Next generation macrocyclic and acyclic cationic lipids for gene transfer

Synthesis and in vitro evaluation

Emilie Jubeli, Amanda B. Maginty, Nada Abdul Khalique, Liji Raju, Mohamad Abdulhai, David G. Nicholson, Helge Larsen, Michael D. Pungente, William P.D. Goldring

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid–DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those formulated with DOPE. A number of the lipid formulations with cholesterol as co-lipid performed as well as, or better than Lipofectamine 2000™ and EPC, the two positive controls employed in these studies. These results suggest that our novel cyclic and acyclic cationic lipid vectors are effective nonviral gene transfer agents that warrant further investigation
OriginalsprogEngelsk
TidsskriftBioorganic & Medicinal Chemistry Letters
Vol/bind23
Udgave nummer19
Sider (fra-til)6364-6378
Antal sider15
ISSN0968-0896
DOI
StatusUdgivet - 28 aug. 2015
Udgivet eksterntJa

Citer dette

Jubeli, Emilie ; Maginty, Amanda B. ; Khalique, Nada Abdul ; Raju, Liji ; Abdulhai, Mohamad ; Nicholson, David G. ; Larsen, Helge ; Pungente, Michael D. ; Goldring, William P.D. . / Next generation macrocyclic and acyclic cationic lipids for gene transfer : Synthesis and in vitro evaluation. I: Bioorganic & Medicinal Chemistry Letters. 2015 ; Bind 23, Nr. 19. s. 6364-6378.
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title = "Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation",
abstract = "Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid–DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those formulated with DOPE. A number of the lipid formulations with cholesterol as co-lipid performed as well as, or better than Lipofectamine 2000™ and EPC, the two positive controls employed in these studies. These results suggest that our novel cyclic and acyclic cationic lipid vectors are effective nonviral gene transfer agents that warrant further investigation",
author = "Emilie Jubeli and Maginty, {Amanda B.} and Khalique, {Nada Abdul} and Liji Raju and Mohamad Abdulhai and Nicholson, {David G.} and Helge Larsen and Pungente, {Michael D.} and Goldring, {William P.D.}",
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doi = "10.1016/j.bmc.2015.08.032",
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Jubeli, E, Maginty, AB, Khalique, NA, Raju, L, Abdulhai, M, Nicholson, DG, Larsen, H, Pungente, MD & Goldring, WPD 2015, 'Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation', Bioorganic & Medicinal Chemistry Letters, bind 23, nr. 19, s. 6364-6378. https://doi.org/10.1016/j.bmc.2015.08.032

Next generation macrocyclic and acyclic cationic lipids for gene transfer : Synthesis and in vitro evaluation. / Jubeli, Emilie; Maginty, Amanda B.; Khalique, Nada Abdul; Raju, Liji; Abdulhai, Mohamad; Nicholson, David G.; Larsen, Helge; Pungente, Michael D. ; Goldring, William P.D. .

I: Bioorganic & Medicinal Chemistry Letters, Bind 23, Nr. 19, 28.08.2015, s. 6364-6378.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Next generation macrocyclic and acyclic cationic lipids for gene transfer

T2 - Synthesis and in vitro evaluation

AU - Jubeli, Emilie

AU - Maginty, Amanda B.

AU - Khalique, Nada Abdul

AU - Raju, Liji

AU - Abdulhai, Mohamad

AU - Nicholson, David G.

AU - Larsen, Helge

AU - Pungente, Michael D.

AU - Goldring, William P.D.

PY - 2015/8/28

Y1 - 2015/8/28

N2 - Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid–DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those formulated with DOPE. A number of the lipid formulations with cholesterol as co-lipid performed as well as, or better than Lipofectamine 2000™ and EPC, the two positive controls employed in these studies. These results suggest that our novel cyclic and acyclic cationic lipid vectors are effective nonviral gene transfer agents that warrant further investigation

AB - Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid–DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those formulated with DOPE. A number of the lipid formulations with cholesterol as co-lipid performed as well as, or better than Lipofectamine 2000™ and EPC, the two positive controls employed in these studies. These results suggest that our novel cyclic and acyclic cationic lipid vectors are effective nonviral gene transfer agents that warrant further investigation

U2 - 10.1016/j.bmc.2015.08.032

DO - 10.1016/j.bmc.2015.08.032

M3 - Journal article

VL - 23

SP - 6364

EP - 6378

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 19

ER -