Synthetic Delivery Systems for DNA, siRNA, and mRNA Based on Pyridinium Amphiphiles

Ilies, Marc A.; Satyal, Uttam; Sharma, V. D.

doi:10.1021/bk-2017-1271.ch001

Cited by 7 publications

(9 citation statements)

References 81 publications

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“…One of the major challenges in developing LNP-based technologies is finding optimized lipid formulations for enhancing protein production, which are typically target-specific, differing between various cells/tissues. Extensive efforts have been made on tuning the components’ chemical structures and mixing proportions to enhance the LNP’s delivery efficiency in different applications. ,− Changes in lipid type and composition alter their interactions and result in different nanostructures such as inverted micelles and inverted-hexagonal, multiple-lamellar and amorphous phases for different formulations . Moreover, the LNP nanostructure is related to its capacity for cellular uptake and release of the payload. , However, LNP development studies must rely on high-throughput screening work in vitro and in vivo due to the nature of multiple components and the complexity of LNP manufacturing.…”

Section: Introductionmentioning

confidence: 99%

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Carter

Santos

et al. 2023

ACS Nano

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The rational design of lipid nanoparticles (LNPs) for enhanced gene delivery remains challenging because of incomplete knowledge of their formulation–structure relationship that impacts their intracellular behavior and consequent function. Small-angle neutron scattering has been used in this work to investigate the structure of LNPs encapsulating plasmid DNA upon their acidification (from pH 7.4 to 4.0), as would be encountered during endocytosis. The results revealed the acidification-induced structure evolution (AISE) of the LNPs on different dimension scales, involving protonation of the ionizable lipid, volume expansion and redistribution of aqueous and lipid components. A similarity analysis using an LNP’s structural feature space showed a strong positive correlation between function (measured by intracellular luciferase expression) and the extent of AISE, which was further enhanced by the fraction of unsaturated helper lipid. Our findings reveal molecular and nanoscale changes occurring during AISE that underpin the LNPs’ formulation–nanostructure–function relationship, aiding the rational design of application-directed gene delivery vehicles.

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Section: Introductionmentioning

confidence: 99%

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Carter

Santos

et al. 2023

ACS Nano

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“…[3]. Different SAINT pyridinium salts with alkyl chain variations at the quaternized pyridine N-atom or as substituents at the pyridinium cycle were proposed as active gene delivery agents by several research groups [4][5][6]. Additionally, gemini dioleylbispyridinium-based amphiphiles were elaborated for nucleic acid transfection [7].…”

Section: Resultsmentioning

confidence: 99%

“…84-85 • C (EtOH). 1 H NMR (400 MHz, CDCl 3 ) δ: 8.60 (s, 1H, Py), 8.51 (dd, 3 J H-H = 4.8 Hz, 4 J H-H = 1.5 Hz, 1H, Py), 7.71 (d, 3 J H-H = 7.6 Hz, 1H, Py), 7.22 (dd, 3 J H-H = 8.0 Hz, 3 J H-H = 4.8 Hz, 1H, Py), 4.92 (t, 3 J H-F = 29.3 Hz, 1H, CH), 4.33−4.19 (m, 4H, 2 × OCH 2 CH 3 ), 2.02 (m, 6H, 2× COCH 3 ), 1.31 (t, 3 J H-H = 7.2 Hz, 6H, 2 × OCH 2 CH 3 ) ppm. 19 F NMR (376 MHz, CDCl 3 ) δ: −166.5 (d, 3 J F-H = 29.3 Hz, 2F) ppm.…”

Section: Diethyl 24-diacetyl-24-difluoro-3-(pyridin-3-yl)pentanedioat...mentioning

confidence: 99%

“…Pyridinium ionic liquids and pyridinium ylides are used in synthetic chemistry and in material science and biological issues related to gene delivery, antimicrobial, anticancer and antimalarial activities [3]. Different SAINT pyridinium salts with alkyl chain variations at the quaternized pyridine N-atom or as substituents at the pyridinium cycle were proposed as active gene delivery agents by several research groups [4][5][6]. Additionally, gemini dioleylbispyridinium-based amphiphiles were elaborated for nucleic acid transfection [7].…”

Section: Introductionmentioning

confidence: 99%

“…C NMR (101 MHz, CDCl 3 ) δ: 200.5 (dd, 2 J C-F = 28.7 Hz,4 J C-F = 12.8 Hz, 2 × C(O)CH 3 ), 164.6 (dd, 2 J C-F = 25.5 Hz,4 J C-F = 15.6 Hz, 2 × C(O)OC 2 H 5 ), 152.2 (s, Py), 149.8 (s, Py), 139.2 (s, Py), 128.3 (s, Py), 123.3 (s, Py), 100.3 (dd, 1 J C-F = 213.0 Hz, 3 J C-F = 3.4 Hz, 2 × CF), 63.6 (s, 2 × OCH 2 CH 3 ), 49.9 (t, 2 J C-F = 18.3 Hz, CH), 26.4 (s, 2 × CH 3 ), 13.9 (s, 2 × OCH 2 CH 3 ) ppm. IR ν max (film) 2987 (w), 2941 (m), 1757 (s), 1737 (s), 1570 (s) cm −1 .…”

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confidence: 99%

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Synthesis and Evaluation of Self-Assembling Properties of 3-(3,5-Difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium Iodides

Pikun

Lacis

Sobolev

et al. 2022

Molbank

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A synthesis of 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides with ethyl or nonyl ester groups at positions 3 and 5 was performed. Treatment of the corresponding 2’,6’-dimethyl-1’,4’-dihydro-[3,4’-bipyridine]-3’,5’-dicarboxylates with Selectfluor® followed by quaternization of pyridine moiety in the obtained dialkyl 2,4-diacetyl-2,4-difluoro-3-(pyridin-3-yl)pentanedioates with methyl iodide gave the desired 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides. This type of compound would be useful as synthetic lipids for further development of the delivery systems. The obtained target compounds were fully characterized by 1H NMR, 19F NMR, 13C NMR, HRMS, IR and UV data. The estimation of self-assembling properties and characterization of the nanoparticles obtained by ethanol solution injection in an aqueous media were performed by dynamic light scattering (DLS) measurements. DLS measurement data showed that 3-(3,5-difluoro-3,5-bis((nonyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide created liposomes with the average diameter of 300–400 nm and polydispersity index (PDI) value around 0.30–0.40, while 3-(3,5-difluoro-3,5-bis((ethyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide formed a heterogeneous sample with PDI value 1, which was not prospective for delivery system development.

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High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

Seo

Jeon

Kwon

et al. 2023

Adv Healthcare Materials

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The recent development of RNA-based therapeutics in delivering nucleic acids for gene editing and regulating protein translation has led to the effective treatment of various diseases including cancer, inflammatory and genetic disorder, as well as infectious diseases. Among these, lipid nanoparticles (LNP) have emerged as a promising platform for RNA delivery and have shed light by resolving the inherent instability issues of naked RNA and thereby enhancing the therapeutic potency. These LNP consisting of ionizable lipid, helper lipid, cholesterol, and poly(ethylene glycol)-anchored lipid can stably enclose RNA and help them release into the cells' cytosol. Herein, the significant progress made in LNP research starting from the LNP constituents, formulation, and their diverse applications is summarized first. Moreover, the microfluidic methodologies which allow precise assembly of these newly developed constituents to achieve LNP with controllable composition and size, high encapsulation efficiency as well as scalable production are highlighted. Furthermore, a short discussion on current challenges as well as an outlook will be given on emerging approaches to resolving these issues.

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Synthetic Delivery Systems for DNA, siRNA, and mRNA Based on Pyridinium Amphiphiles

Cited by 7 publications

References 81 publications

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Acidification-Induced Structure Evolution of Lipid Nanoparticles Correlates with Their In Vitro Gene Transfections

Synthesis and Evaluation of Self-Assembling Properties of 3-(3,5-Difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium Iodides

High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

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