Trithiocarbonate-Mediated RAFT Polymerization Enables the Synthesis of Homotelechelic <i>N-</i>Vinylpyrrolidone Oligomers with Surfactant Properties

Poly(N-vinylpyrrolidone) (PVP) is a well-known biocompatible polymer widely used in cosmetics, pharmaceuticals, and many other applications and is usually synthesized via radical polymerization. High molar mass PVP lacks biodegradability according to the OECD 301 F standard and can lead to permanent accumulation within the body or in the environment. Nowadays, lower molar mass PVP is produced via xanthate-mediated reversible addition–fragmentation chain-transfer (RAFT) polymerization. However, this type of polymerization also leads to a large amount of undesired dimer formation. Herein, various homotelechelic PVP oligomers were prepared via a trithiocarbonate-mediated RAFT polymerization with the production of a minimal amount of unsaturated dimer. These PVP oligomers showed similar surfactant properties as the well-known Lutensol AT50 surfactant, and they were used as a nonionic surfactant in a typical radical aqueous miniemulsion polymerization of methyl methacrylate (MMA) to produce well-defined PMMA nanoparticles. Additionally, PVP oligomers showed no toxicity to the bacterial strain Escherichia coli and to the water fleas Daphnia pulex, which is promising for safe release in wastewater systems

Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Pharmacokinetic properties determine the efficacy of protein therapeutics. The covalent attachment of poly­(ethylene glycol) (PEG) extends the half-life of such biologicals to maintain a therapeutically effective concentration over a prolonged period of time and improves administration and compliance. A major obstacle of these polymer–protein conjugates is the chemical stability of the PEG preventing its metabolism and leading to side effects. Instead, we propose the PPEylation, that is, the conjugation of degradable poly­(phosphoester)­s (PPE) to proteins, in order to generate fully biodegradable polymer–protein conjugates. The structure of the PPEylated protein conjugates was verified with mass spectrometry and size exclusion chromatography. They were compared to structural analogues, except classical, PEGylated proteins, and exhibit comparable bioactivity, but avoiding any nondegradable polymer in the conjugate. We proved the degradation of the protective polymer shell surrounding the conjugate in aqueous environments at physiological conditions by online triple detection size exclusion chromatography and gel electrophoresis. We believe that this research will provide an attractive alternative for future drug design with implications for the clinical use of biologicals

Polyphosphonate-Based Macromolecular RAFT-CTA Enables the Synthesis of Well-Defined Block Copolymers Using Vinyl Monomers

Reversible addition–fragmentation chain transfer (RAFT) polymerization has become a straightforward approach to block copolymers using a wide variety of functional vinyl monomers. Polyphosphoester (PPE) macroinitiators from ring-opening polymerization (ROP) of their corresponding cyclic phosphoesters have been previously prepared for atom transfer radical polymerization; however, to date, these biodegradable macroinitiators for RAFT polymerization have not been reported. Herein, a macromolecular RAFT-chain transfer agent (CTA) based on poly­(ethyl ethylene phosphonate) was prepared by the organocatalytic ROP of 2-ethyl-2-oxo-1,3,2-dioxaphospholane using 2-cyano-5-hydroxypentan-2-yl dodecyl trithiocarbonate as the initiator and 1,8-diazabycyclo[5.4.0]­undec-7-ene as the catalyst. Precise macro-CTAs of degrees of polymerization (DPn) from 34 to 70 with Đ ≤ 1.10 were prepared and used in the dioxane solution RAFT polymerization of acrylamide, acrylates, methacrylates, and 2-vinylpyridine to yield a library of well-defined block copolymers. Additionally, the PPE-based macro RAFT-CTA was used as a nonionic surfactant in a typical aqueous emulsion polymerization of styrene to produce well-defined nanoparticles with the hydrophilic PPEs on their surface as the stabilizing agent. This general protocol allowed the combination of polyphosphoesters with RAFT polymerization

Water-Soluble Poly(phosphonate)s via Living Ring-Opening Polymerization

A small difference brings high control: In poly­(phosphonate)­s a stable carbon–phosphorus linkage attaches a side chain to a degradable poly­(phosphoester)-backbone. A novel cyclic phosphonate monomer was developed to generate water-soluble aliphatic poly­(ethylene methylphospho-nate)s. The monomer is accessible via a robust three-step protocol that can be easily scaled-up. Polymerization was initiated by a primary alcohol, mediated by 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) in less than 2 h at 0 °C. The molecular weight distributions were monomodal and very narrow (below 1.1) in all cases and molecular weights up to about 20000 g/mol have been prepared, proving the living nature of this polymerization. The resulting polymers were characterized in detail via NMR spectroscopy, size exclusion chromatography, and differential scanning calorimetry. Also, the reaction kinetics have been evaluated for several monomer/initiator ratios and found to guarantee a living behavior in all cases superior to other poly­(phosphate)­s reported earlier. The polymers are all highly water-soluble without a lower critical solution temperature and are nontoxic against HeLa cells

Multihydroxy Polyamines by Living Anionic Polymerization of Aziridines

Acetal-protected and sulfonamide-activated aziridines (Az) have been prepared and polymerized by living anionic polymerization with molecular weight dispersities in most cases below <i><i>Đ</i></i> < 1.2 and controlled molecular weights. Three new monomers have been prepared varying in the length of the pendant chain. The resulting double protected polymers can be selectively deprotected in order to release the polyamine or the polyol structures. Detailed structural characterization was performed for all polymers, and chain extension proves their living polymerization behavior and the formation of block copolymers. Thermal analysis can be used in order to follow the deprotection steps. These new protected monomers broaden the scope of the azaanionic polymerization of aziridines and may find useful applications as well-defined functional poly­(ethylene imine) derivatives

Poly(alkylidene chlorophosphate)s via Acyclic Diene Metathesis Polymerization: A General Platform for the Postpolymerization Modification of Poly(phosphoester)s

Reactive poly­(phosphoester)­s (PPEs) have been prepared via the acyclic diene metathesis polymerization of the monomers di­(buten-3-yl) chlorophosphate and di­(undecen-10-yl) chlorophosphate. Molecular weights can be adjusted from 3000 to ca. 50 000 g/mol and have been prepared and characterized in detail. This is the first report on olefin metathesis polymerization of highly electrophilic phosphochlorides, which were postmodified with different nucleophiles, i.e., alcohols, amines, and water, thus allowing the synthesis of side chain polyphosphoamidates, poly­(phosphoester)­s, and free acids from the same starting polymer. High side-chain functionality was found in all cases

A Library of Well-Defined and Water-Soluble Poly(alkyl phosphonate)s with Adjustable Hydrolysis

Poly­(alkyl ethylene phosphonate)­s with different alkyl side chains exhibit significant differences in their degradation behavior. Three novel 2-alkyl-2-oxo-1,3,2-dioxaphospholanes, cyclic monomers for the ring-opening polymerization (ROP) toward poly­(alkyl alkylene phosphonate)­s, were synthesized by robust two- or three-step protocols in reasonable yields and high purity. The polymerization was promoted by the organocatalysts 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]­dec-5-ene (TBD) and proceeded with high control over molecular weight and narrow molecular weight distributions (<i>Đ</i> < 1.2) up to full conversion. These polymers with methyl, ethyl, and isopropyl side chains are perfectly soluble in water (up to 25 mg mL^–1) without a temperature-dependent phase separation. They showed no toxicity against HeLa cells after 24 h of incubation at any tested concentration. Polymers with butyl side chains exhibit decreased solubility and concentration-dependent cloud point temperatures and show toxicity against HeLa cells at concentrations above 25 μg mL^–1. The polymers showed no acetylcholinesterase inhibition. All polymers exhibited significantly different degradation times under both neutral as well as basic conditions (variation of the alkyl side chain allowed stabilities from 8 h up to 6 days)

Aliphatic Long-Chain Polypyrophosphates as Biodegradable Polyethylene Mimics

Biodegradable polyethylene mimics have been synthesized by the introduction of pyrophosphate groups into the polymer backbone, allowing not only hydrolysis of the backbone but also further degradation by microorganisms. Because of cost, low weight, and good mechanical properties, the use of polyolefins has increased significantly in the past decades and has created many challenges in terms of disposal and their environmental impact. The durability and resistance to degradation make polyethylene difficult or impossible for nature to assimilate, thus making the degradability of polyolefins an essential topic of research. The biodegradable polypyrophosphate was prepared via acyclic diene metathesis polymerization of a diene monomer. The monomer is accessible via a three-step synthesis, in which the pyrophosphate was formed in the last step by DCC coupling of two phosphoric acid derivatives. This is the first report of a pyrophosphate group localized in an organic polymer backbone. The polypyrophosphate was characterized in detail by NMR spectroscopy, size exclusion chromatography, FTIR spectroscopy, differential scanning calorimetry, and thermogravimetry. X-ray diffraction was used to compare the crystallization structure in comparison to analogous polyphosphates showing poly­(ethylene)-like structures. In spite of their hydrophobicity and water insolubility, the pyrophosphate groups exhibited fast hydrolysis, resulting in polymer degradation when films were immersed in water. Additionally, the hydrolyzed fragments were further biodegraded by microorganisms, rendering these PE mimics potential candidates for fast release of hydrophobic cargo, for example, in drug delivery applications