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Review
. 2017:2017:6971297.
doi: 10.1155/2017/6971297. Epub 2017 Nov 9.

Targeted Delivery of siRNA Therapeutics to Malignant Tumors

Qixin Leng  1 , Martin C Woodle  2 , A James Mixson  1
Affiliations
Review

Targeted Delivery of siRNA Therapeutics to Malignant Tumors

Qixin Leng et al. J Drug Deliv. 2017.

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 single-chain 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.

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Figures

Figure 1
Figure 1
Schematic overview of the different ligands and core particles that target tumors. An array of core particles and ligands has been used to carry siRNA which inhibit oncogenes or induce apoptosis of tumor cells.
Figure 2
Figure 2
Peptide ligands targeting tumor endothelial cells and tumor cells. Ligands and their receptors are shown with associated cells.
Figure 3
Figure 3
Proposed mechanism of CendR tumor-peptides to transport NPs into tumor matrix. After a CendR peptide such as iRGD binds to av integrins, furin-like enzymes cleave the cyclic peptide (dash line) on the carboxyl side of the lysine group. With reduction of the cystine linkage (solid line), the peptide, KDGR, binds to the neuropilin receptor and activates the transcytosis pathway. The peptide together with the NP is then endocytosed and transported through the endothelial cell to the tumor milieu. E, endosome.
Figure 4
Figure 4
Aptamer mediated delivery of siRNA. (a) Aptamers and siRNAs have been conjugated with one another to form a chimera (upper). To enhance lysis of endosomes and minimize formation of polyplexes, aptamer-siRNA conjugates have been complexed to double stranded DNA domain- (DSD-) polyhistidine conjugates (lower). Upon entry into acidic endosomes, the polyhistidine component becomes protonated which aids in the lysis of endosomes. (b) Alternatively, aptamers have been conjugated to the surface of core particles (i.e., liposomes, polyplexes) that have incorporated siRNA.
Figure 5
Figure 5
Antibody mediated delivery of siRNA. (a) siRNA can interact with the cationic proteins such as protamine that has been directly conjugated with the antibody. (b) Similar to aptamers, antibodies may be conjugated to a carrier of siRNA (liposomes, polyplexes). In addition to their direct conjugation to the membrane surface of NP, the antibody may be attached to PEG (far right). The antibody ligand includes not only the parent antibody or its Fab fragment, but as in this case, it may include the single-chain variable fragment form of the antibody.
Figure 6
Figure 6
Enhanced tumor uptake of MMP2-degraded NP. Several tumors secrete high levels of the MMP2 enzyme into their stroma. By incorporating the substrate, GPLGIAGQ, between PEG and the NP, the MMP2 cleaved the peptide and releases PEG from the NP. This enables the NP to bind to the negatively charged surface of tumor cells with subsequent endocytosis of the NP.
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