Cylindrical Brush Polymers with Polysarcosine Side Chains: A Novel Biocompatible Carrier for Biomedical Applications

Abstract

Cylindrical brush polymers constitute promising polymeric drug delivery systems (nanoDDS). Because of the densely grafted side chains such structures may intrinsically exhibit little protein adsorption (“stealth” effect) while providing a large number of functional groups accessible for bioconjugation reactions. Polysarcosine (PSar) is a highly water-soluble, nonionic and nonimmunogenic polypeptoid based on the endogenous amino acid sarcosine (N-methyl glycine). Here we report on the synthesis, characterization and biocompatibility of cylindrical brush polymers with either polysarcosine side chains or poly-l-lysine-b-polysarcosine side chains. The latter leads to block copolypept­(o)­id based core–shell cylindrical brushes with a cationic poly-l-lysine (PLL) core and a neutral polysarcosine corona. The cylindrical brush polymers were prepared by ring-opening polymerization of the respective N-carboxyanhydrides (NCA) from a macroinitiator chain. Preliminary experiments on complex formation with siRNA demonstrate that a core–shell cylindrical brush polymer may complex on average up to 270 RNA molecules amounting to a high loading efficiency of N+/P– = 1.1. No bridging between cylindrical brushes leading to larger aggregates is observed. In vitro studies on the silencing of the expression of ApoB100, which is abundantly expressed in AML-12 hepatocytes, induced by siRNA-cylindrical core–shell brush complexes showed high efficiency, leading to a knock-down efficiency of ApoB100 mRNA of 70%.

Molecular Polymer Brushes in Nanomedicine

“…A positively charged core (poly‐ L ‐lysine) was protected by a non‐charged polymer shell (polysarcosine), which enabled selective loading of the core compartment with double‐stranded siRNA to obtain unimolecular brush polyplexes, comprising on average up to 270 siRNA molecules. Moreover, the siRNA was successfully transported into cell interiors and able to initiate knock‐down in liver cells …”

Synthesis and Applications of Compartmentalised Molecular Polymer Brushes

“…Molecular brushes,with their high molecular weights,also display promise for the delivery of large therapeutic entities, such as nucleosides.T he challenge of delivering RNA-based therapeutics to cells is often approached through their complexation with positively charged synthetic polymers or lipids, [42] which can lead to cytotoxicity.S chmidt and coworkers have constructed xy-compartmentalised polymer brushes with ap olylysine core capable of binding siRNA, and an eutral poly(sarcosine) shell to mask positive charges. [43] Polymers were shown to deliver siRNAt oc ells and effectively silence aleukemia-associated gene during in vitro experiments,whilst displaying low cytotoxicity.…”

Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery

“…[71] This unique conformation, which has a large directional persistence length similar to DNA, may provide substantially enhanced in vivo circulation times and cellular uptake. [72] Brush copolymers are prepared using some of the same general approaches as star polymers (i.e. core-first, arm-first, and coupling-onto); however, the large number of arm segments can lead to high levels of brush-brush coupling when using radical-based polymerization techniques.…”