Synthesis and characterization of bisalkylated polysarcosine-based lipopolymers

Abstract

The use of PEGylated lipids for the synthesis of stealth liposomes and lipid formulations for nucleic acid delivery has promoted the development of nanoparticle based drugs for cancer therapy, and chronic diseases. Moreover, several other nanomedicines based on these materials have advanced into clinical trails. This enormous success, however, has recently been compromised by the occurrence of immune responses towards PEG, which render pharmacokinetics and can substantially reduce the therapeutic efficiency of drugs. Therefore, alternatives for PEGylated lipids with comparable or even identical solution properties are required. In this work, we report the synthesis of polysarcosine based lipopolymers, which combine the stealth material polysarcosine with bisalkylamines. The lipopolymers are obtained by nucleophilic ring opening polymerization of sarcosine NCAs using C12 and C18 based bisalkyl amines, namely, didodecyl and dioctadecyl amine. To achieve a controlled living polymerization conditions have been optimized yielding the desired lipopolymers with precise control over chain length, end group integrity and low polymer dispersity (Đ<1.2) as demonstrated by size exclusion chromatography, 1H DOSY nuclear magnetic resonance spectroscopy and MALDI-ToF mass spectroscopy. In addition, the critical micelle concentrations and the incorporation of these lipids in lipid bilayers are reported. Therefore, this work sets the synthetic foundation for the development of alternatives to PEGylated lipids.