A biodegradable amphiphilic poly(aminoester) dendrimer for safe and effective siRNA delivery

Ma, Chi; Zhu, Dandan; Lin, Wenyi; Liu, Ying; Huang, Yuanzheng; Zhu, Hui‐Ling; Ye, Mengyun; Wang, Yang; Peng, Ling; Liu, Xiaoxuan

doi:10.1039/d1cc06655b

Cited by 6 publications

(5 citation statements)

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“…Amphiphilic dendrimers 12 and 13 bearing poly(aminoester) and glycerol dendrons, respectively, for siRNA delivery. , Adapted with permission from ref (Copyright 2022 Royal Society of Chemistry) ref (Copyright 2012 American Chemical Society).…”

Section: Amphiphilic Dendrimer Vectorsmentioning

confidence: 99%

“…Recently, we also elaborated a biodegradable amphiphilic dendrimer 12 ( Figure 7 ) bearing poly(aminoester) dendron ( 12 in Figure 7 ). 41 Poly(aminoester) skeleton is widely employed for constructing biodegradable materials thanks to its multiple advantageous features: first, the ester linkage is acid-, base- and enzyme-labile, thus degradable via ester hydrolysis; second, the amine functionality can serve as the buffer to neutralize the acid generated from the ester hydrolysis, rending the degradation process within a benign and nonaggressive environment. Indeed, 12 was readily disintegrated upon enzymatic action and exhibited more effective siRNA delivery with a better safety profile than its PAMAM dendrimer counterpart.…”

Section: Amphiphilic Dendrimer Vectorsmentioning

confidence: 99%

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Amphiphilic Dendrimer Vectors for RNA Delivery: State-of-the-Art and Future Perspective

et al. 2022

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Metrics & MoreArticle Recommendations CONSPECTUS: Dendrimers, a special family of polymers, are particularly promising materials for various biomedical applications by virtue of their well-defined dendritic structure and cooperative multivalency. Specifically, in this Account, we present state-of-the-art amphiphilic dendrimers for nucleic acid delivery. Ribonucleic acid (RNA) molecules are fast becoming an important drug modality, particularly since the recent success of mRNA vaccines against COVID-19. Notably, RNA therapeutics offer the unique opportunity to treat diseases at the gene level and address "undruggable" targets. However, RNA therapeutics are not stable and have poor bioavailability, imposing the need for their protection and safe delivery by vectors to the sites-of-action to allow the desired therapeutic effects. Currently, the two most advanced nonviral vectors are based on lipids and polymers, with lipid vectors primarily exploiting the membrane-fusion mechanism and polymer vectors mainly endocytosis-mediated delivery. Notably, only lipid vectors have been advanced through to their clinical use in the delivery of, for example, the first siRNA drug and the first mRNA vaccine. The success of lipid vectors for RNA delivery has motivated research for further innovative materials as delivery vectors. Specifically, we have pioneered lipid/dendrimer conjugates, referred to as amphiphilic dendrimers, for siRNA delivery with the view to harnessing the delivery advantages of both lipid and polymer vectors while enjoying the unique structural features of dendrimers. These amphiphilic dendrimer vectors are lipid/dendrimer hybrids and are thus able to mimic lipid vectors and exploit membranefusion-mediated delivery, while simultaneously retaining the multivalent properties of polymer vectors that allow endocytosis-based delivery. In addition, they have precisely controllable and stable nanosized chemical structures and offer nanotechnology-based delivery.Effective amphiphilic dendrimer vectors share two important elements: chemical hydrophilic entities to bind RNA and RNA complex-stabilizing hydrophobicity. These two combined features allow the encapsulation of RNA within a stable complex before its release into the cytosol following endocytosis. This hydrophilic/hydrophobic balance permitted by the structural features of amphiphilic dendrimers plays a determining role in RNA delivery success.In this Account, we provide a conceptual overview of this exciting field with the latest breakthroughs and key advances in the design of amphiphilic dendrimers for the delivery of siRNA and mRNA. Specifically, we start with a short introduction to siRNA-and mRNA-based therapeutics and their delivery challenges. We then outline the pioneering and representative studies on amphiphilic dendrimer vectors to highlight their historical development and promising features that offer to facilitate the once challenging RNA delivery. We conclude by offering perspectives for the future of amphiphilic dendrimer vectors for nucleic aci...

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Section: Amphiphilic Dendrimer Vectorsmentioning

confidence: 99%

Section: Amphiphilic Dendrimer Vectorsmentioning

confidence: 99%

Amphiphilic Dendrimer Vectors for RNA Delivery: State-of-the-Art and Future Perspective

et al. 2022

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“…[44][45][46] Hitherto, a limited number of cases have reported on enzyme-responsive RNA delivery using peptide conjugates, [47] modified siRNA, [48] and ester-based amphiphilic dendrimers. [49] Herein, we report the synthesis of amphiphiles with positively charged triazolium head groups that self-assemble into vesicular structures and are able to complex siRNA. After addition of a stimulus (here: esterase) the polar head group of the amphiphiles degrades irreversibly by forming a neutral triazole and siRNA gets released.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to these endogenous pH and redox effectors, enzymes also represent a trigger of choice for controlled drug delivery [44–46] . Hitherto, a limited number of cases have reported on enzyme‐responsive RNA delivery using peptide conjugates, [47] modified siRNA, [48] and ester‐based amphiphilic dendrimers [49] …”

Section: Introductionmentioning

confidence: 99%

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A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

Hollstein

Ali

Coste

et al. 2022

Chemistry A European J

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The increased importance of RNA-based therapeutics comes with a need to develop next-generation stimuliresponsive systems capable of binding, transporting and releasing RNA oligomers. In this work, we describe triazoliumbased amphiphiles capable of siRNA binding and enzymeresponsive release of the nucleic acid payload. In aqueous medium, the amphiphile self-assembles into nanocarriers that can disintegrate upon the addition of esterase. Key to the molecular design is a self-immolative linker that is anchored to the triazolium moiety and acts as a positively-charged polar head group. We demonstrate that addition of esterase leads to a degradation cascade of the linker, leaving the neutral triazole compound unable to form complexes and therefore releasing the negatively-charged siRNA. The reported molecular design and overall approach may have broad utility beyond this proof-of-principle study, because the underlying CuAAC "click" chemistry allows bringing together three groups very efficiently as well as cleaving off one of the three groups under the mild action of an esterase enzyme.

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Stimuli-Responsive Dendrimers as Nanoscale Vectors in Drug and Gene Delivery Systems: A Review Study

Torabi Fard,

Ahmad Panahi,

Moniri

et al. 2024

J Polym Environ

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A biodegradable amphiphilic poly(aminoester) dendrimer for safe and effective siRNA delivery

Abstract: Small interfering RNA (siRNA)-based therapeutics represent a novel and compelling drug modality, provided that safe and competent vectors are available for their delivery. Here, we report a biodegradable amphiphilic poly(aminoester)...

Cited by 6 publications

References 28 publications

Amphiphilic Dendrimer Vectors for RNA Delivery: State-of-the-Art and Future Perspective

Amphiphilic Dendrimer Vectors for RNA Delivery: State-of-the-Art and Future Perspective

A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

Stimuli-Responsive Dendrimers as Nanoscale Vectors in Drug and Gene Delivery Systems: A Review Study

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