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Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo

Ma, Yuan ; Zhao, Wenting ; Li, Yiding ; Pan, Yufei ; Wang, Shuhe ; Zhu, Yuejie ; Kong, Lingxuan ; Guan, Zhu ; Wang, Jiancheng ; Zhang, Lihe ; Yang, Zhenjun

Biomaterials, 2019-03, Vol.197, p.182-193 [Periódico revisado por pares]

Netherlands: Elsevier Ltd

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Título:
Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo
Autor: Ma, Yuan ; Zhao, Wenting ; Li, Yiding ; Pan, Yufei ; Wang, Shuhe ; Zhu, Yuejie ; Kong, Lingxuan ; Guan, Zhu ; Wang, Jiancheng ; Zhang, Lihe ; Yang, Zhenjun
Assuntos: Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis - drug effects ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Proliferation - drug effects ; Cytidine - analogs & derivatives ; DNCA ; Drug Carriers - chemistry ; Drug Delivery Systems ; Female ; G3139 ; Gene delivery ; Humans ; Lipids - chemistry ; LNA-gapmer ; MCF-7 Cells ; Mice, Inbred BALB C ; Oligonucleotides, Antisense - administration & dosage ; Oligonucleotides, Antisense - pharmacokinetics ; Oligonucleotides, Antisense - pharmacology ; Oligonucleotides, Antisense - therapeutic use ; PS modification ; Thionucleotides - administration & dosage ; Thionucleotides - pharmacokinetics ; Thionucleotides - pharmacology ; Thionucleotides - therapeutic use
É parte de: Biomaterials, 2019-03, Vol.197, p.182-193
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Antisense oligonucleotides (ASOs) usually contain a fully phosphorothioate (PS) backbone, which possibly interact with many genes and proteins under intracellular conditions. G3139 is an ASO that targets Bcl-2 mRNA and induces cell apoptosis. Here, we report a kind of cytidinyl-lipid combined with a cationic lipid (DNCA/CLD, molar ration, 28:3, named mix), which may interact with oligonucleotides via H-bond formation, pi-stacking and electrostatic interaction, accompanied by low zeta potentials. The IC50 value of G3139 delivered by mix-lipid reduced from above 20 μM to 0.158 μM for MCF-7/ADR, and exhibited stronger antiproliferation upon other cancer cell lines. In addition, PS modification in the 3′-half of G3139 (especially at positions 13-16) enhanced serum stability, target specificity and anticancer activity. Also, a locked nucleic acid (LNA) gapmer G3139 (LNA-G3139) showed superior antiproliferation (78.5%) and Bcl-2 mRNA suppression effects (85.5%) at 200 nM, mainly due to its high complementary RNA affinity. More apoptosis-associated targets were identified, and a lower level of non-specific protein binding (HSA) revealed that both antisense and aptamer mechanisms might simultaneously exist. A combination of a new delivery system and chemical modifications, such as in LNA-G3139, may have potential clinical application prospects in the future. Outlined description: Encapsulation and delivery by cytidinyl-lipid/cationic lipid (DNCA/CLD), ASOs phosphrothiolated in 3′-half region (such as site 13-16) significantly enhance target specificity and serum stability, while its LNA-gapmer (LNA-G3139) shows great mRNA affinity, inhibition of multiple targets expression (Bcl-2, ATAD3A and AARS), and antitumour ability in vitro and in vivo. [Display omitted]
Editor: Netherlands: Elsevier Ltd
Idioma: Inglês

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Structural optimization and additional targets identification of antisense oligonucleotide G3139 encapsulated in a neutral cytidinyl-lipid combined with a cationic lipid in vitro and in vivo

Ma, Yuan ; Zhao, Wenting ; Li, Yiding ; Pan, Yufei ; Wang, Shuhe ; Zhu, Yuejie ; Kong, Lingxuan ; Guan, Zhu ; Wang, Jiancheng ; Zhang, Lihe ; Yang, Zhenjun

Netherlands: Elsevier Ltd

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