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Frontiers of Chemical Science and Engineering

ISSN 2095-0179

ISSN 2095-0187(Online)

CN 11-5981/TQ

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Front. Chem. Sci. Eng.    2017, Vol. 11 Issue (4) : 663-675    https://doi.org/10.1007/s11705-017-1623-5
REVIEW ARTICLE
Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing
Yu Cao1, Xiaoxuan Liu2, Ling Peng1()
1. Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, Equipe Labellisée Ligue Contre le Caner, 13288 Marseille, France
2. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
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Abstract

Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined molecular architecture and multivalent cooperativity. However, the clinical translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufacturing practice standard. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramolecular structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amount and superior quality. Indeed, the concept of supramolecular dendrimers has proved to be very promising, and has opened up a new avenue for dendrimer-mediated siRNA delivery. A series of self-assembling supramolecular dendrimers have consequently been established, some of them out-performing the currently available nonviral vectors in delivering siRNA to various cell types in vitro and in vivo, including human primary cells and stem cells. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating self-assembling amphiphilic dendrimers to construct supramolecular dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramolecular dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.
Keywords gene therapy      RNAi therapeutics      dendrimer      nanovectors      gene silencing     
Corresponding Author(s): Ling Peng   
Just Accepted Date: 12 January 2017   Online First Date: 31 March 2017    Issue Date: 06 November 2017
 Cite this article:   
Yu Cao,Xiaoxuan Liu,Ling Peng. Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing[J]. Front. Chem. Sci. Eng., 2017, 11(4): 663-675.
 URL:  
https://academic.hep.com.cn/fcse/EN/10.1007/s11705-017-1623-5
https://academic.hep.com.cn/fcse/EN/Y2017/V11/I4/663
Fig.1  The mechanism of RNA interference. Silencing is triggered by long double-stranded RNAs, which are recognized and processed into small interfering RNAs (siRNAs) by the enzyme Dicer. The duplex siRNAs are then passed to the RISC (RNA-induced silencing complex), which is activated by unwinding of the siRNA. The sense strand of the siRNA is cleaved and discarded, while the antisense strand remains associated with the active RISC complex, guiding it to a target mRNA containing a complementary sequence. The complex then cleaves the mRNA, resulting in silencing of the targeted gene. The RISC can destroy multiple identical transcripts by undergoing further catalytic cycles of binding and cleavage of target mRNAs
Fig.2  Nonviral vector-mediated siRNA delivery and gene silencing
Fig.3  General presentation of the structure of a dendrimer, which is composed of a central core, the repetitive branching units which form the generations and the terminal groups. The central core itself is generation 0 (G0); generation 1 (G1), generation 2 (G2) and generation 3 (G3) refer to dendrimers with the first, second and third levels of branching, respectively
Fig.4  Molecular structure of a PAMAM dendrimer with a triethanolamine (TEA) core. For clarity, only a generation 4 dendrimer is presented
Fig.5  Cartoon presentation of siRNA delivery mediated by a dendrimer
Fig.6  (A) Self-assembly of a small amphiphilic dendrimer to create a supramolecular dendrimer that mimics a covalently synthesized high-generation dendrimer for siRNA delivery [43]; (B) amphiphilic dendrimer 1, carrying a hydrophobic C18 alkyl chain and a hydrophilic PAMAM dendron with 8 terminal amine groups [42]
Fig.7  Structural derivatives of the amphiphilic dendrimer 1[42,43]
Fig.8  Arginine-terminated amphiphilic dendrimer 10 to enhance cellular uptake for more efficient siRNA delivery [45]
Fig.9  (A) Amphiphilic dendrimer 11 bearing two hydrophobic alkyl chains and a hydrophilic PAMAM dendron; (B) 11 forms dendrimersomes, which upon addition of siRNA, undergo spontaneous rearrangement into micelles, in order to provide maximal exposure of the positively-charged dendrimer terminals for interaction with the negatively-charged siRNA [47]
Fig.10  The bola-amphiphilic dendrimer 12 designed for ROS-responsive siRNA delivery. (A) Chemical structure of 12; (B) schematic representation of 12for the ROS-triggered delivery of siRNA and consequential gene silencing. The dendrimer 12is able to form nanosized complexes with siRNA, which can be internalized by the cancer cell before releasing siRNA in response to ROS, leading to effective gene silencing [49]
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