Low Molecular Weight Chitosan (LMWC)-based Polyplexes for pDNA Delivery: From Bench to Bedside
Abstract
:1. Introduction
2. Formation and Characterization of LMWC-pDNA Polyplexes
2.1. LMWC-pDNA Polyplexes Formation Process
2.2. Physico-Chemical Characterization of LMWC-pDNA Polyplexes
Characterization technique | Parameter |
---|---|
Acid-base titration | Buffering capacity |
Agarose gel electrophoresis | Binding affinity Release capacity Protection against endonuclease Stability |
Asymmetrical flow field-flow fractionation (AF4) coupled with light scattering | Size Stoichiometry |
Atomic force microscopy | Size Morphology |
Electronic microscopy | Size Morphology |
Dynamic light scattering | Size Colloidal stability |
EtBr displacement assay | Stability |
Laser Doppler velocimetry | Zeta potential |
Isothermal titration calorimetry | Binding affinity Stability |
Nanoparticle tracking analysis | Size Mw Concentration |
Orange II dye depletion assay (AF4 results confirmation) | Stoichiometry |
Polyanion competition assay | Stability |
Potentiometric titration | Buffering capacity |
Static light scattering | Mw |
2.2.1. Size
2.2.2. Zeta Potential
2.2.3. Morphology
2.2.4. Binding Affinity
2.2.5. Buffering Capacity
2.2.6. Colloidal Stability in Physiological Conditions
3. In vivo Evaluation of LMWC-pDNA Polyplexes Transfection Process
3.1. Cellular Binding and Uptake
3.2. Endolysosomal Escape and Polyplex Dissociation
3.3. Tools for the Study of Uptake Pathways
3.4. Nuclear Import
3.5. Factors Involved in the Transfection Efficiency of LMWC based Polyplexes
4. Chemical Modifications of Ch to Overcome Transfection Barriers
5. Freeze-Drying of Polyplexes
6. In vitro Applications of LMWC based Vectors for pDNA Delivery
6.1. Ocular Delivery
6.2. Lung Delivery
6.3. Other Delivery Routes
Route of Administration | Animal Model | Chitosan | pDNA | Comments | Objective | Reference |
---|---|---|---|---|---|---|
Corneal injection | Sprague-Dawley rats | Novavect O15 (5.7 kDa, DDA 99%); Novafect O25 (7.3 kDa, DDA 99%) | gWiz-Luc (luciferase encoding reporter gene) 1.5 μg; gWiz-GFP (GFP encoding reporter gene) 1.5 μg | – | Treatment of acquired and inherited corneal disorders | [27] |
Corneal injection | Sprague-Dawley rats | Novafect O15 (5.7 kDa, DDA 99%) | gWiz,-Luc, pCpG-Luc, pEPI-CMV, pEPI-UbC (encoding for luciferase) 1.5 μg; gWiz-GFP, pCpG-GFP (encoding for GFP) 1.5 μg | – | Treatment of acquired and inherited corneal disorders | [33] |
Subretinal, intravitreous injection | Sprague-Dawley rats | Novafect O15 (5.7 kDa, DDA 99%) | pCMS-EGFP reporter gene (100 ng) | – | Treatment of retinal disorders | [28] |
Subretinal, intravitreous injection | Sprague-Dawley rats | Novafect O25 (7.3 kDa, DDA 99%) | pCMS-EGFP reporter gene (100 ng) | – | Treatment of retinal disorders | [32] |
Topic administration | Rabbits | Ultrapure Ch hydrochloride salt (113 kDa) | pEGFP reporter gene (25 μg, 50 μg, 100 μg) | Ch was mixed with HA salt, and NPs were prepared by ionotropic gelification | Treatment of ocular diseases | [89] |
Aerosol | Balb/c mice | Ch Chitoclear (126 kDa, DDA 98%) | pGL3-control plasmid encoding luciferase | Electrostatially formed polyplexes were conjugated with FAP-B | Lung targeting | [90] |
Intratracheal administration | Balb/c mice | UPC, Protasan UPG 210 | gWiz-Luc, pCMV-Luc (luciferase encoding reporter genes) 5 μg, 10 μg, 25 μg | Fully deacetylated Ch was depolymerized to obtain oligomers with number average DPn 25 and 18 | Lung targeting | [21] |
Intratracheal administration | Balb/c mice | Fully de- N-acetylated Ch (3.6–7 kDa) | gWiz-Luc, pCMV-Luc (luciferase encoding reporter genes) | Ch oligomers were substituted with trisaccharides, obtaining oligormes with 7%, 23%, 40% of substituted amines | Lung targeting | [50] |
Intranasal administration | Sprague-Dawley rats | Ch Mw: 5, 173 kDa | pEGFP-C3 encoding GFP;pDNA encoding CETP-C | – | Immunotherapeutic DNA vaccine for atherosclerosis treatment | [93] |
Intranasal administration | C57BL/6 mice | Ch Mw: 115 kDa, DDA 95% | pGRP (0.5 mg) | Ch was conjugated with D-mannose | Production of anti-GRP IgG and inhibition of tumor growth | [94] |
Intramuscular and subcutaneous administration | Balb/c mice | Depolymerized Ch 92–10 and 80–80 (Mw-DDA) | pVax1-4sFGF-2 and pVax1-PDGF-BB (encoding for FGF-2 and PDGF recombinant proteins) | – | Enhancing the repair of cartilage lesions or enhancing bone defect fill | [95] |
Intramuscular and subcutaneous administration | Zucker Diabetic Fatty rats | Depolymerized Ch 92–10 and 80–80 (Mw-DDA) | pVax1-GLP1 encoding for the recombinant GLP-1 (165 μg) | – | Type 2 diabetes treatment | [96] |
Intratumoral administration | C.B-17/Icr-scid-bg mice | Ch Mw 15.5 kDa, DDA 75%–85% | pAcEGFP1-C1 and Luc reporter plasmids encoding GFP and luciferase (100 μg) | – | Cancer treatment | [97] |
Intravenous administration | Mice | – | pUC 19 encoding β-galactosidase reporter gene | Hydrophobically modified LMWC | – | [98] |
Intravenous administration | Balb/c mice | Depolimerized Ch (7 kDa and 10 kDa) | pGL3 luciferase reporting gene (25 μg) | Ch was conjugated with bPEI and further with tuftsin | – | [99] |
7. Future Prospects
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Agirre, M.; Zarate, J.; Ojeda, E.; Puras, G.; Desbrieres, J.; Pedraz, J.L. Low Molecular Weight Chitosan (LMWC)-based Polyplexes for pDNA Delivery: From Bench to Bedside. Polymers 2014, 6, 1727-1755. https://doi.org/10.3390/polym6061727
Agirre M, Zarate J, Ojeda E, Puras G, Desbrieres J, Pedraz JL. Low Molecular Weight Chitosan (LMWC)-based Polyplexes for pDNA Delivery: From Bench to Bedside. Polymers. 2014; 6(6):1727-1755. https://doi.org/10.3390/polym6061727
Chicago/Turabian StyleAgirre, Mireia, Jon Zarate, Edilberto Ojeda, Gustavo Puras, Jacques Desbrieres, and Jose Luis Pedraz. 2014. "Low Molecular Weight Chitosan (LMWC)-based Polyplexes for pDNA Delivery: From Bench to Bedside" Polymers 6, no. 6: 1727-1755. https://doi.org/10.3390/polym6061727