1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
2. Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Rm 2972, Skaggs Pharmacy Institute, 30S 2000E, Salt Lake City, Utah 84112, USA.
3. School of Pharmaceutical Science, Shanxi Medical University, No. 56, Xinjian Nan Road, Taiyuan 030001, Shanxi, People's Republic of China.
Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing cis-diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated “sheddable” PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat. By virtue of the pH-dependent stability of borate ester in an aqueous medium, the PEG-shell could “shield” the PBA ligand in systemic circulation to reduce its “off-target effect”, while PEG was detached at tumor extracellular pH (~6.5) to expose intact PBA moiety. Simultaneously, the PBA ligand could bind with overexpressed sialic acid residues on cancer cells, giving rise to enhanced cellular internalization. In addition, the PBA moieties could also couple with each 3'-end ribose of double-stranded siRNA. siRNAs were used as both a payload and a pH-responsive intermolecular cross-linker, and thereby acquired sufficient stability during circulating in blood and a rapidly triggered release in response to acidic endosomal/lysosomal pH-stimuli. As a result, this dual pH-sensitive nanoparticle showed enhanced siRNA uptake, gene silencing efficacy and anti-metastatic effects in vitro. Furthermore, in vivo studies demonstrated that PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration.
Keywords: Phenylboronic acid, pH-Responsive, Sialic acid targeting, Systemic siRNA delivery, Cancer Metastasis, Orthotopic breast murine model.