Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Drug Delivery

Background:

• Surface PEGylation of siRNA vectors prevents protein adsorption and RES clearance but hinders cellular uptake.
• Stimuli-responsive, shell-detachable nanovectors offer a solution for enhanced cellular internalization and prolonged circulation.
• Tumor extracellular pH (pHe) is a promising stimulus, but designing sensitive systems is challenging due to subtle pH differences.

Purpose of the Study:

• To develop a novel acid-sensitive bridged copolymer for tumor-targeted systemic delivery of siRNA.
• To create stimuli-responsive nanovectors that enhance cellular uptake while maintaining prolonged blood circulation.
• To overcome the dilemma of PEGylation's dual effect on siRNA vector performance.

Main Methods:

• Development of a simple acid-sensitive bridged copolymer.
• Formation of micelleplex delivery systems (Dm-NP) with a poly(ethylene glycol) (PEG) corona.
• Incorporation of a pH-responsive linkage for PEG detachment and a cell-penetration peptide for enhanced uptake.

Main Results:

• Dm-NP demonstrated a stable PEG corona for prolonged circulation and RES evasion.
• Acid-sensitive linkage breakage at tumor sites triggered PEG detachment, facilitating cell targeting.
• Exposure of cell-penetration peptide upon PEG removal significantly enhanced cellular uptake.
• Dm-NP achieved effective tumor accumulation and enhanced inhibition of non-small cell lung cancer growth.

Conclusions:

• The developed Dm-NP system successfully balances prolonged circulation and targeted cellular delivery.
• Stimuli-responsive PEG detachment is a viable strategy for enhancing nanovector efficacy in tumors.
• This approach offers a safe and effective method for siRNA delivery and cancer treatment.