RAFT-synthesized copolymers and conjugates designed for therapeutic delivery of siRNA

Smith, DeeDee; Holley, Andrew C.; McCormick, Charles L.

doi:10.1039/c1py00038a

Cited by 65 publications

(65 citation statements)

References 202 publications

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“…Methods for preparing biopolymer conjugates have been reviewed. [53,54,57,89] The most common method involves coupling the RAFT-synthesized polymer with the biopolymer through reactive functionality present on either the 'R' or 'Z' groups. Note that use of functionality on 'Z' leaves the thiocarbonylthio group as a potentially degradable link at the block juncture.…”

Section: Biopolymer Conjugates Post-raft Polymerizationmentioning

confidence: 99%

“…[47,53] The temperature-responsive triblock copolymer, PEO-b-poly(APMAm)-b-poly(NIPAm), was synthesized by RAFT polymerization in aqueous medium. [380] At room temperature, the polymer is hydrophilic and exists as unimers in aqueous solution.…”

Section: Microgels and Nanoparticlesmentioning

confidence: 99%

“…include those on the kinetics and mechanism of RAFT polymerization, [26,27] RAFT agent design and synthesis, [28] the use of RAFT to probe the kinetics of radical polymerization, [29] microwaveassisted RAFT polymerization, [30,31] RAFT polymerization in microemulsion, [32] end-group removal/transformation, [33][34][35][36] the use of RAFT in organic synthesis, [37] the combined use of RAFT polymerization and click chemistry, [38] the synthesis of star polymers and other complex architectures, [39][40][41][42] the synergistic use of RAFT polymerization and ATRP, [43,44] the synthesis of self assembling and/or stimuli-responsive polymers, [45][46][47] and the use of RAFT-synthesized polymers in green chemistry, [48] polymer nanocomposites, [49][50][51] drug delivery and bioapplications, [41,46,47,[52][53][54][55][56][57][58][59][60] and applications in cosmetics [61] and optoelectronics. [62] The process is also given substantial coverage in most recent reviews that, in part, relate to polymer synthesis, living or controlled polymerization or novel architectures.…”

Section: Introductionmentioning

confidence: 99%

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Living Radical Polymerization by the RAFT Process – A Third Update

2012

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This paper provides a third update to the review of reversible deactivation radical polymerization (RDRP) achieved with thiocarbonylthio compounds (ZC(¼S)SR) by a mechanism of reversible addition-fragmentation chain transfer ( Chem. 2009Chem. , 62, 1402. This review cites over 700 publications that appeared during the period mid 2009 to early 2012 covering various aspects of RAFT polymerization which include reagent synthesis and properties, kinetics and mechanism of polymerization, novel polymer syntheses, and a diverse range of applications. This period has witnessed further significant developments, particularly in the areas of novel RAFT agents, techniques for end-group transformation, the production of micro/nanoparticles and modified surfaces, and biopolymer conjugates both for therapeutic and diagnostic applications.

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Section: Biopolymer Conjugates Post-raft Polymerizationmentioning

confidence: 99%

Section: Microgels and Nanoparticlesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Living Radical Polymerization by the RAFT Process – A Third Update

2012

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“…29 As a synthetic technique, RAFT offers a convenient platform for molecular engineering of polymeric systems for drug delivery, biotechnology, nanotechnology and nanomedicine applications. [30][31][32][33][34][35][36][37] It has already been used to synthesise a range of polymeric structures for siRNA delivery, [38][39][40][41][42][43][44][45][46] with certain RAFT generated polymers found to have low levels of cytotoxicity. 47,48 In this study a novel polycationic system that is capable of selfassembly in aqueous solutions and of forming small, stable nanoparticles when complexed to siRNAs has been synthesized, imbuing nonviral carrier characteristics such as gene protection, phase transition and buffering capacity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers

et al. 2012

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Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to generate welldefined pH-responsive biofunctional polymers as potential 'smart' gene delivery systems. A series of five poly(dimethylamino ethyl methacrylate-co-cholesteryl methacrylate) P(DMAEMA-co-CMA) statistical copolymers, with similar molecular weights and varying cholesterol content, were prepared. The syntheses, compositions and molecular weight distributions for P(DMAEMA-co-CMA) were monitored by nuclear magnetic resonance (NMR), solid-state NMR and gel permeation chromatography (GPC) evidencing well-defined polymeric structures with narrow polydispersities. Aqueous solution properties of the copolymers were investigated using turbidimetry and light scattering to determine hydrodynamic diameters and zeta potentials associated with the phase transition behaviour of P(DMAEMA-co-CMA) copolymers. UV-Visible spectroscopy was used to investigate the pH-responsive behaviour of copolymers. Hydrodynamic radii were measured in the range 10-30 nm (pH, temperature dependent) by dynamic light scattering (DLS). Charge studies indicated that P(DMAEMA-co-CMA) polymers have an overall cationic charge, mediated by pH. Potentiometric studies revealed that the buffering capacity and pK a values of polymers were dependent on cholesterol content as well as on cationic charge. The buffering capacity increased with increasing charge ratio, overall demonstrating transitions in the pH endosomal region for all five copolymeric structures. Cell viability assay showed that the copolymers displayed increasing cytotoxicity with decreasing number of cholesterol moieties. These preliminary results show the potential of these welldefined P(DMAEMA-co-CMA) polymers as in vitro siRNA delivery agents.

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“…The polymer carriers usually incorporate a pH buffering molecule that acts as a 'proton sponge' or binds to the endosome membrane to facilitate their escape 12,13 . Although such systems have demonstrated utility in nonhuman primate studies for liver-related diseases due to the natural accumulation of the carrier in the liver [14][15][16][17] , the permanent cationic charge of the nanocarriers 18,19 makes release of the siRNA difficult [20][21][22] . The accumulation of cationic species could result in unwanted toxicity especially when administered in multiple doses.…”

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confidence: 99%

An influenza virus-inspired polymer system for the timed release of siRNA

et al. 2013

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Small interfering RNA silences specific genes by interfering with mRNA translation, and acts to modulate or inhibit specific biological pathways; a therapy that holds great promise in the cure of many diseases. However, the naked small interfering RNA is susceptible to degradation by plasma and tissue nucleases and due to its negative charge unable to cross the cell membrane. Here we report a new polymer carrier designed to mimic the influenza virus escape mechanism from the endosome, followed by a timed release of the small interfering RNA in the cytosol through a self-catalyzed polymer degradation process. Our polymer changes to a negatively charged and non-toxic polymer after the release of small interfering RNA, presenting potential for multiple repeat doses and long-term treatment of diseases.

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RAFT-synthesized copolymers and conjugates designed for therapeutic delivery of siRNA

Cited by 65 publications

References 202 publications

Living Radical Polymerization by the RAFT Process – A Third Update

Living Radical Polymerization by the RAFT Process – A Third Update

Synthesis, self-assembly and stimuli responsive properties of cholesterol conjugated polymers

An influenza virus-inspired polymer system for the timed release of siRNA

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