Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers
Abstract
:1. Introduction
2. Challenges and Breakthrough of siRNA Delivery: From Concept to Clinical Trial
3. In-Vivo Delivery of siRNAs and shRNAs Directed against Different Cancer-Causing Genes in Various Cancer Models
3.1. Silencing of Bcl-2 Gene
3.2. Silencing of VEGF Gene
3.3. Silencing of EGF Receptor Genes
3.4. Silencing of Survivin Gene
3.5. Silencing of Cyclin-B1 Gene
3.6. Silencing of RhoA and RhoC Gene
3.7. Silencing of β-Catenin Gene
3.8. Silencing of EphA2 Gene
3.9. Silencing of MDM-2 Gene
3.10. Silencing of IGF-1R Gene
3.11. Silencing of Livin Gene
3.12. Silencing of WT1 Gene
3.13. Miscellaneous
4. Future Directions
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug Formulation | Target Gene | NPs | Treatment | Diseases | Phase | Status | Identifier Trial Number (https://clinicaltrails.gov) |
---|---|---|---|---|---|---|---|
DCR-MYC | MYC | Lipid | siRNAs | Hepatocellular carcinoma | 1/2 | Ongoing, not recruiting 2014-present | NCT02314052 |
DCR-MYC | MYC | Lipid | siRNAs | Solid tumors, multiple myeloma, non-Hodgkin lymphoma, or pancreatic neuroendocrine tumors | 1 | Ongoing, not recruiting 2014-present | NCT02110563 |
ALN-VSP02 | KSP and VEGF | Lipid | siRNAs | Solid tumors | 1 | Completed | NCT00882180 |
Atu 027 | PKN3 | Lipid Nanoparticles | siRNAs | Advanced cancers | 1 | Completed | NCT00938574 |
TKM-080301 | PLK1 | Lipid | siRNAs | Primary and secondary liver cancer | 1 | completed | NCT01437007 |
PLK1 | Lipid | siRNAs | Neuroendocrine tumors | 1/2 | completed | NCT01262235 | |
PLK1 | Lipid | siRNAs | Advanced hepatocellular carcinoma | 1/2 | completed | NCT02191878 | |
siRNA-EphA2-DOPC | EphA2 | Lipid | siRNAs | Advanced solid tumors | 1 | Recruiting | NCT01591356 |
siG12D-LODER | KRAS | LODER polymer | siRNAs | Ductal adenocarcinoma or pancreatic cancer | 1 | completed | NCT01188785 |
siG12D-LODER | KRAS | LODER polymer | siRNAs | pancreatic cancer | 2 | Not yet recruiting | NCT01676259 |
SNS01-T | eIF5A | polyethyleneimine | siRNAs plasmids | Multiple myeloma | 1/2 | unknown | NCT01435720 |
Target Genes | Role of Genes | Delivery Vehicle | Treatment | Preclinical Studies Application | Preclinical Studies Outcome | Refs. |
---|---|---|---|---|---|---|
Bcl-2 | Inhibits apoptosis pathways and promote cellular growth and survival in breast, lung, liver and gastric cancer | Liposome-protamine | siRNA | Balb/c mouse model inoculated with H22 liver tumor cells | 66.5% reduction of tumor growth by suppressing Bcl-2 gene expression | 65 |
Bcl-2 | pSilencerTM-EGFP sh515 | shRNA | Balb/C mouse model inoculated with GBC-SD, gallbladder carcinoma cells | 50% reduction of tumor volume and decreased tumor growth rate | 72 | |
Bcl-2 | Cationic liposome, LIC-101 | siRNA | Balb/C nu++ mouse model inoculated with PC-3 prostate cancer cells | 63% reduction of tumor volume | 73 | |
Bcl-2 | PEG-LIC complex | siRNA | Balb/C mouse model inoculated with PC-3 human prostate cancer cells | Increased siRNA uptake, 65% tumor reduction without any systemic toxicity | 74 | |
VEGF | Stimulates angiogenesis and vascular permeability | Adenoviral vector (Ad5CMV) | siRNA | Athymic female mouse model inoculated with MDA251-MB, human breast cancer cells | Reduced 80% of tumor through anti-angiogenesis mechanism | 97 |
VEGF | Polyelectrolyte complex (PEG/PEI PEC micelles) | siRNA | Female nude mice (nu/nu) model inoculated with PC-3 human prostate cancer cells | Intratumoral injection caused 79% tumor inhibition; Intravenous administration reduced 86% of tumor volume | 103 | |
VEGF-C | Promotes lymphogenesis, tumorigenesis and initiates metastasis | Hifectin-mediated transfection | siRNA | Balb/C mouse model inoculated with 4T1 cells, mouse breast cancer cells | Reduced 28% of tumor volume. | 120 |
VEGF-C | Lentivirus vector (Lv) | siRNA | Balb/C mouse model inoculated with A549, human NSCLC cells | 64% tumor inhibition and 48% reduction of tumor volume by decreasing VEGF-C expression | 121 | |
NRP-2 | Binds with VEGF and regulates vascularization and lymphogenesis of various tumors | DOPC (neutral lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl choline) | siRNA | Male athymic nude mouse model inoculated with HTC-116, human colorectal carcinoma cell lines | Reduced 91.3% of tumor volume via increasing anti-angiogenic mechanism | 125 |
VEGF R2 | Regulates angiogenesis and tumor growth | RGD (Ar3-Gly-Asp peptides)-PEG-PEI nanoplexes | siRNA | Female nude mouse model inoculated with N2A, mouse neuroblastoma cells | Enabled tissue-specific delivery and inhibited more than 90% of tumor volume | 100 |
EGFR 1 & ERBB2 | Activate downstream signaling pathways and play key role in cell division and proliferation | Carbonate apatite Nano-particle | siRNA | Female Balb/C mouse model inoculated with 4T1 cells, mouse breast cancer cells | 61% reduction of tumor volume without any toxicity | 143 |
Survivin | Suppresses apoptosis by inhibiting both intrinsic and extrinsic pathways of apoptosis, as well as improves chemo-resistance to various chemotherapeutics and increases tumor recurrence rate | PEGylated chitosan (PEG-CS) | siRNA | Female Balb/C mouse model inoculated with 4T1 cells, mouse breast cancer cells | Increased biological stability and targeted gene delivery, reduced 55% of tumor volume | 165 |
Survivin | Chiosan-6-poly arginine and histidine (H6R6-CS) | siRNA | Female Balb/C mouse model inoculated with 4T1 cells, mouse breast cancer cells | Improved cellular uptake and endosomal escape with 63% tumor inhibition | 176 | |
Survivin | Cationic linear polyethyleneimine (PEI) | Sticky siRNA (ssiRNA) | NMRI nude female mouse model inoculated with B16-F10 cells, murine melanoma cell lines | Reduced 50% of tumor volume through silencing of Survivin gene | 181 | |
Survivin | PCPP (PEG-CPB-PEI) nano-particle | siRNA | Balb/C mouse model inoculated with 4T1 cells, mouse breast cancer cells | Increased tumor accumulation and improved cellular uptake with 66% reduction of tumor volume | 185 | |
Cyclin-B1 | As a mitosis promoting factor triggers uncontrolled cell proliferation and hampers the stability of chromosomes | MPG-8 (Primary amphipathic peptide carrier)-cholesterol (MPG-8/chol) | siRNA | Swiss nude mouse model inoculated with PC-3 cells, human prostate cancer cells | 90% tumor size inhibition for maximum dose, 60–80% reduction of Cyclin B1 expression and extended survival rate | 206 |
Cyclin-B1 | Cationic linear polyethyleneimine (PEI) | Sticky siRNA (ssiRNA) | NMRI nude female mouse model inoculated with B16-F10 cells, Murine melanoma cell lines | Reduced 44% of tumor volume via down regulating Cyclin B1 expression | 181 | |
RhoA & RhoC | Triggers signal transduction and drives a series of pathologies of cancer including cell motility, proliferation, apoptosis inhibition, cell cycle progression, invasion, metastasis and inflammation | Adenoviral vector | shRNA | Male Balb/C mouse model inoculated with HTC-116, human colorectal carcinoma cell lines | Slowed tumor growth (2.38 fold) and reduced 37% of tumor volume | 225 |
RhoA & RhoC | Cytofectin-mediated transfection | siRNA | Athymic female mouse model inoculated with MDA251-MB, human breast cancer cells | Reduced tumor volume 85% (anti-RhoA) and 53% (anti-RhoC), lowered angiogenesis index | 227 | |
RhoA | Chitosan-PIHCA (polyisohexylcyanoacrylate) | siRNA | Athymic female mouse model inoculated with MDA251-MB, human breast cancer cells | At higher dose the tumor were completely removed | 228 | |
RhoC | Lipofectamine-mediated transfection | siRNA | Balb/C-nu mouse model inoculated with SUM149, human IBC cells | Reduced tumor volume by 35%, increased survival rate to 85%, up-regulated metastasis suppressor gene KAll | 234 | |
β-Catenin | Regulates cell-cell adhesion and gene transcription, ultimately controlling cellular proliferation | Oligofectamine-mediated transfection | siRNA | Female nude/nu mouse model inoculated with HTC-116, human colorectal carcinoma cell lines | Three-fold smaller in size of tumor in comparison to control with extended survival rate | 253 |
β-Catenin | Lentivirus vector | shRNA | Male athymic nude mouse model inoculated with AGS cells, human gastric cancer cells | 75% reduction of tumor volume by inhibiting CCAR1 gene expression | 259 | |
EphA2 | Enhances cell-extracellular matrix (ECM) adhesion, anchorage-dependent growth and metastasis | DOPC (neutral lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl choline) | siRNA | Female athymic nude (Ncr-nu) mouse model inoculated with SkOV3ip1 cells, ovarian cancer cell lines | Reduced 35–50% of tumor size | 275 |
EphA2 and FAK | DOPC (neutral lipid 1,2-dioleoyl-sn-glycero-3-phosphatidyl choline) | siRNA | Female athymic nude (Ncr-nu) mouse model inoculated with SkOV3ip1 cells, ovarian cancer cell lines | Reduced 62–82% of tumor metastasis and slowed down tumor growth rate | 283 | |
EphA2 | Liposome | siRNA | Balb/C mouse model inoculated with SGC 7901, human gastric adenocarcinoma cells | 43.1% inhibition of tumor growth, with reduction in expression of metastatic gene MMP-9 | 285 | |
MDM-2 | Inhibits the regulation of p53 tumor suppressor gene | PMPC-b-PDPA (di-block copolymer of poly (methacryloyloxy ethyl phosphorylcholine)-b-poly (diisopropanolamine ethyl methacrylate) | siRNA | Athymic mouse model inoculated with H2009 cells, NSCLC cells | 67% reduction of tumor growth via down regulation of MDM-2 gene expression without any systemic toxicity | 290 |
MDM-2, c-myc and VEGF | cationic lipid-PEG | siRNA | Female C57B216 mouse model inoculated with B16-F10 cells, murine melanoma cell lines | 20–30% reduction of tumor load with extended survival rate | 291 | |
IGF-1R | Promotes cellular metabolism, differentiation, apoptosis, chemo resistance and angiogenesis as well as protecting cells from UV irradiation, cytokine and gamma radiation-induced apoptosis | Plasmids-PEI | siRNA | Male nude mouse model inoculated with A549 cells, human lung adenocarcinoma cell lines | 60% of reduction of tumor volume, Increasing apoptotic cells | 305 |
IGF-1R | Magnetic lipoplexes | shRNA | Male Balb/C AnNcrj-nu mouse model inoculated with A549 cells (NSCLC cells line with overexpression of IGF-1R) | Improved site specificity and cellular uptake, and reduced 85.1 ± 3% of IGF-1R gene expression | 306 | |
Livin | Thwarts both extrinsic and intrinsic apoptosis pathways by interacting with specific cysteine proteases or caspases, while playing a significant role in tumor progression and chemo resistance development | Single chain antibody | siRNA | Nude mouse model inoculated with LiBr cells, malignant melanoma cell lines. | Reduces approximately 64% of tumor size. | 324 |
Livin | Plasmid vector | siRNA | Balb/C nu/nu mouse model inoculated with SPCA-1 cells, human lung cancer cell lines. | 73% reduction of mean tumor size, with increased apoptotic fraction and improved survival rate | 325 | |
WT1 | The key drivers that control cell proliferation and apoptosis via regulation of the expression of proliferative genes | Plasmid vector | shRNA | Balb/C nu/nu mouse model inoculated with A549, H1299 and H1650 cells | 69–76% reduction of tumor volume without any systemic toxicity | 348 |
WT1 | Liposome-PEG | shRNA | Female C57BL/6 mouse model inoculated with B16F10 cell, murine melanoma cell lines | Reduced 34% of tumor weight and extended survival rate (62.5%) | 353 | |
Bag-1 | Regulates Bcl-2 gene expression and mimics the anti-apoptotic activities via bridging between the growth factor and anti-apoptotic mechanisms | Magnetic gold nanoparticles | siRNA | Balb/C nude mouse model inoculated with LoVo cell, human colon cancer cell lines | 69% of tumor inhibition without toxicity | 360 |
PTTG1 | Plays a vital role in several cellular processes like mitosis, DNA repair, apoptosis and gene regulation and causes aneuploidy. | Adenoviral vector | siRNA | Balb/C nude mouse model inoculated with SH-J1 cells, hepatoma cell lines | Significant tumor inhibition efficacy (84%) | 375 |
CD-47 | Causes the tumor cells escape from immunosurveillance with the result of tumor progression | Liposome-protamine-hyaluronic acid | siRNA | C57B2/6 mouse model inoculated with B16F10 cell, murine melanoma cell lines | Above 90% tumor inhibition without toxicity | 382 |
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Karim, M.E.; Tha, K.K.; Othman, I.; Borhan Uddin, M.; Chowdhury, E.H. Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers. Pharmaceutics 2018, 10, 65. https://doi.org/10.3390/pharmaceutics10020065
Karim ME, Tha KK, Othman I, Borhan Uddin M, Chowdhury EH. Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers. Pharmaceutics. 2018; 10(2):65. https://doi.org/10.3390/pharmaceutics10020065
Chicago/Turabian StyleKarim, Md. Emranul, Kyi Kyi Tha, Iekhsan Othman, Mohammad Borhan Uddin, and Ezharul Hoque Chowdhury. 2018. "Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers" Pharmaceutics 10, no. 2: 65. https://doi.org/10.3390/pharmaceutics10020065
APA StyleKarim, M. E., Tha, K. K., Othman, I., Borhan Uddin, M., & Chowdhury, E. H. (2018). Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers. Pharmaceutics, 10(2), 65. https://doi.org/10.3390/pharmaceutics10020065