Ring-opening Polymerization Of N-carboxyanhydrides Research Articles

Shear-Thinning Extrudable Hydrogels Based on Star Polypeptides with Antimicrobial Properties.

Hydrogels with low toxicity, antimicrobial potency and shear-thinning behavior are promising materials to combat the modern challenges of increased infections. Here, we report on 8-arm star block copolypeptides based on poly(L-lysine), poly(L-tyrosine) and poly(S-benzyl-L-cysteine) blocks. Three star block copolypeptides were synthesized with poly(S-benzyl-L-cysteine) always forming the outer block. The inner block comprised either two individual blocks of poly(L-lysine) and poly(L-tyrosine) or a statistical block copolypeptide from both amino acids. The star block copolypeptides were synthesized by the Ring Opening Polymerization (ROP) of the protected amino acid N-carboxyanhydrides (NCAs), keeping the overall ratio of monomers constant. All star block copolypeptides formed hydrogels and Scanning Electron Microscopy (SEM) confirmed a porous morphology. The investigation of their viscoelastic characteristics, water uptake and syringe extrudability revealed superior properties of the star polypeptide with a statistical inner block of L-lysine and L-tyrosine. Further testing of this sample confirmed no cytotoxicity and demonstrated antimicrobial activity of 1.5-log and 2.6-log reduction in colony-forming units, CFU/mL, against colony-forming reference laboratory strains of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, respectively. The results underline the importance of controlling structural arrangements in polypeptides to optimize their physical and biological properties.

Open-vessel polymerization of N-carboxyanhydride (NCA) for polypeptide synthesis.

Synthetic polypeptides, also known as poly(α-amino acids), have the same polyamide backbone structures as natural proteins and peptides. As an important class of biomaterials, polypeptides have been widely used because of their biocompatibility, bioactivity and biodegradability. Ring-opening polymerization of N-carboxyanhydride (NCA) is a classical and widely used method for the synthesis of polypeptides. The dominantly used primary amine-initiated NCA polymerization can yield well-defined polymers and complex macromolecular architectures, but the reaction is slow and sensitive to moisture, making it necessary to use anhydrous solvents and a glovebox. One solution is to use lithium hexamethyldisilazide (LiHMDS) as the initiator, as described in this protocol. LiHMDS-initiated NCA polymerization is less sensitive to moisture and can be carried out in an open vessel outside the glovebox. It is also very fast; the reaction can be complete within 5 min to produce 30-mer polypeptides. In this protocol, poly(γ-benzyl-L-glutamate) is prepared as an example, but the protocol can easily be adapted to the synthesis of other polypeptides by generating NCAs from different amino acids, making it particularly suitable for the efficient parallel synthesis of polypeptide libraries. We provide detailed procedures for NCA synthesis and purification, the method of polymer end-group modification and measurement of polymerization kinetics and reactivity ratio. The procedure for synthesis of monomers and polymerization to form polypeptides requires <1 d. The superfast and open-vessel NCA polymerization method described here will probably enable a wide range of applications in the synthesis and functional study of polypeptide biomaterials.

Efficient Catalyst-Free One-Pot Synthesis of Polysaccharide-Polypeptide Hydrogels in Aqueous Solution.

The preparation of polysaccharide-peptide hydrogels usually involves multiple synthetic steps, thus reducing the effectiveness and practicality of these approaches. Inspired by recent discoveries in aqueous N-carboxyanhydride (NCA) ring-opening polymerization (ROP) and ring-opening polymerization-induced nanogelation, we present an aqueous one-pot strategy to prepare polysaccharide-polypeptide hydrogels. In this study, water-soluble polysaccharide carboxymethyl chitosan is used as the macromolecular initiator to prepare polysaccharide-polypeptide copolymers through the aqueous ROP of NCA. The catalyst-free approach afforded hydrogels with properties that could be controlled by adjusting the type and amount of NCA used, with the elastic modulus ranging from 50 Pa to 18000 Pa. The hydrogen bond-cross-linked hydrogel exhibited self-healing and injectable properties. Morphology characterization revealed that micelles were formed in the early stage of reaction, suggesting that the polymerization follows an aqueous ring-opening polymerization-induced self-assembly (ROPISA) mechanism and that aggregation of micelles during the reaction caused the gelation. Moreover, the hydrogels displayed high swelling ratios (>95% water content), and hemolysis and cytotoxicity experiments demonstrated that the hydrogels had excellent biocompatibility, indicating their potential in medical applications.

Dextran Macroinitiator for Synthesis of Polysaccharide-b-Polypeptide Block Copolymers via NCA Ring-Opening Polymerization.

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (Đ < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.

Toward Synthetic Intrinsically Disordered Polypeptides (IDPs): Controlled Incorporation of Glycine in the Ring-Opening Polymerization of N-Carboxyanhydrides.

Intrinsically disordered proteins (IDPs) do not have a well-defined folded structure but instead behave as extended polymer chains in solution. Many IDPs are rich in glycine residues, which create steric barriers to secondary structuring and protein folding. Inspired by this feature, we have studied how the introduction of glycine residues influences the secondary structure of a model polypeptide, poly(l-glutamic acid), a helical polymer. For this purpose, we carried out ring-opening copolymerization with γ-benzyl-l-glutamate and glycine N-carboxyanhydride (NCA) monomers. We aimed to control the glycine distribution within PBLG by adjusting the reactivity ratios of the two NCAs using different reaction conditions (temperature, solvent). The relationship between those conditions, the monomer distributions, and the secondary structure enabled the design of intrinsically disordered polypeptides when a highly gradient microstructure was achieved in DMSO.

Well-defined star (co)polypeptides via a fast, efficient, and metal-free strategy

Polypeptides, especially star polypeptides, as a unique kind of biological macromolecules have broad applications in biomedical fields such as drug release, gene delivery, tissue engineering, and regenerative medicines due to their close structural similarity to naturally occurring peptides and proteins, biocompatibility, and amino acid functionality. However, the synthesis of star polypeptide mainly relies on the conventional primary amine-initiated ring-opening polymerization (ROP) of N-carboxyanhydrides (NCA) and suffers from low polymerization activity and limited controllability. This study proposes a fast, efficient and metal-free strategy to access star (co)polypeptides by combining the Michael reaction between acrylates and secondary aminoalcohols with the hydrogen-bonding organocatalytic ROP of NCA. This approach enables the preparation of a library of star (co)polypeptides with predesigned molecular weights, narrow molecular weight distributions, tunable arm number, and arm compositions. Importantly, this method exhibits high activity and selectivity at room temperature, making it both practical and versatile in synthesis applications.

Precision Synthesis of Polysarcosine via Controlled Ring-Opening Polymerization of N-Carboxyanhydride: Fast Kinetics, Ultrahigh Molecular Weight, and Mechanistic Insights.

The rapid and controlled synthesis of high-molecular-weight (HMW) polysarcosine (pSar), a potential polyethylene glycol (PEG) alternative, via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is rare and challenging. Here, we report the well-controlled ROP of sarcosine NCA (Sar-NCA) that is catalyzed by various carboxylic acids, which accelerate the polymerization rate up to 50 times, and enables the robust synthesis of pSar with an unprecedented ultrahigh molecular weight (UHMW) up to 586 kDa (DP ∼ 8200) and exceptionally narrow dispersity (D̵) below 1.05. Mechanistic experiments and density functional theory calculations together elucidate the role of carboxylic acid as a bifunctional catalyst that significantly facilitates proton transfer processes and avoids charge separation and suggest the ring opening of NCA, rather than decarboxylation, as the rate-determining step. UHMW pSar demonstrates improved thermal and mechanical properties over the low-molecular-weight counterparts. This work provides a simple yet highly efficient approach to UHMW pSar and generates a new fundamental understanding useful not only for the ROP of Sar-NCA but also for other NCAs.

Facile Preparation of Polysarcosine-Tethered Inorganic Nanospheres by Using Unimolecular Polypept(o)ides as Template.

Polymer-inorganic nanocomposites that integrate the advantages of both polymers and inorganic nanoparticles (NPs) are broadly exploited for versatile applications. Especially, emerging polymer-templated preparation of inorganic NPs has drawn extensive attention, which is ascribed to simplified synthesis and feasible tunability. However, how to precisely fabricate biocompatible polymer-inorganic NPs remains unsolved. In this article, by mild ring opening polymerization (ROP) of β-benzyl L-aspartate N-carboxyanhydrides (BLA-NCAs) and sarcosine N-carboxyanhydrides (Sar-NCAs) and subsequent debenzylation, a series of poly(amino acid)-based unimolecular micelles (PAMAM-g-(PLA-b-PSar)) are facilely synthesized. Afterward, by utilization of these star-like polymers as template, the controllable preparation of various PSar-tethered inorganic NPs is investigated and characterized meticulously. This general strategy for the preparation of PSar-tethered inorganic NPs can bring a great chance for future fabrication of biomedical nanoplatforms.

Design and synthesis of a shikimoyl-functionalized cationic di-block copolypeptide for cancer cell specific gene transfection.

Targeted and efficient gene delivery systems hold tremendous potential for the improvement of cancer therapy by enabling appropriate modification of biological processes. Herein, we report the design and synthesis of a novel cationic di-block copolypeptide, incorporating homoarginine (HAG) and shikimoyl (LSA) functionalities (HDA-b-PHAGm-b-PLSAn), tailored for enhanced gene transfection specifically in cancer cells. The di-block copolypeptide was synthesized via sequential N-carboxyanhydride (NCA) ring-opening polymerization (ROP) techniques and its physicochemical properties were characterized, including molecular weight, dispersity, secondary conformation, size, morphology, and surface charge. In contrast to the cationic poly-L-homoarginine, we observed a significantly reduced cytotoxic effect of this di-block copolypeptide due to the inclusion of the shikimoyl glyco-polypeptide block, which also added selectivity in internalizing particular cells. This di-block copolypeptide was internalized via mannose-receptor-mediated endocytosis, which was investigated by competitive receptor blocking with mannan. We evaluated the transfection efficiency of the copolypeptide in HEK 293T (noncancerous cells), MDA-MB-231 (breast cancer cells), and RAW 264.7 (dendritic cells) and compared it with commonly employed transfection agents (Lipofectamine). Our findings demonstrate that the homoarginine and shikimoyl-functionalized cationic di-block copolypeptide exhibits potent gene transfection capabilities with minimal cytotoxic effects, particularly in cancer cells, while it is ineffective for normal cells, indicative of its potential as a promising platform for cancer cell-specific gene delivery systems. To evaluate this, we delivered an artificially designed miRNA-plasmid against Hsp90 (amiR-Hsp90) which upon successful transfection depleted the Hsp90 (a chaperone protein responsible for tumour growth) level specifically in cancerous cells and enforced apoptosis. This innovative approach offers a new avenue for the development of targeted therapeutics with an improved efficacy and safety profile in cancer treatment.

A Novel Polyamino Acid Sulfur Dioxide Prodrug Synergistically Elevates ROS with β-Lapachone in Cancer Treatment

Due to the distorted redox balance, cancer cells are considered more vulnerable to excessive reactive oxygen species (ROS). In a variety of oxidative stress-related therapies, gas therapy has emerged as a new therapeutic strategy owing to its efficacy and biosafety. Herein, a newly-discovered gasotransmitter sulfur dioxide (SO2) and a tumor specific ROS generation agent β-lapachone (Lapa) were firstly combined for anticancer therapy. Firstly, amphiphilic glutathione (GSH) responsive polypeptide SO2 prodrug PEG-b-poly(Lys-DNs) was synthesized by ring opening polymerization of SO2-containing N-carboxyanhydride. Then, Lapa was encapsulated into the polymeric micelles with loading content of 8.6 % and loading efficiency of 51.6 %. The obtained drug-loaded nanoparticles (NPs(Lapa)) exhibited a fast release of Lapa and SO2 in the stimuli of 10 mM GSH in PBS. Subsequently, in vitro experiment showed that NPs(Lapa) exhibited obvious cytotoxicity towards 4 T1 cancer cells at a concentration of 2.0 μg/mL, which may be attributed to the depletion of intracellular GSH and upregulation of ROS level both by SO2 release and by the ROS generation from lapachone transformation. In vivo fluorescence imaging showed that the NPs were gradually enriched in tumor tissues in 24 h, probably due to the enhanced permeability and retention effect of NPs. Finally, NPs(Lapa) showed the best anticancer effect in 4 T1 tumor bearing mice with a tumor inhibiting rate (IRT) of 61 %, whereas IRT for free Lapa group was only 23.6 %. This work may be a new attempt to combine SO2 gas therapy with ROS inducer for anticancer therapy through oxidative stress.

Precision Synthesis of Polypeptides via Living Anionic Ring-Opening Polymerization of N-Carboxyanhydrides by Tri-thiourea Catalysts.

The chemistry of α-amino acid N-carboxyanhydrides (NCAs) has a history of over 100 years, but precise and efficient ring-opening polymerization methods for NCAs remain highly needed to facilitate the studies of polypeptides─that is, mimics of natural proteins─in various disciplines. Moreover, the universally accepted NCA polymerization mechanisms are largely limited to the "amine" and the "activated monomer" mechanisms, and the anionic ring-opening polymerization of NCAs has so far not been invoked. Herein, we show an unprecedented anion-binding catalytic system combining tripodal tri-thiourea with sodium thiophenolate that enables the fast and selective anionic ring-opening polymerization of NCAs. This method leads to the precision construction of various polypeptides with living polymerization behavior and is evidenced by narrow molecular weight distributions (Mw/Mn < 1.2), chain extension experiments, and minimal "activated monomer" pathway. Calculations and experimental results elucidate a living anionic polymerization mechanism, and high selectivities for monomer propagation relative to other deleterious side reactions, such as the "activated monomer" pathway, are attributed to the enhanced stabilization of the propagating carbamate anion, which is enforced by an intramolecular hydrogen bond within the tri-thiourea structure.

Improving aqueous solubility of paclitaxel with polysarcosine-b-poly(γ-benzyl glutamate) nanoparticles

New stealth amphiphilic copolymers based on polysarcosine (PSar) rather than poly(ethylene glycol) (PEG) have gained more attention for their use as excipients in nanomedicine. In this study, several polysarcosine-b-poly(γ-benzyl glutamate) (PSar-b-PGluOBn) block copolymers were synthesized by ring opening polymerization (ROP) of the respective N-carboxyanhydrides (NCAs) and were characterized by Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR) and size-exclusion chromatography (SEC). Copolymers had different PGluOBn block configuration (racemic L/D, pure L or pure D), degrees of polymerization of PSar between 28 and 76 and PGluOBn between 9 and 93, molar masses (Mn) between 5.0 and 24.6 kg.mol−1 and dispersities (Đ) lower than 1.4. Nanoparticles of PSar-b-PGluOBn loaded with paclitaxel (PTX), a hydrophobic anti-cancer drug, were obtained by nanoprecipitation. Their hydrodynamic diameter (Dh) ranged from 27 to 118 nm with polydispersity indexes (PDI) between 0.01 and 0.20, as determined by dynamic light scattering (DLS). Their morphology was more spherical for copolymers with a racemic L/D PGluOBn block configuration synthesized at 5 °C. PTX loading efficiency was between 63 and 92 % and loading contents between 7 and 15 %. Using PSar-b-PGluOBn copolymers as excipients, PTX apparent water-solubility was significantly improved by a factor up to 6600 to 660 µg.mL−1.

Influence of polymer molar mass and mixture stoichiometry on polyelectrolyte complexes of poly(l-arginine) and Poly(l-glutamic acid)

Poly(l-arginine) (PARG) and poly(l-glutamic acid) (PLGA) homopolypeptides were custom synthesized by precision N-carboxyanhydride ring-opening polymerization methods with two molar masses, matched for pairs of cationic and anionic polypeptides (degrees of polymerization n = 100 and n = 500). The conformations of the homopolypeptides were probed using circular dichroism (CD) and FTIR spectroscopy which revealed the presence of mainly polyproline II (PPII) conformation. Small-angle X-ray scattering (SAXS) showed concentration-dependent polyelectrolyte peaks and form factor with high q scaling due to the excluded volume behaviour of the wormlike chains. We then examined polyelectrolyte complexation in mixtures of pairs of PARG and PLGA polypeptides with matched molar masses. Precipitation was generally observed and the structures of precipitates, supernatant and resuspended precipitates were investigated using CD, SAXS and cryo-TEM. These revealed that, contrary to prior suggestions in the literature, the precipitates contain mostly polypeptides in a PPII-like conformation, and there is only a minimal β-sheet content (which is enhanced upon drying the sample during preparation for certain measurements). The precipitates have a fractal-like structure as revealed by cryo-TEM and SAXS. Our findings on the structure of polypeptide complex precipitates contribute to the understanding of phase separation of polyelectrolyte complexes and coacervation and may shed light on the formation of inter-cellular bodies of proteins and peptides such as Lewy and other inclusion bodies.

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride.

The production of polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is usually conducted under stringent anhydrous conditions. The ROP of proline NCA (ProNCA) for the synthesis of poly-L-proline (PLP) is particularly challenging due to the premature product precipitation as polyproline type I helices, leading to slow reactions for up to one week, poor control of the molar mass and laborious workup. Here, we report the unexpected water-assisted controlled ROP of ProNCA, which affords well-defined PLP as polyproline II helices in 2–5 minutes and almost-quantitative yields. Experimental and theoretical studies together suggest the as-yet-unreported role of water in facilitating proton shift, which significantly lowers the energy barrier of the chain propagation. The scope of initiators can be expanded from hydrophobic amines to encompass hydrophilic amines and thiol-bearing nucleophiles, including complex biomacromolecules such as proteins. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP modification not only preserves the biological activities of the native proteins, but also enhances their resistance to extreme conditions. Moreover, PLP modification extends the elimination half-life of asparaginase (ASNase) 18-fold and mitigates the immunogenicity of wt ASNase >250-fold (ASNase is a first-line anticancer drug for lymphoma treatment). This work provides a simple solution to a long-standing problem in PLP synthesis, and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs. The facile access to PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.

Ion-Triggered Hydrogels Self-Assembled from Statistical Copolypeptides.

Statistical copolypeptides comprising lysine and tyrosine with unprecedented ion-induced gelation behavior are reported. Copolypeptides are obtained by one-step N-carboxyanhydride (NCA) ring-opening polymerization. The gelation mechanism is studied by in situ SAXS analyses, in addition to optical spectroscopy and transmission electron microscopy (TEM). It is found that the gelation of these statistically polymerized polypeptides is due to the formation of stable intermolecular β-sheet secondary structures induced by the presence of salt ions as well as the aggregation of an α-helix between the copolypeptides. This behavior is unique to the statistical lysine/tyrosine copolypeptides and was not observed in any other amino acid combination or arrangement. Furthermore, the diffusion and mechanical properties of these hydrogels can be tuned through tailoring the polypeptide chain length and ion strength.

Tunable Hydrogels with Improved Viscoelastic Properties from Hybrid Polypeptides

Hydrogels that can respond to a number of external stimuli and at the same time show impressive rheological properties are promising materials for a wide range of bioapplications. Here, we present a series of well-defined linear amphiphilic pentablock hybrid polypeptides of the ABCBA type, where A is poly(l-lysine), B is poly(l-histidine)-co-poly(γ-benzyl-l-glutamate), and C is poly(ethylene oxide) (PEO). The polymers were synthesized by the sequential primary amine ring-opening polymerization of N-carboxy anhydrides using bis amine poly(ethylene oxide) (PEO) as a bifunctional macroinitiator, and the length of all of the blocks was varied. The resulting materials formed novel extrudable in situ forming quickly self-healing hydrogels, responsive to the alteration of pH and increase of temperature. The connection between the alteration of the secondary structure of the polypeptides with the viscoelastic behavior was revealed by means of rheology and circular dichroism. Small-angle neutron scattering and scanning electron microscopy were employed to shed light on the structure of the polymers and how it affects their rheological properties. The obtained polymers were subjected to enzymatic degradation tests with trypsin and leucine aminopeptidase. The results suggest that these biomaterials have the potential to be used in a number of bioapplications like drug delivery, 3D printing, and tissue engineering.

Heparin-like anticoagulant polypeptides with tunable activity: Synthesis, characterization, anticoagulative properties and clot solubilities in vitro

Due to the uncontrollable anticoagulant activity and limited source, Heparin, which is commonly used in clinical anticoagulation therapies, faces the risk of spontaneous bleeding and thrombocytopenia. Herein, a series of anionic poly(amino acid) s poly (l-Serine-ran-L-Glutamic acid-ran-L-Cysteine-SO3) (PSEC-SO3) were prepared by the controlled Ring Opening Polymerization (ROP) of N-Carboxyanhydrides (NCAs). The anticoagulant activities of PSEC-SO3 can be regulated by simply adjusting the feeding ratio of monomers. In vitro tests show that these polypeptides can effectively prolong the Activated Partical Thromboplastin Time (APTT) and inhibit Factor IIa and Factor Xa, but has no significant effect on Prothrombin Time (PT) and Thrombin Time (TT), which indicates that PSEC-SO3 mainly act on the intrinsic pathway. In summary, the activity-tunable heparin-like polypeptides are expected to have good application prospects in the anticoagulant field.

Nanoengineered polypeptides from tetraphenylethylene-functionalized N-carboxyanhydride: Synthesis, self-assembly and intrinsic aggregation-induced emission

Ring-opening polymerization of N-carboxyanhydrides (NCAs) bearing pendant groups creates functional polypeptides. In this paper, we report the design, synthesis and polymerization of tetraphenylethylene (TPE)-modified NCA, which is used to incorporate aggregation-induced emission (AIE)-active segments into polypeptides. Specifically, we attempted the synthesis of amphiphilic methoxy poly(ethyleneglycol)-block-poly(γ-benzyl-l-glutamate)-block-poly(γ-4-(1,2,2-triphenylvinyl)benzyl-l-glutamate) (PEG-PBLG-PTPELG), which had well-controlled molecular weight and narrow polydispersity. The hydrophilic PEG and hydrophobic PBLG-PTPELG assembled into micelles in aqueous solution with diameter around 70 ​nm, displaying AIE at 480 ​nm. Our work demonstrates that the TPE-modified NCA is applicable for the preparation of the AIE-active polypeptides, integrating the AIE luminogens into the polypeptides which may offer unique opportunities for tuning AIE properties by adjusting the composition and conformation of polypeptides. We preliminarily explored the use of the amphiphilic polypeptides for the formulation of doxorubicin-containing micelles that can potentially be used for real-time monitoring of the nanomedicine distribution.

Synthesis and Characterization of Macroinitiators Based on Polyorganophosphazenes for the Ring Opening Polymerization of N-Carboxyanhydrides

Among the various biocompatible amphiphilic copolymers, biodegradable ones are the most promising for the preparation of drug delivery systems since they are destroyed under physiological conditions, that, as a rule, reduce toxicity and provide controlled release of the drug. Hybrid graft-copolymers consisting of the main inorganic polyphosphazene chain and polypeptide side chains are of considerable interest for the development of delivery systems with a controlled degradation rate, since the main and side chains will have different degradation mechanisms (chemical and enzymatic hydrolysis, respectively). Variable particle degradation rate, controlled by the adjusting the composition of substituents, will allow selective delivery in vivo and controlled drug release. The present work proposes the preparation of biodegradable macroinitiators based on polyorganophosphazenes for the synthesis of hybrid copolymers. Synthesis of novel biodegradable macroinitiators based on polyorganophosphazenes was performed via macromolecular substitution of a polydichlorophosphazene chain with the sodium alcoholates, amines and amino acids. The composition of copolymers obtained was calculated using NMR. These polyorganophosphazenes bearing primary amino groups can be considered as convenient macroinitiators for the polymerization of NCA of α-amino acids in order to prepare hybrid copolymers polyphosphazene-graft-polypeptide. The developed macroinitiators were amphiphilic and self-assembled in the aqueous media into nanoparticles. Furthermore, the ability to encapsulate and release a model substance was demonstrated. In addition, the in vitro cytotoxicity of synthesized polymers was evaluated using two cell lines.

Photo-liberated amines for N-carboxyanhydride (PLANCA) ring-opening polymerization

Photo-liberated amines for N-carboxyanhydride (PLANCA) ring-opening polymerization affords narrow molecular weights, chain-end retention, and the formation of block copolypeptides.