Recently, Prof. Gao Zhonggao's group of State Key Laboratory of Bioactive Substance and Function of Natural Medicines in the Institute of Materia Medica of Chinese Academy of Medical Science and Peking Union Medical College has successfully developed a novel stimuli-responsive siRNA delivery system. Taking advantages of the tumor microenvironment, this kind of delivery system was able to realize tumor-targeted therapy. The relevant article “Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma” has been published by the international authorized journalTheranostics (IF 8.854).
Phenylboronic acid (PBA) is a Lewis acid and is able to form reversible borate esters with cis -diol-containing compounds such as sialic acids (SA) expressed on cell surface, ribose in the siRNA and the small molecule compound catechol. Therefore, in this study, catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) could be conjugated via the borate ester formed between PBA and Cat, and the conjugation PEG-Cat-PBA-PEI (PCPP) was able to condense the negatively charged siRNA through electrostatic force and the covalent interaction between PBA and the 3’-end ribose of double-stranded siRNA. These two kinds of interactions contributed to the stability of the nanoparticle. After intravenous injection, the PCPP/siRNA nanoparticles were accumulated in the tumor tissues through the EPR effect. Then, the extracellular acidity activated the detachment of PEG-shell and exposure of PBA, and the exposed PBA could recognize the SA and trigger the SA receptor-meditated cellular internalization. In cytoplasm, PEI assisted the endosomal/lysosomal escape, ultimately, the RNAi response induced by the released siRNA silenced the target gene and achieved the purpose of treatment.
This research work not only overcame the "PEG dilemma", but also solved the conflict between the extracellular stability and the intracellular siRNA release ability of the siRNA delivery system. Moreover, in vivo studies demonstrated that such PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration. This novel stimuli-responsive siRNA delivery system holds great potential for tumor-targeted therapy.
The article is available online.
