Polymeric vehicles for nucleic acid delivery

Piotrowski-Daspit, Alexandra S.; Kauffman, Amy; Bracaglia, Laura G.; Saltzman, W. Mark

doi:10.1016/j.addr.2020.06.014

Cited by 133 publications

(109 citation statements)

References 243 publications

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“…As the cationic membranes neutralize the phosphate groups on the DNA, those small counterions gain in entropy because they are now free to diffuse and no longer bound to the DNA or cationic membranes. This driving force is also important in the assembly of other oppositely charged macro-ions, e.g., cationic polymers and DNA [ 123 ] or CLs and anionic proteins.…”

Section: The Lamellar L α C Phase Of Cationic Liposome–dna Complexesmentioning

confidence: 99%

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

et al. 2021

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Cationic liposomes (CLs) are effective carriers of a variety of therapeutics. Their applications as vectors of nucleic acids (NAs), from long DNA and mRNA to short interfering RNA (siRNA), have been pursued for decades to realize the promise of gene therapy, with approvals of the siRNA therapeutic patisiran and two mRNA vaccines against COVID-19 as recent milestones. The long-term goal of developing optimized CL-based NA carriers for a broad range of medical applications requires a comprehensive understanding of the structure of these vectors and their interactions with cell membranes and components that lead to the release and activity of the NAs within the cell. Structure–activity relationships of lipids for CL-based NA and drug delivery must take into account that these lipids act not individually but as components of an assembly of many molecules. This review summarizes our current understanding of how the choice of the constituting lipids governs the structure of their CL–NA self-assemblies, which constitute distinct liquid crystalline phases, and the relation of these structures to their efficacy for delivery. In addition, we review progress toward CL–NA nanoparticles for targeted NA delivery in vivo and close with an outlook on CL-based carriers of hydrophobic drugs, which may eventually lead to combination therapies with NAs and drugs for cancer and other diseases.

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Section: The Lamellar L α C Phase Of Cationic Liposome–dna Complexesmentioning

confidence: 99%

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

et al. 2021

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“…[12,[17][18][19][20][21][22][23] Depending on the morphology employed, PEG-b-PPS nanocarriers can retain both hydrophobic and hydrophilic payloads, respectively, in their cores or aqueous interior compartments [20,21,[24][25][26] and are highly customizable through control of charge, size, and targeting moieties on their surfaces. [8,27] Nanomaterials provide a wide range of options for sustained drug and gene delivery, [19,22,28] and the development of SC targeted nanocarriers will thus provide versatile options for the long term delivery of glaucoma therapeutics following a single intracameral injection. Here, we report on the design and development of a PEG-b-PPS controlled delivery system to deliver latrunculin A to SC cells.…”

Section: Doi: 101002/smll202004205mentioning

confidence: 99%

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma

Stack

Vincent

Vahabikashi

et al. 2020

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Increased stiffness of the Schlemm's canal (SC) endothelium in the aqueous humor outflow pathways has been associated with elevated intraocular pressure (IOP) in glaucoma. Novel treatments that relax this endothelium, such as actin depolymerizers and rho kinase inhibitors, are in development. Unfortunately, these treatments have undesirable off‐target effects and a lower than desired potency. To address these issues, a targeted PEG‐b‐PPS micelle loaded with actin depolymerizer latrunculin A (tLatA‐MC) is developed. Targeting of SC cells is achieved by modifying the micelle surface with a high affinity peptide that binds the VEGFR3/FLT4 receptor, a lymphatic lineage marker found to be highly expressed by SC cells relative to other ocular cells. During in vitro optimization, increasing the peptide surface density increased micellar uptake in SC cells while unexpectedly decreasing uptake by human umbilical vein endothelial cells (HUVEC). The functional efficacy of tLatA‐MC, as measured by decreased SC cell stiffness compared to non‐targeted micelles (ntLatA‐MC) or targeted blank micelles (tBL‐MC), is verified using atomic force microscopy. tLatA‐MC reduced IOP in an in vivo mouse model by 30–50%. The results validate the use of a cell‐softening nanotherapy to selectively modulate stiffness of SC cells for therapeutic reduction of IOP and treatment of glaucoma.

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“…Also, the degree of complexation quantified by the N/P ratio affects the net charge, size, and stability of the delivery system 148 . Typically, an excess of the polymer is needed to generate stable cationic vehicles and facilitate their internalization 149 . However, an excessively high positive charge may cause cytotoxicity 150 .…”

Section: Sirna Delivery Systems For Treatment Of Ali/ardsmentioning

confidence: 99%

“…Appropriate surfactants or cationic polymers such as PEI or chitosan can be added to the matrix 175 . Practically, the delivery of siRNA by these materials is challenged by their relatively low nucleic acid loading and transfection efficiency 148 , 149 .…”

Section: Sirna Delivery Systems For Treatment Of Ali/ardsmentioning

confidence: 99%

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

Zoulikha

Xiao

Boafo

et al. 2022

Acta Pharmaceutica Sinica B

154

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The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the clinical translation of siRNA is hampered by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

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Polymeric vehicles for nucleic acid delivery

Cited by 133 publications

References 243 publications

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

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