Ring-chain equilibrium for polyester recycling

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Thermoresponsive Copolymers with Well-Defined Composition and Phase Separation Via Semi-Batch Free-Radical Polymerization in a Non-Polar Medium

Thermoresponsive polymers formulated in non-polar media are finding a plethora of applications in the oil and gas and lubricant sectors. Their great adaptability mainly comes from the possibility of tuning their cloud point (T-cp), which is achieved by copolymerizing two or more monomers. In this direction, good control over the copolymer composition is crucial to ensure a sharp phase separation and, as a consequence, a prompt and well-defined response. For this reason, controlled radical polymerizations (CRPs) are often used to synthesize these materials. However, these pseudoliving polymerization techniques are still far from industrial maturity because of their cost and low polymerization rate. On the other hand, free-radical polymerization (FRP) is notoriously affected by the compositional drift of the copolymer chains, which for thermoresponsive polymers is reflected in broad phase separations. To overcome the disadvantages of FRP and guarantee remarkable control of the copolymer composition typical of CRPs, in this work we develop a semibatch power feed process for the copolymerization of diethylene glycol methyl ether methacrylate (EG(2)MA) and lauryl methacrylate in Dectol (i.e., a mixture of decane/toluene 50:50 v/v). First, their reactivity ratios were determined by analyzing the variation in the residual monomer phase composition over time at different initial molar ratios of the two monomers. These were subsequently employed for designing the inlet flow rate of the power feed strategy. Through this approach, we demonstrated for the first time that semibatch FRP is a valuable strategy to afford compositionally well-defined copolymers with a controllable upper critical solution temperature and sharp phase separations while maintaining high productivity and avoiding CRPs

Influence of pH on the kinetics of polymer hydrolysis: The case of polylactic acid

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The Combination Of Rop And Raft Polymerization For The Synthesis Of Polymeric Nanoparticles

Polymeric nanoparticles (NPs) are colloids in the nanometric size that find application in several field, such as optics, coating and medicine. In this latter case, they are used as drug delivery systems for different therapeutics ranging from lipophilic drugs to oligonucleotides. These nano-colloids are generally made up of polyesters as long as they are able to degrade into safe and easy removable compounds, such as lactic acid and hydroxycaproic acid. In this work, starting from a geometrical model developed for the synthesis of NPs with the same NP size and different molecular weight (MW) block copolymers1, a method to independently control the main characteristics of biodegradable NPs stabilized by highly hydrophilic polymers has been developed and here presented. The method consists in the synthesis of block-copolymers with a brush-like structure via the combination of two living polymerizations: the ring opening polymerization (ROP) and the reversible addition-fragmentation chain transfer (RAFT) polymerization. A library of block copolymers has been produced and self-assembled into water to generate NPs with different size and block-copolymer MWs. As long as these NPs are intended for biomedical applications, the degradation behavior of these colloids has been studied and correlated with the structure of the lipophilic part of the block copolymer. It has been found that the number of the lactone units and their geometrical disposition in the block copolymers impact the degradation behavior of the NPs they are composed of. Thanks to this novel method, it is possible to synthesize NPs with the same size, but with different degradation time. References 1. Palmiero, U. C.; Agostini, A.; Gatti, S.; Sponchioni, M.; Valenti, V.; Brunel, L.; Moscatelli, D., Raft macro-surfmers and their use in the ab initio raft emulsion polymerization to decouple nanoparticle size and polymer molecular weight. Macromolecules 2016, 49 (22), 8387-8396

Polyester-based excipients to formulate lipophilic drugs into nanoparticles directly at the bed of the patient

In recent decades there has been an increased interest in polymeric nanoparticles as drug delivery systems thanks to their several advantages, such as continuous maintenance of drug levels in a therapeutically desirable range, and reduction of harmful side effects. These nano-colloids are generally made up of polyesters as long as they are able to easily degrade into the body. However, NP production is often a process that requires complex microfluidic devices. In addition, expensive purification steps are necessary to eliminate the unloaded drug and the high amount of organic solvent used in the NP production step. In the end, a lyophilization step is general adopted to assure a good shelf-life of the final product. All the above-mentioned steps hamper the cost-effective use of a re-formulation of the same therapeutic agent and, in turn, reduce the availability of these treatments among the patient population. For this reason, in this work, a novel NP production protocol that consists only in the use of a syringe and a needle without the need of subsequent purification and freeze-drying steps has been developed. This has been possible by the optimization of the hydrophilic/lipophilic balance of block-copolymers that are able to directly self-assemble in water. The additional degree of freedom necessary for this optimization was introduced via the synthesis of these materials thorough the combination of the reversible addition-fragmentation chain transfer (RAFT) polymerization and the ring opening polymerization (ROP). The NPs has been used to formulate Trabectedin (ET-743), a widely adopted anticancer therapeutic known for its local adverse effect. The pharmacokinetic behavior, antitumor activity and toxicity of this novel NP-based formulation has been compared to the commercially available formulation Yondelis®. NPs have shown the ability to retain the drug into circulation for a longer time in the blood stream compared to the free ET-743 allowing to considerably reduce the local toxic effects. In addition, the shift of the NP preparation step from a specialist to the final user allows to avoid all the purifications and post-processing steps necessary to assure a good shelf-life of the product. In this way, a ET-743 formulation less toxic than the commercially available Yondelis® can be produced at a competitive price taking also into account that this expensive drug is not lost in any of the NP production steps here adopted. In order to prove the versatility of this novel technology, Paclitaxel (PTX), an anticancer therapeutic that it usually formulated with a toxic surfactant (Chremophor EL), have been also formulated into this NPs. In this way, a novel PTX formulation can be produced at a lower cost compared to the ones already approved and present into the market. In particular, it has shown the same advantage in reduction of the toxicity given by the elimination of the Chremophor EL (e.g in Abraxane® and Genexol®)

Synthesis of zwitterionic-functionalized conjugated nanoparticles for targeted drug delivery applications

Polymeric Nanoparticles (NPs) represent a promising pharmacological tool, since their structure can be modified to obtain: i) encapsulation and controlled release of a wide range of active compounds, ranging from small molecules to siRNA or oligonucleotides; ii) selective cell targeting, thus allowing precise drug delivery to the desired site of action. A powerful strategy to achieve selectivity of uptake in specific cell types is to conjugate the nanoparticles to a ligand specific for receptors expressed by the target cell type. This offers the advantage of a potentially improved drug efficacy with limited side effects and toxicity. Polymeric nanoparticles in a range of 20–100 nm have a high potential for in vivo applications, due to their ability to circulate in the blood for a long period of time. In fact, this size range allows to avoid renal and lymphatic clearance, to prevent opsonization and at the same time improves the internalization by cells. In this work we address the synthesis by reversible addition-fragmentation chain transfer (RAFT) of biodegradable, zwitterionic-based nanoparticles. This Zwitterionic nanoparticles act as super non-fouling surfaces that prevent protein adsorption from complex biological media. The nanoparticles were functionalized with different numbers of selective ligands through click chemistry; different dimensions were synthetized changing the length of the hydrophobic part. In vitro studies were performed to evaluate the uptake of functionalized nanoparticles

Role of the Polymer Microstructure in Controlling Colloidal and Thermo-Responsive Properties of Nano-Objects Prepared Via RAFT Polymerization in a Non-polar Medium

After having demonstrated their potential in biomedicalapplications,thermo-responsive block copolymers that are able to self-assembleinto nano-objects in response to temperature modifications are becomingmore and more appealing in other sectors, such as the oil and gasand lubricant fields. Reversible addition-fragmentation chaintransfer (RAFT) polymerization-induced self-assembly has been demonstratedas a valuable strategy for producing nano-objects from modular blockcopolymers in non-polar media, required for the mentioned applications.Although the influence of the nature and size of the thermo-responsiveblock of these copolymers on the properties of the nano-objects isextensively studied in the literature, the role of the solvophilicblock is often neglected. In this work, we elucidate the role of themain microstructural parameters, including those of the solvophilicportion, of block copolymers produced by RAFT polymerization in thehydrocarbon blend decane/toluene 50:50 v/v on the thermo-responsivebehavior and colloidal properties of the resulting nano-objects. Twolong-aliphatic chain monomers were employed for the synthesis of fourmacromolecular chain transfer agents (macroCTAs), with increasingsolvophilicity according to the number of units (n) or length of the alkyl side chain (q). Subsequently,the macroCTAs were chain-extended with different repeating units ofdi(ethylene glycol) methyl ether methacrylate (p),leading to copolymers that are able to self-assemble below a criticaltemperature. We show that this cloud point can be tuned by actingon n, p, and q.On the other hand, the colloidal stability, expressed in terms ofarea of the particle covered by each solvophilic segment, is onlya function of n and q, which providesa way for controlling the size distribution of the nano-objects andto decouple it from the cloud point

A new solution for in situ monitoring of shape fidelity in extrusion-based bioprinting via thermal imaging

Bioprinting is an interdisciplinary study field, where additive manufacturing is combined with tissue engineering and material sciences. The ever-increasing need for personalized medicine fueled interest in the possibility of using this technique to reproduce biological tissues, allowing bioprinting to establish itself as one of the most promising approach in biomedical research. Producing bioconstructs that resemble living tissues is a very complex and multi-step procedure. Given the complexity of the processes involved, the literature still lacks robust solutions for monitoring the bioprinted construct quality, especially in situ and in-line. Here, a novel non-destructive approach for monitoring the geometries of bioprinted constructs based on infrared (IR) imaging is proposed. Besides the intuitive use of IR information to gain insight on the temperature signature, we propose IR video imaging as a viable solution to overcome traditional problems of visible-range imaging for geometry reconstruction with transparent bioinks, especially when precise information on the last printed layer only is required. The results obtained show a significant new direction for in-line monitoring of bioprinting processes

Poly(HPMA)-based copolymers with biodegradable side chains able to self-assemble into nanoparticles

Poly(N-(2-Hydroxypropyl) methacrylamide) (poly(HPMA)) is gaining pharmaceutical attention in replacement to PEG as a hydrophilic stabilizer for polymer nanoparticles (NPs) devoted to systemic administration.[1] This is due to its biocompatibility, prolonged circulation time and, compared to PEG, to the avoidance of allergic reactions and of the accelerated blood clearance effect.[2, 3] In this work, a lipophilic HPMA-based macromonomer with a predetermined and controllable structure is synthesized for the first time attaching a short oligo(caprolactone) chain obtained via Ring Opening Polymerization (ROP) to the HPMA using a succinic acid unit as a spacer. This biodegradable monomer (hereinafter HPMA-CL) was then used to synthesize well-defined amphiphilic block copolymers comprising a hydrophilic poly(HPMA) block and a hydrophobic poly(HPMA-CL) segment via Reversible Addition-Fragmentation Transfer (RAFT) polymerization. The combination of ROP and RAFT allows the production of a library of polymers with a predetermined and controlled structure that are able to self-assemble in water into biodegradable NPs with different size. In particular, such NPs are designed to degrade in aqueous environment into completely water soluble poly(HPMA), with a molecular weight that is below the critical threshold for the renal excretion. This is a very important feature since it allows to avoid polymer accumulation into the body once the NPs are injected.[4] The degradation time is a function of the number of caprolactone units in the HPMA-CL macromonomer and of its degree of polymerization in the NP forming copolymer. Then, the polymer structure can be adjusted to obtain the desired degradation time. Finally, the possibility for such nanoparticles to physically incorporate and mediate the release of a lipophilic antineoplastic drug was evaluated in the case of Trabectedin. The formulation proved to be biocompatible and to sustainedly release the drug for up to 24 hours. Please click Additional Files below to see the full abstract

Synthesis and nanoprecipitation of HEMA-CLnbased polymers for the production of biodegradable nanoparticles

The control over the size distribution and stability of polymeric nanoparticles (NPs) is crucial in many of their applications, especially in the biomedical field. These characteristics are typically influenced by the production method and the nature of the starting material. To investigate these aspects, the controlled radical polymerization of functionalized methacrylates constituted by 2-hydroxyethyl methacrylate (HEMA) functionalized with a controlled number of ε-caprolactone (CL) units (HEMA-CLn), was carried out via reversible addition–fragmentation chain transfer polymerization (RAFT) in solution. The living reaction allows for good control over the molar mass of the final polymer with a low molar mass dispersity. The obtained polymer solutions were nanoprecipitated in order to produce NPs suitable for drug delivery applications with narrow particle size distribution and a wide size range (from 60 to 250 nm). The NP synthesis has been performed using a mixing device, in order to control the parameters involved in the nanoprecipitation process. As already seen for similar systems, the size of the produced NPs is a function of the polymer concentration during the nanoprecipitation process. Nevertheless, when the polymer concentration is kept constant, the NP size is influenced by the chemical structure of the polymer used, in terms of the presence of PEG (poly(ethylene glycol)), the degree of RAFT polymerization, and the length of the caprolactone side chain. These characteristics were also found to influence the stability and degradation properties of the produced NPs