Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

Abstract

Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment.In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen.

A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo

“…PEGylation enhances the stability and half-life of nano carriers in blood circulation by avoiding recognition and clearance by phagocytic cells of the reticuloendothelial system and is widely used in in vivo applications of nano carriers. As the conventional MEND was composed of a cationic lipid, such as DOTAP, it was necessary to modify the conventional cationic MEND with high amounts of PEG lipids to suppress non-specific electrostatic interactions with internal components, such as negatively charged proteins [22,23,26]. However, it is also known that PEGylation results in a significant loss of gene silencing efficiency.…”

“…We previously reported on the production of a functional PEG-lipid, PPD, that is affected by matrix metalloproteinases (MMPs), which are secreted by various tumor cells and succeeded in silencing marker gene expression in tumor tissue by the systemic administration of PPD modified MEND [22,23]. In addition, we reported that GALA, a pH-sensitive fusogenic peptide, modified MEND could be applied to an in vivo intratumoral injection model and shGALA, a new shorter version of GALA to improve the pharmacokinetics of the MEND, which was modified to achieve gene silencing in tumor tissue followed by systemic administration [23][24][25][26]. As other strategy, Semple S.C. et.…”

Intelligent drug delivery systems for the treatment of solid tumors

“…Particles might be also functionalized with cancer cell targeting ligands, the ligands after cleavage of the PEG shell become exposed, and this can enhance intracellular delivery. Using this methodology, siRNA-loaded nanoparticles improved by approximately 70% the gene-silencing activity in mice bearing fibrosarcomas (34).…”

Nanobiodevice-based Single Biomolecule Analysis, Single-Cell Analysis, and in vivo Imaging for Cancer Diagnosis, Cancer Theranostics, and iPS Cell-based Regenerative Medicine

“…These QD conjugated materials are being applied to a wide variety of biomedical applications, including cancer cell detection, cancer therapy (Fig. 4D), 35 and in vivo imaging of iPS cells (Fig. 4B).…”

“…[1][2][3][4][5][6][7] In this review article, we mainly overview our research activities, including nanobiodevices for single-cell analysis, [20][21][22][23][24][25] single biomolecule analysis, 19,[26][27][28][29]41,46,50,[54][55][56][57][58] biomarker detections, 23,[30][31][32][33]39,[47][48][49] cancer theranostics, and iPS cell in vivo imaging. [20][21][22][23][24][25][34][35][36][37][38]40,[42][43][44][45]…”