Synthesis of Passerini‐3CR Polymers and Assembly into Cytocompatible Polymersomes

Abstract

The versatility of the Passerini three component reaction (Passerini‐3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self‐assembles into polymersomes. Carboxy‐functionalized poly(ethylene glycol) methyl ether is reacted with AB‐type bifunctional monomers and tert‐butyl isocyanide in a single process via Passerini‐3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini‐3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post‐functionalization with a dye, Cyanine‐5 (Cy5). The obtained P1‐Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA‐MB‐231 triple‐negative breast cancer cells. P1‐Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini‐3CR.

Self‐assembly of polymers from multicomponent reactions

“…2(a)). 54 The product polymer self‐assembled in phosphate buffer and formed polymersomes of ca 145 nm in size which were used to encapsulate doxorubicin, an anticancer drug (Fig. 2(b)).…”

“…(d) Cellular uptake quantification via mean fluorescence intensity (MFI) from flow cytometry of P‐Cy5 polymersomes (three replicates, * P < 0.05, t ‐test). Reproduced with permission from Travanut et al 54 . Copyright 2021, Wiley‐VCH.…”

L‐glutamic acid as a versatile platform for rapid synthesis of functional polyesters via facile Passerini multicomponent polymerization

“…In combination with green chemistry, P‐3CP provides a facile and eco‐friendly approach to synthesize polymers due to its mild reaction conditions (low reaction temperature and in air atmosphere), high atom economy, catalyst‐free synthesis and no by‐product 14–18 . A variety of linear, 19–21 hyperbranched, 22 and dendritic 3 poly(ester amide)s have been successfully developed by P‐3CP with controlled polymer architectures. However, there are few reports regarding to bio‐based functional polyesters obtained via P‐3CR.…”

Ring‐Opening Metathesis Polymerization of Norbornene‐Based Monomers Obtained via the Passerini Three Component Reaction

“…[ 10 ] While peptide synthesis typically entails multistep reactions, [ 11 ] multicomponent reactions (MCRs) have emerged as an alternative method to introduce multiple functionalities into a molecule in a one‐step process. [ 12 ] MCRs are particularly attractive in polymer chemistry where they have been used to introduce selected functionalities to monomers, [ 13 ] polymer end groups, [ 14 ] but also in the preparation of polymers, [ 15 ] and sequence‐defined oligomers with applications in drug delivery and data storage. [ 16 ] MCRs have also been employed in metathesis reactions where, in a recent example, carboxylic acid‐functionalized norbornenes and a range of aldehydes were reacted in an Ugi four component reaction, resulting in a small library of monomers with dipeptide‐like functional groups.…”

“…[ 18 ] The resulting polymers have the ability to hydrogen bond, making them interesting, e.g., in the field of drug delivery. [ 15 ]…”