulation, reversible conjugation, lysosome-targeting pH-responsiveness, high co-delivery efficiency, and functional expandability by further accommodating other building blocks.
Zhenzhen Feng,Yanyun Ma,Bingjie Li,Leiliang He,Qing Wang,Jin Huang,Jianbo Liu,Xiaohai Yang,Kemin Wang
Acatastatic pH values of organelles are associated with cell dysfunction and various diseases, which may increase the risk of diabetes, obesity, cancer, Alzheimer's disease and so on. Thus, in situ monitoring of the pH of organelles is extremely essential. Herein, we designed ratiometric fluorescent nanoprobes based on self-assembly for imaging of mitochondrial pH in living cells. The nanoprobes consisted of three parts: (1) a β-cyclodextrin polymer (β-CDP) acted as the backbone of the nanoprobes; (2) two lipophilic dyes acted as the pH sensitive unit and reference unit, i.e. adamantane-labeled fluorescein (Ad-F) and adamantane-labeled rhodamine (Ad-R); (3) adamantane-labeled triphenylphosphonium (Ad-TPP) acted as the mitochondrial targeting unit. Confocal microscopy images proved that the nanoprobes have been successfully applied to monitor intracellular pH in the range of pH 4.0–8.0. Moreover, as evidenced by co-localization imaging, the nanoprobes also showed good ability to target mitochondria (Pearson correlation coefficient was 0.88). Additionally, the nanoprobes showed low toxicity, excellent pH reversibility, and flexibility of construction, and have the potential to monitor pH of other organelles if different targeting units are conjugated. Our strategy is expected to provide new tools for pH monitoring in specific organelles and diagnosis of pH related diseases.
危险品化学品经营许可证（带存储）