Copolymer micelles function as pH-responsive nanocarriers to enhance the cytotoxicity of a HER2 aptamer in HER2-positive breast cancer cells.

ABSTRACT: Efficient delivery of nucleic acids into target cells is crucial for nucleic acid-based therapies. Various nucleic acid delivery systems have been developed, each with its own advantages and limitations. We previously developed a nanoparticle-based delivery system for small chemical drugs using pH-responsive PEG8-PDPA100-PEG8 polymer micelles as carriers. In this study, we extend the application of these pH-responsive micelle-like nanoparticles (MNPs) to deliver oligonucleotides. We demonstrate that the MNPs efficiently encapsulate and deliver oligonucleotides of different lengths (20-100 nt) into cells. The cargo oligonucleotides are rapidly released at pH 5.0. We prepared MNPs carrying a Texas red-fluorescently labeled anti-human epidermal growth factor receptor 2 (HER2) aptamer (HApt). Compared to free HApt, the HApt-MNPs resulted in significantly better cellular uptake, reduced cell viability, and increased apoptosis in SKBR3 breast cancer cells, which overexpress HER2. Moreover, HApt-MNPs were significantly less cytotoxic to MCF7 breast cancer cells, which express low levels of HER2. After cellular uptake, HApt-MNPs mainly accumulated in lysosomes; inhibition of lysosomal activity using bafilomycin A1 and LysoTracker Red staining confirmed that lysosomal activity and low pH were required for HApt-MNP accumulation and release. Furthermore, HER2 protein expression declined significantly following treatment with HApt-MNPs in SKBR3 cells, indicating that HApt-induced translocation of HER2 to lysosomes exerted a potent cytotoxic effect by altering signaling downstream of HER2. In conclusion, this pH-responsive and lysosome-targeting nanoparticle system can efficiently deliver oligonucleotides to specific target cells and has significant potential for nucleic acid-based cancer therapies.

SUBMITTER: Shen Y 

PROVIDER: S-EPMC5790103 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature