Polymer Nanoparticles Modified with Photo- and pH-Dual-Responsive Polypeptides for Enhanced and Targeted Cancer Therapy

Abstract

The cationic nature of cell penetrating peptides (CPPs) and their absence of cell selectivity restrains their applications in vivo. In this work, polymer nanoparticles (NPs) modified with photo- and pH-responsive polypeptides (PPPs) were successfully developed and respond to near-infrared (NIR) light illumination at the tumor site and a lowered tumor extracellular pH (pHe). In PPPs, the internalization function of CPPs (positively charged) is quenched by a pH-sensitive inhibitory peptide (negatively charged), which is linked via a photocleavable group. Small interfering RNA (siRNA) was loaded into NPs by a double-emulsion technique. In vivo experiments included siRNA loading, cellular uptake, cell apoptosis, siRNA transfection, tumor targeting delivery, and the in vivo antitumor efficacy. Results showed that the prepared PPP-NPs could selectively accumulate at the tumor sites and internalized into the tumor cells by the NIR light illumination and the lowered pHe at the tumor site. These studies demonstrated that PPP-NPs are a promising carrier for future tumor gene delivery.

Cell Penetrating Peptides, Novel Vectors for Gene Therapy

“…The cell penetrating ability of the cationic CPPs was quenched by a pH-sensitive, negatively charged inhibitory peptide that was released in the lower pH microenvironment of the tumor. These NPs, loaded with siRNA, accumulated within tumor cells upon near-infrared light illumination, resulting in increased antitumor efficacy in vivo [109]. Another approach employed was PEGylation of glycosaminoglycan-binding peptides coupled with DNA through electrostatic charge interactions, which formed NPs that targeted bronchial epithelial cell lines with precision cut lung slices in vitro showing that PEGylation rates of >40% were the optimal formulation [110].…”

Breaking in and busting out: cell-penetrating peptides and the endosomal escape problem

“…Given that infection results in high levels of reactive oxygen species, the constructs would ideally only be cleaved in regions undergoing an inflammatory response (perhaps cleverly harnessing the endosomal entrapment problem in a good way, withholding cargos from off-target cell cytoplasms and targeting them for destruction!). In 2016, Yang et al successfully delivered siRNA in nanoparticles to tumors by exploiting lower pH conditions present in those tumors (69). However, that cleavage of the linker relied on both low pH conditions and exposure to near IR-light confers substantial accessibility limitations.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…The CPP was quenched by the pH‐sensitive inhibitory peptide to avoid its non‐specific internalization to normal cells, and the CPP was linked via a photocleavable group. This photo‐ and pH‐responsive polypeptides (PPPs) modified NPs responded to NIR light illumination and a lowered extracellular pH at the tumor to expose the CPP for specific penetration to cancer cells …”