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Polyelectrolyte Complexation of Oligonucleotides by Charged Hydrophobic-Neutral Hydrophilic Block Copolymers.

ABSTRACT: Polyelectrolyte complex micelles (PCMs, core-shell nanoparticles formed by complexation of a polyelectrolyte with a polyelectrolyte-hydrophilic neutral block copolymer) offer a solution to the critical problem of delivering therapeutic nucleic acids, Despite this, few systematic studies have been conducted on how parameters such as polycation charge density, hydrophobicity, and choice of charged group influence PCM properties, despite evidence that these strongly influence the complexation behavior of polyelectrolyte homopolymers. In this article, we report a comparison of oligonucleotide PCMs and polyelectrolyte complexes formed by poly(lysine) and poly((vinylbenzyl) trimethylammonium) (PVBTMA), a styrenic polycation with comparatively higher charge density, increased hydrophobicity, and a permanent positive charge. All of these differences have been individually suggested to provide increased complex stability, but we find that PVBTMA in fact complexes oligonucleotides more weakly than does poly(lysine), as measured by stability versus added salt. Using small angle X-ray scattering and electron microscopy, we find that PCMs formed from both cationic blocks exhibit very similar structure-property relationships, with PCM radius determined by the cationic block size and shape controlled by the hybridization state of the oligonucleotides. These observations narrow the design space for optimizing therapeutic PCMs and provide new insights into the rich polymer physics of polyelectrolyte self-assembly.

SUBMITTER: Marras AE

PROVIDER: S-EPMC6402004 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:Polyelectrolyte complex micelles are hydrophilic nanoparticles that self-assemble in aqueous environments due to associative microphase separation between oppositely charged blocky polyelectrolytes. In this work, we employ a suite of physical characterization tools to examine the effect of charged block length mismatch on the equilibrium structure of double diblock polyelectrolyte complex micelles (D-PCMs) by mixing a diverse library of peptide and synthetic charged-neutral block polyelectrolytes with a wide range of charged block lengths (25-200 units) and chemistries. Early work on D-PCMs suggested that this class of micelles can only be formed from blocky polyelectrolytes with identical charged block lengths, a phenomenon referred to as chain length recognition. Here, we use salt annealing to create PCMs at equilibrium, which shows that chain length recognition, a longstanding hurdle to repeatable self-assembly from mismatched polyelectrolytes, can be overcome. Interestingly, D-PCM structure-property relationships display a range of values that vary systematically with the charged block lengths and chemical identity of constituent polyelectrolyte pairings and cannot be described by generalizable scaling laws. We discuss the interdependent growth behavior of the radius, ionic pair aggregation number, and density in the micelle core for three chemically distinct diblock pairings and suggest a potential physical mechanism that leads to this unique behavior. By comparing the results of these D-PCMs to the scaling laws recently developed for single diblock polyelectrolyte complex micelles (S-PCMs: diblock + homopolymer), we observe that D-PCM design schemes reduce the size and aggregation number and restrict their growth to a function of charged block length relative to S-PCMs. Understanding these favorable attributes enables more predictive use of a wider array of charged molecular building blocks to anticipate and control macroscopic properties of micelles spanning countless storage and delivery applications.

Project description:In this work the electrostatic complexation of two strong polyelectrolytes (PEs) was studied, the hydrophilic and positively charged poly (diallyldimethylammonium chloride) (PDADMAC) and the hydrophobic and negatively charged poly (styrene-co-sodium styrene sulfonate) (P(St-co-SSNa)), which was prepared at different sulfonation rates. The latter is known to adopt a pearl necklace conformation in solution for intermediate sulfonation rates, suggesting that a fraction of the P(St-co-SSNa) charges might be trapped in these hydrophobic domains; thus making them unavailable for complexation. The set of complementary techniques (DLS, zetametry, ITC, binding experiment with a cationic and metachromatic dye) used in this work highlighted that this was not the case and that all anionic charges of P(St-co-SSNa) were in fact available for complexation either with the polycationic PDADMAC or the monocationic o-toluidine blue dye. Only minor differences were observed between these techniques, consistently showing a complexation stoichiometry close to 1:1 at the charge equivalence for the different P(St-co-SSNa) compositions. A key result emphasizing that (i) the strength of the electrostatic interaction overcomes the hydrophobic effect responsible for pearl formation, and (ii) the efficiency of complexation does not depend significantly on differences in charge density between PDADMAC and P(St-co-SSNa), highlighting that PE chains can undergo conformational rearrangements favoring the juxtaposition of segments of opposite charge. Finally, these data have shown that the formation of colloidal PECs, such as PDADMAC and P(St-co-SSNa), occurs in two distinct steps with the formation of small primary complex particles (<50 nm) by pairing of opposite charges (exothermic step) followed by their aggregation within finite-size clusters (endothermic step). This observation is in agreement with the previously described mechanism of PEC particle formation from strongly interacting systems containing a hydrophobic PE.

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Polyelectrolyte Complexation of Oligonucleotides by Charged Hydrophobic-Neutral Hydrophilic Block Copolymers.

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