Polymers for siRNA Delivery: A Critical Assessment of Current Technology Prospects for Clinical Application

Cooper, Bailey M.; Putnam, David

doi:10.1021/acsbiomaterials.6b00363

Cited by 14 publications

(11 citation statements)

References 146 publications

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“…The most common cationic formulations utilized for intracellular drug or protein delivery have been lipid nanoparticles and polymeric micelles . For lipid nanoparticles, PEG content can be modulated by the ratio of PEG‐containing lipid incorporated during nanoparticle formation.…”

Section: Introductionmentioning

confidence: 99%

Control of cationic nanogel PEGylation in heterogeneous ARGET ATRP emulsion polymerization with PEG macromonomers

Spencer

Luu

Beckman

et al. 2018

J. Polym. Sci. Part A: Polym. Chem.

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Crosslinked cationic nanoscale networks with hydrophobic cores are an environmentally robust alternative to self-assembled polymeric drug delivery carriers with respect to therapeutic encapsulation and stability to dilution. However, the ability to tune the degree of PEG incorporated into nanogels during synthesis is more challenging. In this work, biodegradable cationic nanogels were synthesized by ARGET ATRP emulsion polymerization in a single step. The density of PEG in the final nanogels ranged from zero to 40 wt % and was dependent on the feed concentration of PEG monomer, surfactant concentration, surfactant hydrophilic–lipophilic balance, and the ratio of cationic to nonionic surfactant. A comprehensive analysis of nanogel material properties as a function of PEG graft density is presented including analysis of composition, monomer conversion, thermal properties, size, surface charge, and degradation. This study provides a robust analysis for the synthesis of degradable cationic nanogels via a controlled radical polymerization with predictable degrees of PEGylation.

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Section: Introductionmentioning

confidence: 99%

Control of cationic nanogel PEGylation in heterogeneous ARGET ATRP emulsion polymerization with PEG macromonomers

Spencer

Luu

Beckman

et al. 2018

J. Polym. Sci. Part A: Polym. Chem.

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“…Based on published data accumulated over the past decade, average gene silencing efficiencies of 64.6 ± 24.7% in vitro and 61.5 ± 19.6% in vivo have been achieved (Figure and Table ). The three most frequently employed types of polymer nanoparticles for siRNA delivery have been solid polymeric nanoparticles, dendrimers, and hydrogels, but across the wide range of structural designs in polymeric delivery systems, there are a number of proven components that are regularly used: poly(lactic‐co‐glycolic acid) (PLGA), poly‐L‐lysine (PLL), chitosan, and polyethyleneimine (PEI) …”

Section: Protective Carriers For Sirna Deliverymentioning

confidence: 99%

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

2019

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The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201903637.With the recent FDA approval of the first siRNA-derived therapeutic, RNA interference (RNAi)-mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. Therefore, the main aims is to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA-mediated gene silencing agents in vivo. The problem is broken into three elements: 1) protection of siRNA from degradation and clearance; 2) selective homing to target cell types; and 3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The in vitro and in vivo gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field.

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“…The use of siRNA as therapeutic agents necessarily requires the use of a vector, which by neutralizing the negative charge may allow them to enter cells, as well as increasing their stability against enzymatic degradation by nucleases. Among gene vectors, polymeric materials have many advantages, as they can carry large quantities of genetic material and can be chemically derivatized to obtain systems specifically oriented towards particular target tissues [9,10]. The cationic character of such polymers, necessary for the establishment of interactions with negative-charged gene material to form polyplexes, is conferred by protonable amino groups at physiological or neutral pH.…”

Section: Introductionmentioning

confidence: 99%

Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy

et al. 2020

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Here, a novel protonable copolymer was realized for the production of polyplexes with a siRNA (inhibitor of STAT6 expression in asthma), with the aim of a pulmonary administration. The polycation was synthesized by derivatization of α,β-poly(N-2-hydroxyethyl)d,l-aspartamide (PHEA) with 1,2-Bis(3-aminopropylamino)ethane (bAPAE) in proper conditions to obtain a PHEA-g-bAPAE graft copolymer with a derivatization degree in amine (DDbAPAE%) equal to 35 mol%. The copolymer showed a proper buffering behavior, i.e., ranging between pH 5 and 7.4, to potentially give the endosomal escape of the obtained polycations. In effect, an in vitro experiment demonstrated the effect on biological membranes of the copolymer on bronchial epithelial cells (16-HBE) strongly dependent on the pH of the medium, i.e., higher at pH 5. bAPAE-based copolymers were further obtained with an increasing pegylation degree, i.e., equal to 1.9, 2.7, and 4.4 mol%, respectively. All the obtained copolymers were able to complex siRNA at a N/P ratio that decreases as the pegylation degree increases. At the same time, the tendency of polyplexes to aggregate and the capability to interact with mucin also decreases as the pegylation in the copolymer increases. Gene silencing experiments on 16-HBE showed that these copolymers have a significant role in improving the intracellular transport of naked siRNA, where the presence of PEG does not seem to hinder the cellular uptake of polyplexes. The latter obtained at polymer/siRNA weight ratio (R) equal to 10 with PHEA-g-PEG(C)-g-bAPAE also seems to be not susceptible to the presence of mucin, avoiding the polyanionic exchange of complexed siRNA, thus showing adequate behavior to be used as an effective vector for siRNA.

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Polymers for siRNA Delivery: A Critical Assessment of Current Technology Prospects for Clinical Application

Cited by 14 publications

References 146 publications

Control of cationic nanogel PEGylation in heterogeneous ARGET ATRP emulsion polymerization with PEG macromonomers

Control of cationic nanogel PEGylation in heterogeneous ARGET ATRP emulsion polymerization with PEG macromonomers

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy

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