Structural exploration of hydrophobic core in polycationic micelles for improving siRNA delivery efficiency and cell viability

Huang, Wen‐Jun; Wang, Xiaoxia; Wang, Changrong; Du, Liqing; Zhang, Jianhua; Deng, Liandong; Dong, Anjie

doi:10.1039/c8tb02706d

Cited by 9 publications

(3 citation statements)

References 45 publications

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“…7,8 In this context, nanomedicine-based approaches for RNA delivery have been explored, aiming to improve pharmacological effectiveness at disease sites and reduce off-target effects. [9][10][11][12][13][14][15] However, the features of nanoparticle (NP) delivery systems need to be refined carefully in terms of composition, structure, size, surface and stability, and to take into account (i) the drugs to be delivered, (ii) the characteristics of the tumor microenvironment, (iii) the administration route and (iv) the final target. 16 Current research is focused on the design of carrier materials able to respond to intrinsic or extrinsic stimuli ( pH decrease, redox gradients, enzyme action, light, magnetic fields, temperature, ultrasound or electric currents) for "on demand" delivery at a diseased site.…”

Section: Introductionmentioning

confidence: 99%

Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells

et al. 2021

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“…In the past few decades, a variety of nucleic acid vectors have been developed, including viral and nonviral vectors. ,− Viral vectors are efficient at gene delivery, but their applications are restricted by immunogenic and inflammatory responses. , Nonviral vectors including lipids, , polymers, − peptides, , and inorganic/organic hybrid nanoparticles (NPs) , have been constructed for the delivery of pDNA, , siRNA, , and mRNA , with varying lengths. Among these nonviral vectors, delivery vehicles based on liposomes and polymers have been extensively researched and developed .…”

Section: Introductionmentioning

confidence: 99%

Structural Exploration of Polycationic Nanoparticles for siRNA Delivery

Yan

Zhang

et al. 2022

ACS Biomater. Sci. Eng.

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RNA interference (RNAi) is a promising approach to the treatment of genetic diseases by the specific knockdown of target genes. Functional polymers are potential vehicles for the effective delivery of vulnerable small interfering RNA (siRNA), which is required for the broad application of RNAi-based therapeutics. The development of methods for the facile modulation of chemical structures of polymeric carriers and an elucidation of detailed delivery mechanisms remain important areas of research. In this paper, we synthesized a series of methacrylate-based polymers with controllable structures and narrow distributions by atom transfer radical polymerization using various combinations of cationic monomers (2-dimethylaminoethyl methacrylate, 2-diethylaminoethyl methacrylate, and 2-dibutylaminoethyl methacrylate) and hydrophobic monomers (2-butyl methacrylate (BMA), cyclohexyl methacrylate, and 2-ethylhexyl methacrylate). These polymers exhibited varying hydrophobicities, charge densities, and pK a values, enabling the discovery of effective carriers for siRNA by in vitro delivery assays. For the polymers with BMA segments, 50% of cationic segments were beneficial to the formation of siRNA nanoparticles (NPs) and the in vitro delivery of siRNA. The optimal ratio varied for different combinations of cationic and hydrophobic segments. In particular, 20k PMB 0.5, PME 0.5, and PEB 1.0 showed >75% luciferase knockdown. Efficacious delivery was dependent on high siRNA binding, the small size of NPs, and balanced hydrophobicity and charge density. Cellular uptake and endosomal escape experiments indicated that carboxybetaine modification of 20k PMB 0.5 did not remarkably affect the internalization of corresponding NPs after incubation for 6 h but significantly reduced the endosomal escape of NPs, which leads to the notable decrease in delivery efficacy of polymers. These results provide insights into the mechanism of polymer-based siRNA delivery and may inspire the development of novel polymeric carriers.

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“…[ 4 ] However, the degradability by nuclei acid enzyme and electronegativity had serious impacts on siRNA systematic and intracellular delivery. [ 5,6 ] Therefore, developing an efficient siRNA delivery vehicle is extremely urgent.…”

Section: Introductionmentioning

confidence: 99%

pH‐Sensitive Polycations for siRNA Delivery: Effect of Asymmetric Structures of Tertiary Amine Groups

Yang

Dong

Wang

et al. 2021

Macromolecular Bioscience

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pH‐sensitive polyelectrolytes provide enormous opportunity for siRNA delivery. Especially, their tertiary amine structures can not only bind genes but also act as pH‐sensitive hydrophobic structure to control genes release. However, the influence of molecular structures on siRNA delivery still remains elusive, especially for the asymmetric alkyl substituents of the tertiary amine groups. Herein, a library of N‐methyl‐N‐alkyl aminoethyl methacrylate monomers (MsAM) with asymmetric alkyl substituents on the tertiary amine group is synthesized and used to prepare a series of tri‐block polycationic copolymers poly(aminoethyl methacrylate)‐block‐poly (N‐methyl‐N‐alkyl aminoethyl methacrylate)‐block‐poly(ethylene glycol methacrylate) (PAMA‐PMsMA‐PEG). And the properties of these polycations and their self‐assembled micelles are characterized, including molecular structure, proton buffering capacity, pH‐sensitivity, size, and zeta potential. With the length increase of one alkyl substituent, the proton buffering capacity of both monomers and polycations is demonstrated to be narrowed down. The siRNA delivery efficiency and cytotoxicity of these micelles are also evaluated on HepG2 cells. In particular, poly(aminoethyl methacrylate)‐block‐poly(N‐methyl‐N‐ethyl aminoethyl methacrylate)‐block‐poly(ethylene glycol methacrylate) (PAMA‐PMEMA‐PEG) elicited the best luciferase knockdown efficiency and low cytotoxicity. Besides, PAMA‐PMEMA‐PEG/siRRM2 also induced significant anti‐tumor activity in vitro. These results indicated PAMA‐PMEMA‐PEG has potential for further use in the design of gene vehicles with the improved efficiency of siRNA delivery.

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Structural exploration of hydrophobic core in polycationic micelles for improving siRNA delivery efficiency and cell viability

Abstract: Improving siRNA delivery efficiency often encounters a dilemma with poor or decreased biocompatibility for polycationic micelles.

Cited by 9 publications

References 45 publications

Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells

Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells

Structural Exploration of Polycationic Nanoparticles for siRNA Delivery

pH‐Sensitive Polycations for siRNA Delivery: Effect of Asymmetric Structures of Tertiary Amine Groups

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