Biodegradable Inorganic Nanovector: Passive versus Active Tumor Targeting in siRNA Transportation

Abstract

The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system.

2D Layered Double Hydroxide Nanoparticles: Recent Progress toward Preclinical/Clinical Nanomedicine

“…Considering these constraints, active targeting appears advantageous in increasing the amount of particles accumulated at the tumor site via interactions between targeting ligands and characteristic receptors. Park et al reported Survivin siRNA delivery systems by constructing passive LDH with a particle size of 100 nm and active LDH conjugated with folic acid (FA), a ligand targeting cancer overexpressing folic acid receptor . The folic acid surface modification of LDHs was achieved by coupling reactions with APTES and 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐carbodiimide (EDC) ( Figure a) .…”

“…Park et al reported Survivin siRNA delivery systems by constructing passive LDH with a particle size of 100 nm and active LDH conjugated with folic acid (FA), a ligand targeting cancer overexpressing folic acid receptor . The folic acid surface modification of LDHs was achieved by coupling reactions with APTES and 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐carbodiimide (EDC) ( Figure a) . The folic acid‐mediated active LDH system exhibited 1.2‐fold higher accumulation of siRNA in tumor tissues compared to other organs (Figure b,c), and most importantly, threefold higher suppression of tumor volume than the passive LDH (Figure d) .…”

“…The folic acid surface modification of LDHs was achieved by coupling reactions with APTES and 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐carbodiimide (EDC) ( Figure a) . The folic acid‐mediated active LDH system exhibited 1.2‐fold higher accumulation of siRNA in tumor tissues compared to other organs (Figure b,c), and most importantly, threefold higher suppression of tumor volume than the passive LDH (Figure d) . In addition to the covalent binding, folic acid was also linked onto the LDH surface by facile electrostatic absorption or chelating interaction, and displayed evident targeting capability that enabled particle to preferably accumulate in cancer tissues.…”

“…d) In vivo anticancer effect via intraperitoneal injection of LDHFA/siSurvivin and control agents every 7 d, shown by photographic images of tumor‐bearing mice on 18 d post‐treatment and tumor volumes measured at a 2 d interval. Reproduced with permission . Copyright 2016, Wiley‐VCH.…”

Nanoparticles as Theranostic Vehicles in Experimental and Clinical Applications—Focus on Prostate and Breast Cancer

“…The protein survivin, encoded by the BIRC5 oncogene in the human genome, and which inhibits the caspase activation and therefore downregulates the apoptotic pathway, has received much attention lately. Several attempts, also including NPs, have been made to distribute anti-survivin siRNA in order to silence the BIRC5 gene [445,446,447]. For NP-based GTH applications for PCa, there are also quite few publications the last decade [141,448,449,450,451,452].…”