Biocompatible Unimolecular Micelles Obtained via the Passerini Reaction as Versatile Nanocarriers for Potential Medical Applications

Abstract

A Passerini three-component polymerization was performed for the synthesis of amphiphilic star-shaped block copolymers with hydrophobic cores and hydrophilic coronae. The degree of polymerization of the hydrophobic core was varied from 5 to 10 repeating units, and the side chain ends were conjugated by performing a Passerini-3CR with PEG-isocyanide and PEG-aldehyde (950 g/mol). The resulting amphiphilic star-shaped block copolymers contained thioether groups, which could be oxidized to sulfones in order to further tune the polarity of the polymer chains. The ability of the amphiphilic copolymers to act as unimolecular micellar encapsulants was tested with the water-insoluble dye Orange II, the water-soluble dye Para Red and the macrolide antibiotic azithromycin. The results showed that the new copolymers were able to retain drug cargo at pH levels corresponding to circulating blood and selectively release therapeutically effective doses of antibiotic as measured by bacterial cell kill. The polymers were also well-tolerated by differentiated THP-1 macrophages in the absence of encapsulated drugs.

Catalyst‐Free Four‐Component Polymerization of Propiolic Acids, Benzylamines, Organoboronic Acids, and Formaldehyde toward Functional Poly(propargylamine)s

“…[ 1,2 ] Compared with classic polymerization approaches, MCPs enjoy great structural diversity of products, strong designability of reaction procedure and product structure, mild reaction condition, simple monomer structures, environmental benefits, and so on. [ 3–6 ] Besides the most widely explored isocyanide‐based MCPs including Passerini three‐component polymerization (3CP) of isocyanide, carboxylic acid and oxo‐component (ketone or aldehyde), [ 7–10 ] and Ugi four‐component polymerization (4CP) of isocyanide, carboxylic acid, oxo‐component (ketone or aldehyde) and amine, [ 11–13 ] alkyne‐based MCPs were extensively reported in the past few years, [ 14–16 ] owing to the rich chemistry of alkynes and the unsaturated product structures with potential optoelectronic properties from alkyne chemistry, [ 17 ] which could be applied in optoelectronic devices, [ 18,19 ] or as luminescent materials, [ 14,20 ] and antibacterial materials. [ 21 ]…”

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

“…The CellTiter‐Fluor cell viability assay was performed to determine the cytotoxicity of P1 against MDA‐MB‐231 and MCF10A cells following the protocol provided by the vendor (Promega, Madison WI). [ 5 ] Cells were treated for 48 h with different concentrations of P1 (from 0.2 to 1 mg mL −1 ). Experiments were made in replicates and repeated on different days.…”

“…[ 1 ] The Passerini three component reaction (Passerini‐3CR) is one of the most well‐established of these reactions, combining in a one‐pot procedure a carboxylic acid, an isocyanide, and an oxo‐component (aldehyde or ketone) to synthesize an α‐acyloxycarboxamide. [ 2 ] The versatility of the Passerini‐3CR has, for instance, been exploited for the synthesis of monomers, [ 3 ] multifunctional RAFT agents, [ 4 ] star‐shaped unimolecular micelles, [ 5 ] and linear polymers. [ 6 ] The combination of different monomers through a step‐growth polymerization mechanism allows the synthesis of a variety of tunable, biodegradable, and biocompatible polyesters, and polyamides with functional side chains.…”

“…The fluorescence was recorded as a measure of the constitutive protease activity within live cells and was considered as a biomarker of cell viability. [ 5 ] P1 was found to be well tolerated by MDA‐MB‐231 and MCF‐10A cells at concentrations below 800 µg mL −1 . Therefore, the toxicity of P1 was further investigated by performing Annexin‐V/PI assays, which were used to discriminate between viable, apoptotic and dead cells using flow cytometry.…”

Synthesis and Encapsulation of Uniform Star‐Shaped Block‐Macromolecules

“…[ 36,40 ] Furthermore, the ability of phase‐transfer and drug encapsulation have been shown. [ 38,41,42 ] The sophisticated core and shell structures of such polymers can be tuned to fit different guest molecules and often solvatochromic dyes are applied to quantify encapsulation. [ 42,43 ] However, until now, such star‐shaped block copolymers have only been synthesized with a dispersity higher than one.…”