In-situ FTIR monitoring of sarcosine N-carboxyanhydride from a lysine dendrimer macroinitiator Richard M. England 1 , Qing Yu 1 , Chloe Westley 2 , Carl J. Mallia 2 , Kevin Treacher 3 , Per-Ola Norrby 4 , Marianne Ashford 1 1 Advanced Drug Delivery, Pharmaceutical Sciences, AstraZeneca, UK, 2 Early Chemical Development, Pharmaceutical Sciences, AstraZeneca, UK, 3 Pharmaceutical Technology and Development, Operations, AstraZeneca, UK, 4 Data Science & Modelling, Pharmaceutical Sciences, AstraZeneca, Sweden We have previously reported on the synthesis of 32-arm polysarcosine modified dendrimers as versatile drug delivery platforms for the delivery of SN-38, a topo-1 inhibitor molecule. 1 Polysarcosine is an excellent alternative to polyethylene glycol for uses in drug delivery, having high water solubility and “stealth” properties for enabling prolonged blood circulation for nanoparticles. 2-3 Here we describe the synthesis of the 32-arm star polymers from lysine dendrimer macroinitiators as monitored by in-situ FTIR spectroscopy. The N-carboxyanhydride (NCA) ring-opening polymerisation can be followed by the disappearance of the unique carbonyl absorption bands from this monomer. Interestingly, using this technique we discovered that the polymerisations originating from this dendrimer macroinitiator were faster than equivalent linear polymers. Through experimentation we found that this increased rate of polymerisation was largely coming from residual boc-groups on the dendrimer. Replacing the boc-NH group for a boc-NMe in the last generation of the dendrimer resulted in a greatly reduced rate of polymerisation as the hydrogen bonding from this N-H group was eliminated. By synthesising these star polymers in sequential blocks we observed that the polymerisations of blocks closest to the core were fastest for both dendrimer initiator types, indicating a contribution of the catalytic effect also coming from the dendrimer amide N-H groups as well. Additional computational experimentation was able to show that the boc-NH groups provided stabilisation to the reactive monomer intermediate through hydrogen bonding, resulting in a lowered energy barrier for the decarboxylation process and regeneration of the terminal amine. This is the first report of this behaviour for polysarcosine and may help with the development of future designs of these materials. We also envisage that using in-situ FTIR will aid in the manufacture and scale up of these materials, since the polymerisations are otherwise difficult to monitor. References 1. England, R. M.; Moss, J. I.; Gunnarsson, A.; Parker, J. S.; Ashford, M. B., Synthesis and Characterization of Dendrimer- Based Polysarcosine Star Polymers: Well-Defined, Versatile Platforms Designed for Drug-Delivery Applications. Biomacromolecules 2020, 21 (8), 3332-3341. 2. Bleher, S.; Buck, J.; Muhl, C.; Sieber, S.; Barnert, S.; Witzigmann, D.; Huwyler, J.; Barz, M.; Süss, R., Poly(Sarcosine) Surface Modification Imparts Stealth-Like Properties to Liposomes. 2019, 15 (50), 1904716. 3. Son, K.; Ueda, M.; Taguchi, K.; Maruyama, T.; Takeoka, S.; Ito, Y., Evasion of the accelerated blood clearance phenomenon by polysarcosine coating of liposomes. Journal of Controlled Release 2020, 322 , 209-216.
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