Polysarcosine-Based Lipids: From Lipopolypeptoid Micelles to Stealth-Like Lipids in Langmuir Blodgett Monolayers

Abstract

Amphiphiles and, in particular, PEGylated lipids or alkyl ethers represent an important class of non-ionic surfactants and have become key ingredients for long-circulating ("stealth") liposomes. While poly-(ethylene glycol) (PEG) can be considered the gold standard for stealth-like materials, it is known to be neither a bio-based nor biodegradable material. In contrast to PEG, polysarcosine (PSar) is based on the endogenous amino acid sarcosine (N-methylated glycine), but has also demonstrated stealth-like properties in vitro, as well as in vivo. In this respect, we report on the synthesis and characterization of polysarcosine based lipids with C 14 and C 18 hydrocarbon chains and their end group functionalization. Size exclusion chromatography (SEC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis reveals that lipopeptoids with a degree of polymerization between 10 and 100, dispersity indices around 1.1, and the absence of detectable side products are directly accessible by nucleophilic ring opening polymerization (ROP). The values for the critical micelle concentration for these lipopolymers are between 27 and 1181 mg/L for the ones with C 18 hydrocarbon chain or even higher for the C 14 counterparts. The lipopolypeptoid based micelles have hydrodynamic diameters between 10 and 25 nm, in which the size scales with the length of the PSar block. In addition, C 18 PSar 50 can be incorporated in 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) monolayers up to a polymer content of 3%. Cyclic compression and expansion of the monolayer showed no significant loss of polymer, indicating a stable monolayer. Therefore, lipopolypeptoids can not only be synthesized under living conditions, but my also provide a platform to substitute PEG-based lipopolymers as excipients and/or in lipid formulations.

Poly(Sarcosine) Surface Modification Imparts Stealth‐Like Properties to Liposomes

“…In line with MALDI‐TOF MS (matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry) 1 H DOSY (diffusion‐ordered spectroscopy) NMR shows the presence of only one diffusing species confirming the absence of free initiator and water‐initiated polymer (Figure B). The discrepancy between the molecular weights determined by HFIP‐GPC (hexafluoro‐2‐isopropanol‐gel permeation chromatography) and NMR can be explained with the uncommonly high values of polymethylmethacrylate (PMMA) in HFIP …”

“…In this work, we report the synthesis of the lipid‐like amphiphile bisalkyl polysarcosine (BA‐pSar) and its successful incorporation into the lipid bilayer of preformed liposomes. It was demonstrated earlier that pSar has properties similar to PEG, comprising high water‐solubility, flexibility, and low immunogenicity in vitro, making it a promising candidate for surface modification of liposomes . The aim of this study was to demonstrate that surface modification using pSar‐lipopolymers is a valuable strategy to increase circulation half‐life of liposomes while also ensuring good biocompatibility (i.e., low complement activation).…”

Overcoming Physiological Barriers to Nanoparticle Delivery—Are We There Yet?

“…Polysarcosine (PSar) is a polymer of sarcosine (N-methylated glycine, an intermediate of glycine metabolism) in which tertiary amide bonds in the backbone confer resistance to proteolytic degradation compared to conventional peptides (Miller et al, 1995). Similar to PEG, PSar could be conjugated to lipids, potentially allowing the generation of PSar-protected liposomes and micelles (Weber et al, 2016). When PSar was grafted on a TiO 2 sheet, it reduced the amount of fibrinogen associated with the surface and prevented the attachment of mammalian and bacterial cells (Lau et al, 2012).…”

A transient initiator for polypeptoids post-polymerization α-functionalization via activation of thioester group

“…Hydrophilic polysarcosine (PSar) [23,72] and somewhat lesser hydrophilic poly(N-ethylglycine) (PNEG) [77,78] could be potentially used in the biomedical field. PSar due to nontoxicity [68,79,80], biocompatibility [64,81], non-fouling [82][83][84], low (or no) cytotoxicity [68,72,80,85], electroneutrality [86] is considered as promising alternative to PEG [10,87].…”