Table 9.
Animal model | Delivery system | Route of administration | Silenced gene | Disease/objective | Comments | References |
---|---|---|---|---|---|---|
Female athymic nude mice (NCr-nu). | Chitosan (MW 50–190 kDa), sodium tripolyphosphate (TPP) | Intravenous | Zeste homolog 2 gene | Breast cancer | Significant reduction in tumor growth. | [433] |
Sprague–Dawley female rats bearing breast tumors. | Chitosan (MW 75 kDa; DDA 75–85%) | Intratumoral | Vascular endothelial growth factor (VEGF-A) and VEGF receptor (VEGFR1, VEGFR2) and co-receptors for VEGF; the neuropilin-1 (NRP-1) | Cancer | Nanoplexes containing chitosan and mixture of siRNAs (siVEGF-A, siVEGFR-1, siVEGFR-2, and siNRP-1) have a suppressive effect on VEGF expression and tumor volume. | [364] |
Female athymic nude mice (NCr-nu) bearing IGROV-AF1 or SKOV3TRip2 tumors. | Chitosan (MW 50–190 kDa) | Intravenous | Jagged1 | Ovarian cancer | Treatment with anti-human Jagged1 siRNA-CH and/or anti-murine Jagged1 siRNA-CH in two different orthotopic ovarian cancer models, treatment resulted in significantly reduced tumor weight up to 93%. | [434] |
Female athymic nude mice (NCr-nu) bearing SKOV3ip1 or HeyA8tumors. | Chitosan (MW 50–190 kDa), sodium tripolyphosphate (TPP) Chitosan: TPP (3:1) |
Intravenous | Zeste homologue 2 (EZH2) Also used: Alexa555-labeled siRNA and Cy 5.5 labeled siRNA |
Ovarian cancer | After nanoparticles injection, siRNAs were delivered to the tumor and to various organs, such as kidney, liver, lung, and spleen. EZH2 gene silencing lead to a decrease of tumor burden (reduction up to 83%) and an inhibition of angiogenesis mediated by reactivation of vasohibin1 (VASH1). | [435] |
Female athymic nude mice (NCr-nu) bearing melanoma (A375SM) and breast (MDA-MD231) cancer. | Chitosan hydrogel (CH-HG) chitosan (161 kDa; DDA 80%) | Intratumoral | Tissue Transglutaminase (TG2) Also used: Alexa555-labeled siRNA |
Cancer | Higher localization into tumor cells for siRNA CH-HG compared to siRNA alone. TG2 expression level was suppressed by up to 80% at 2 days and up to 50% until 10 days after a single injection of TG2 siRNA/CH-HG compared to control siRNA/CH-HG. Result in significant inhibition of tumor growth up to 92%. | [365] |
Female athymic nude mice (NCr-nu) bearing SKOV3ip1, HeyA8 or HeyA8-MDR tumors. | Chitosan-tripolyphosphate (TPP) | Intravenous | Src and Fgr (Src family kinases (SFKs)) | Ovarian cancer | Tumor growth was significantly reduced up to 84%. Tumor associated microvessel density significantly reduced up to 75%. Dual silencing resulted in significantly increased tumor cell apoptosis by more than 2-fold compared to all other groups. | [366] |
BALB/C and C57BL/6J mice | Chitosan (MW 130 kDa; DDA 86%) Imidazole-modified chitosan (chitosan-IAA) |
Intranasal | GAPDH | Non-specific disease | Significant silencing was seen in the lungs with chitosan and chitosan-IAA nanoparticles. | [436] |
PEG–chitosan (MW 130 kDa; DDA 86%) PEG–chitosan-IAA |
Intravenous | GAPDH and apolipoprotein B (ApoB) | PEG–chitosan-IAA nanoparticles delivery demonstrated significant knockdown in both lung and liver. | |||
Female athymic nude mice (NCr-nu) bearing SKOV3ip1, HeyA8, and A2780 tumors. | Arg-Gly-Asp peptide-labeled chitosan nanoparticles (RGD-CHNP) CH (MW 50–190 kDa) |
Intravenous | Periostin (POSTN) Focal Adhesion Kinase (FAK) Plexin domain-containing protein 1 (PLXDC1) Also used: Alexa555 siRNA |
Ovarian Cancer | The targeted delivery-mediated gene silencing significantly enhanced tumor localization, downregulation of specific gene and anti-tumor therapeutic efficacy compared to a non-targeted delivery system in ovarian cancer models. | [437] |
Sprague–Dawley rats | Chitosan (Low MW; DDA 75–85%) | Intrathecal | Muscarinic acetylcholine receptors (mAChR) subtypes: M2, M3 and M4. Also used: Alexa Fluor 488-labeled chitosan-siRNA nanoparticles |
Investigation to determine each subtype's role in controlling nociception at the spinal level | Chitosan nanoparticles can be used for efficient delivery of siRNA for silencing in neuronal tissues in vivo. By selective knockdown authors demonstrated that M2 and M4, but not M3, contribute to nociceptive regulation by mAChRs at the spinal level. |
[438] |
Female nu/nu mice bearing B16F10-red fluorescent protein (RFP) tumors. | Chitosan–Poly-l-arginine (PLR)–PEG Chitosan (MW 50–150 kDa; DDA 87% |
Intratumoral | Red fluorescent proteins (RFP) | Cancer | siRFP complexed to CS–PLR or to PEG–CS–PLR produced a significant reduction in RFP fluorescence 16.9 ± 1.7% and 10.4 ± 4.5% respectively compared to untreated tumor tissues. | [257] |
Nude male mice bearing LNCaP or PC3 tumors. | Chitosan-TPP | Intratumoral | RLN family peptide receptor 1 (RXFP1) | Prostate cancer | Treatment leads to a downregulation of RXFP1 receptor expression and an important reduction in tumor growth. | [439] |
Balb/c nude (nu/nu) mice bearing RFP/B16F10 tumors. | Glycol chitosan–polyethylenimine (GC–PEI) GC: MW 250 kDa; DDA 82.7%), |
Intravenous | Red fluorescent proteins (RFP) Also used: Cy5.5 labeled siRNA |
Cancer | siRNA–GC–PEI NPs presented higher tumor-targeting ability and a significant inhibition of gene expression in tumor. | [373] |
EGFP-transgenic mice (C57BL/6-Tg) (ACTb-EGFP). | Chitosan (CS) (MW 50 kDa; DDA 92%) Guanidinylated chitosan (GCS) Guanidinylated chitosan with β(2)-adrenoceptor agonist (SGCS) |
Endotracheal | Green fluorescent protein (GFP) | Respiratory diseases | Guanidinylation of chitosan improve cellular internalization of siRNA nanoparticles, reduce nanoparticle cytotoxicity and thereby increase downregulation of specific gene in the bronchial epithelial cells in vivo compared to unmodified chitosan. | [386] |
Mice bearing PC-3 tumor. Mice bearing SCC-7 tumor. Mice bearing RFP-B16F10 tumor. |
Poly-siRNA/thiolated glycol chitosan nanoparticles (psi-TGC) | Intravenous | Vascular endothelial growth factor (VEGF) Also used: FPR675-labeled poly-siRNA Reed fluorescent protein (RFP) |
Cancer | Chitosan nanoparticles (psi-TGC) provided sufficient in vivo stability for systemic delivery of siRNAs. Knockdown of genes coding for tumor antigens by psi-TGC resulted in a reduction in tumor size (by 80%) and vascularization. psi-TGC were mainly co-localized with tumor cells in animal model. RFP signal in mice RFP-B16F10 tumor clearly diminished to about 17% after psi(RFP)-TGC administration. |
[280] |
C57BL/6J mice Collagen type II DBA/I arthritic mice. |
Chitosan (114 kDa; DDA 84%; N:P ratio 63) | Intraperitoneal | Tumor necrosis factor-alpha (TNF-α) Also used: Cy3-labeled siRNA |
Rheumatoid arthritis | Treatment lead to TNF-α knockdown in peritoneal macrophages, minimal cartilage destruction and inflammatory cell infiltration in collagen-induced arthritic (CIA) mice. | [210] |
EGFP-transgenic mice (C57BL/6-Yg(ACTbEGFP)1Osb/J) |
Chitosan (MW 114 kDa; DDA 84%) | Intranasal | Enhanced green fluorescent protein (EGFP) | Systemic and mucosal disease | Chitosan-based systems to mediate EGFP knockdown in intact epithelial bronchiole. | [14] |
Nude mice bearing RP tumor. | Chitosan-coated poly(isobutylcyanoacrylate) (Chitosan: 20 kDa) |
Intratumoral | Ret tyrosine kinase domain juxtaposed with H4 gene (Ret/PTC1) | Papillary thyroid carcinoma | Chitosan nanoparticles allowed down-regulation of the expression of ret/PTC1 gene and significant tumor growth inhibition. | [440] |
Balb/c mice | Chitosan (MW 160 kDa; DDA 80%) | Intravenous and Intraperitoneal | No target | Chemical Modification and nanoparticle formulation to improve the systemic delivery of siRNA | Chitosan substantially improved the stability and biodistribution of siRNA. High siRNA concentration within the kidney was observed 24 h post IV injection and in peritoneal fluid 30 min post IP injection. | [371] |
Female athymic nude bearing MDA-MB-231 tumors. | Chitosan-coated polyisohexylcyanoacrylate (PIHCA) | Intravenous | Ras homologous A (RhoA) | Aggressive breast cancer | Treatment inhibited angiogenesis and the growth of tumors (more than 90%) in absence of toxicity. | [441] |
Urethane-induced lung cancer model A/J mouse | Folate–chitosan-graft-polyethylenimine (FC-g-PEI) | Intranasal-aerosol | Akt1, aserine/threonine-protein kinase | Lung cancer | Authors used plasmids encoding Akt1 shRNA. Aerosol delivery of FC-g-PEI/Akt1 shRNA complexes suppressed lung tumorigenesis through the Akt signaling pathway. |
[388] |
Fischer 344 rats | High MW chitosan | Intranasal | NS1 gene of respiratory syncytial virus (RSV) | Respiratory syncytial virus infection | Authors used plasmids encoding siNS1. Rats treated with Chitosan-siNS1 prior to RSV exposure showed a switch from a Th2 to a Th1 phenotype and a reduction of CD4 + T cells and thereby lead to effective lung viral clearance without damaging airway tissues. |
[387] |