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Ligand/target1 | Carrier | siRNA and/or active moiety | Cells | Results | Other comments | References |
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High MW endogenous ligands |
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Transferrin (Tfr)/TfR receptor | Polymer (cyclodextrin) | siRRM2 | Neuro2A, murine neuroblastoma, implanted SC | Greater tumor inhibition with targeted than nontargeted NP | Dose-related efficacy using transferrin ligand | [59] |
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Hyaluronic acid/CD44 | Liposomes | siPLK1 | U87MG, human glioblastoma, orthotopic | Prolonged survival, reduced PLK1 mRNA by 80% in tumor xenografts versus control siRNA | CD44 increased on cell surfaces of many cancers | [63] |
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ApoA1/SR-B1 | Liposomes | siVEGF | MCF-7, SC | Inhibited tumor size and prolonged survival | Hepatocellular carcinomas have been targeted | [72] |
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Aptamers |
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Aptamer/PSMA2ā | Aptamer-siRNA chimera | siPLK1 | PSMA+ (22Rv) versus PSMA- (PC-3) cells, SC | Tumor regression of 22Rv xenografts treated with apta-mer-PLK1 siRNA | PSMA upregulated in prostate cancer | [78] |
Aptamer/PSMA | Aptamer- dsRNA binding domain- polyhistidine chimera | siGFP | PSMA+ (LNCaP) versus PSMA- (PC-3) cells, in vitro study only | Silenced GFP efficiently in LNCaP cells | dsRNA-binding domain binds to siRNA; chimera may not efficiently lyse endosomes in vivo | [80] |
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Aptamer/PSMA | Polymer (atelocollagen) | (miR15a and miR-16-1) | Bone metastatic prostate model-LNCap cells | Prolonged mouse survival versus nontargeted NP | Reduced expression of Bcl-2, cyclin D1, and Wnt3a in vitro with targeted NP | [86] |
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Antibodies |
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scFv/Her2+ | scFv-protamine-conjugate | siPLK1 | Her2+ versus Her2- breast cancer, orthotopic | Marked tumor inhibition on Her2+ tumors in vivo versus no/little effect on Her2- tumors | Ionic interaction between siRNA and protamine; siRNA cocktail targeting PLK1, CCND1, and AKT more effective than PLK1 alone | [89] |
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scFv/Her2+ | Polymer (PLA) | siPLK1 | Her2+ (BT474) versus Her 2- (MCF7) breast cancer, orthotopic | Targeted NP inhibited both Her2+/- xenografts but showed the most efficacy toward Her2+ tumors | Dose-dependent antitumor response of the targeted NP was observed | [95] |
Small molecule nonpeptide ligands |
|
Folate/folate receptor | Low MW PEI cross-linked with by cyclodextrin | siVEGF | HeLa xenografts, SC | Targeted NP reduced tumor size more than nontargeted | Folate receptor is widely distributed in epithelial cancers | [109] |
Tetrahedral DNA | siGFPā siLuciferase | KB expressing GFP (in vitro) or luciferase, SC | Folate NP, given IV or IT, reduced tumor luciferase expression by 60% | 3 ligands on same face of tetrahedron to maximize uptake; well-defined NPs | [119] |
Polymer (oligoamine amides) | siEG5 | KB xenografts, SC | Methotrexate/siEG5 NP enhanced survival | Methotrexate targets folate receptor, small NPs (~6 nm) delivered IT | [120] |
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Anisamide/sigma-1, -2 receptors | Liposome | siMDM2, sic-MYC, and siVEGF | B16F10 murine melanoma, SC, and lung metastases | Reduced primary and metastatic tumor burden and prolonged survival | Receptor widely distributed in tumors and proliferating cells; sigma-2 ligands induce apoptosis in tumors | [125, 144] |
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Galactose/asialoglycoprotein receptors | Multilayered NP (mesoporous silica NP, polymers) | siVEGF/doxorubicin | QGY-7703, a hepatocarcinoma, SC | Marked inhibition with targeted NP (91.3%) versus nontargeted NP (75.2%) | Ligand targets primarily liver cells | [130] |
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Peptide ligands |
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T73/transferrin receptor | Cholesterol-grafted polymer/lipid hybrid | siEGFR | MC7 xenografts, SC | About 50% greater reduction in tumor size with targeted than nontargeted NPs | Binding of T7 to receptor is independent of endogenous transferrin concentration | [134] |
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MMP2-cleavable peptide | PEI-lipid hybrid micelle | Fluorescently-labeled siRNA and paclitaxel | A549 lung cancer xenografts, SC | Enhanced tumor uptake by 2.4-fold with MMP2-micelle | MMP2-triggered PEG deshielding | [135] |
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CP15/unknown | Polymer (chitosan) | siPLK1, biotin-labeled RNA | SW480 colon cancer cells, SC | Modest increase in tumor uptake/specificity of targeted NP (versus nontargeted NP) | Identified by phage display; primarily targets colon cancer; study requires validation | [136] |
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LHRH/LHRH receptor | Polymer (PPI) | siCD44/paclitaxel | Ovarian cancer xenograft, SC | Targeted therapy significantly more effective than nontargeted therapy | Combination of paclitaxel and siCD44 NP most effective in reducing tumor size | [139] |
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GRP/BB2 receptor | Conjugate | Fluorescently-labeled siRNA, siSurvivin | MDA-MB-231 xenografts (in vitro) | Competitive inhibition indicates specific uptake of GRP-siRNA conjugates into cells; marked reduction of survivin with targeted NP | Requires in vivo validation; BB2 reported to be on breast, prostate, lung, and colon cancers | [140] |
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RVG/acetylcholine receptor | Polymer (cyclodextrin) | siGADPH | U87 glioblastoma, HeLa (RVG- control), (in vitro) | Targeted NP reduced GADPH mRNA about 25% more than nontargeted NP in U87 | Requires in vivo validation; in vitro efficacy is modest | [142] |
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