Targeted Delivery of siRNA Therapeutics to Malignant Tumors

Abstract

Over the past 20 years, a diverse group of ligands targeting surface biomarkers or receptors has been identified with several investigated to target siRNA to tumors. Many approaches to developing tumor-homing peptides, RNA and DNA aptamers, and singlechain variable fragment antibodies by using phage display, in vitro evolution, and recombinant antibody methods could not have been imagined by researchers in the 1980s. Despite these many scientific advances, there is no reason to expect that the ligand field will not continue to evolve. From development of ligands based on novel or existing biomarkers to linking ligands to drugs and gene and antisense delivery systems, several fields have coalesced to facilitate ligand-directed siRNA therapeutics. In this review, we discuss the major categories of ligand-targeted siRNA therapeutics for tumors, as well as the different strategies to identify new ligands.

Advances in Delivery Systems for Doxorubicin

“…Notably, the dose of Dox was significantly lower than in most other studies in which the dose of Dox was 5 mg/kg or higher. In addition to the targeting ligand NGR, many tumor-selective ligands are promising for conjugation to the surface of the NP [55].…”

Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside

“…In terms of siRNA formulation to accumulate in tumors, specifically, it is only around 20 to 40% higher than that of normal tissue [ 128 ]. The enhanced permeation and retention (EPR) effect, which stems from leaky blood vessels in tumors, allows for the preferential uptake of the formulation in tumors compared to normal tissue but is not significant enough and may ultimately cause more harm than good in the long run [ 128 ]. Thus, to overcome these off-target effects, the use of surface-ligand modifications for siRNA formulations have recently been utilized for more targeted delivery of cargo.…”

“…cRGD can be isolated from in vivo tumor phage selection display and preferentially binds to avβ3 and avβ5 integrins. It is overexpressed on angiogenic endothelial cells of various tumor types and even on the tumors themselves [ 128 ]. cRGD is known to bind to integrin receptors 100-fold more tightly than linear RGD, making it the peptide of choice for surface modification [ 133 ].…”

Folate Receptor-Mediated siRNA Delivery: Recent Developments and Future Directions for RNAi Therapeutics

“…Targeted delivery of siRNAs involves conjugation of specific targeting ligands to the delivery carrier capable of binding to complementary receptors overexpressed on cell surfaces [61]. Several siRNA-targeting ligands conjugates, including antibody, aptamer, cyclodextrin, GalNAc, galactose, cyclodextrin, hyaluronic acid (HA), anisamide, and folic acid (FA), have increased cellular uptake, increased concentration of siRNAs at the target, and potent gene silencing [49,61,62]. For example, GalNAc-conjugated siRNAs bind to the N-asialoglycoprotein receptors overexpressed in liver hepatocytes [62].…”