ML meets MLn: machine learning in ligand promoted homogeneous catalysis

The benefits of using machine learning approaches in the design, optimisation and understanding of homogeneous catalytic processes are being increasingly realised. We focus on the understanding and implementation of key concepts, which serve as conduits to more advanced chemical machine learning literature, much of which is (presently) outside the area of homogeneous catalysis. Potential pitfalls in the ‘workflow’ procedures needed in the machine learning process are identified and all the examples provided are in a chemical sciences context, including several from ‘real world’ catalyst systems. Finally, potential areas of expansion and impact for machine learning in homogeneous catalysis in the future are considered

Greener extraction-chemical modification-polymerization pipeline of vernolic acid from Ethiopian ironweed plant

Epoxidized oils are commonly used in the plastics industry as additives in the formulation of polyvinyl chloride (PVC) and as monomers in the coating industry. They are produced from petrochemical feedstocks or by chemical epoxidation of natural oils. Currently, the synthesis processes of these materials are expensive, utilize volatile organic solvents and hazardous oxidants, which are unfavorable for the environment. There is a need to find natural epoxidized oils. Vernonia galamensis (ironweed) is a plant found in abundance in Ethiopia with no commercial value, but its seeds contain 40 wt% epoxide rich triglycerides. V. galamensis oil contains up to 80 wt% of vernolic acid (VA), a mono-unsaturated fatty acid with an additional epoxide functionality. The presence of alkene and epoxide(oxirane) groups offers excellent opportunities to synthesize new building blocks for polymerisations. Here, we report a green and efficient extraction methodology (up to 80% of extraction-efficiency) of the triglyceride vernonia oil from V. galamensis using supercritical carbon dioxide (scCO2). We then report the synthesis of a series of polymerisable monomers (conversion in monomers 64%–99%) based on the VA obtained from the saponification process. Finally, the novel monomers are polymerized into different polymers through polycondensation using a mixture of metal-based and enzyme catalysts

Antimicrobial ‘inks’ for 3D printing: block copolymer-silver nanoparticle composites synthesised using supercritical CO2

Silver nanoparticles (AgNP) are widely exploited for their effective antimicrobial activity against a range of pathogens. Their high efficacy in this regard has seen the global demand for AgNP in consumer products steadily increase in recent years, necessitating research into novel low environmental impact synthesis approaches. Here we present a new synthetic methodology to produce polymer-AgNP composite microparticles using supercritical carbon dioxide (scCO2) and avoiding use of any petrochemically derived solvents. Poly(methyl methacrylate)-poly(4-vinylpyridine) (PMMA-b-P4VP) block copolymers were synthesised via RAFT-mediated dispersion polymerisation in scCO2, with in situ thermal degradation of various amounts of a CO2-soluble silver complex. Selective interaction of the silver with the pyridinyl moieties of the block copolymer allowed the formation of AgNP, dispersed within the block copolymer microparticles, leading to homogeneous composites. The by-products of the reaction were also removed by extracting with a flow of CO2 to yield a clean dry product in a single process. The composites were found to be non-cytotoxic and proved to have good antimicrobial activity against two bacterial strains. Though no significant activity was seen for at least the first 24 hours, inhibition of bacterial growth afterwards proved to be extremely persistent, with inhibition observed even after 15 days. Finally, the microparticulate nature of the synthesised composites was exploited and tested for compatibility in the Laser Sintering (LS) 3D printing process. Composite microparticles were fused to produce solid objects, without aggregation of the AgNP. With further optimisation, these composites could prove to be an incredibly versatile ‘ink’ that may be used within additive manufacturing and 3D printing to rapidly produce bespoke medical devices with inherent antimicrobial activity

Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid

Objective: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). Methods: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. Results: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. Conclusions: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs

Poly (glycerol adipate) (PGA) backbone modifications with a library of functional diols: Chemical and physical effects

Enzymatically synthesised poly(glycerol adipate) (PGA) has shown a palette of key desirable properties required for a biomaterial to be considered a ‘versatile polymeric tool’ in the field of drug delivery. PGA and its variations can self-assemble into nanoparticles (NPs) and interact at different levels with small active molecules. PGA derivatives are usually obtained by functionalising the glyceryl side hydroxyl group present along the main polymer scaffold. However, if the synthetic pathways are not finely tuned, the self-assembling ability of these new polymeric modifications might be hampered by the poor amphiphilic balance. For this reason, we have designed a straightforward one-pot synthetic modification, using a small library of diols in combination with glycerol, aimed at altering the backbone of the polymer without affecting the hydrophilic glyceryl portion. The diols introduce additional functionality into the backbone of PGA alongside the secondary hydroxyl group already present. We have investigated how extra functionalities along the polymer backbone alter the final polymer reactivity as well the chemical and biological properties of the nanoparticles. In addition, with the intent to further improve the green credentials of the enzymatic synthesis, a solvent derived from renewable resources, (2-methyl tetrahydrofuran, 2-MeTHF) was employed for the synthesis of all the PGA-variants as a replacement for the more traditionally used and fossil-based tetrahydrofuran (THF). In vitro assays carried out to evaluate the potential of these novel materials for drug delivery applications demonstrated very low cytotoxicity characteristic against NIH 3T3 model cell line

Glycerol- and diglycerol-based polyesters: Evaluation of backbone alterations upon nano-formulation performance

Despite the success of polyethylene glycol-based (PEGylated) polyesters in the drug delivery and biomedical fields, concerns have arisen regarding PEG's immunogenicity and limited biodegradability. In addition, inherent limitations, including limited chemical handles as well as highly hydrophobic nature, can restrict their effectiveness in physiological conditions of the polyester counterpart. To address these matters, an increasing amount of research has been focused towards identifying alternatives to PEG. One promising strategy involves the use of bio-derived polyols, such as glycerol. In particular, glycerol is a hydrophilic, non-toxic, untapped waste resource and as other polyols, can be incorporated into polyesters via enzymatic catalysis routes. In the present study, a systematic screening is conducted focusing on the incorporation of 1,6-hexanediol (Hex) (hydrophobic diol) into both poly(glycerol adipate) (PGA) and poly(diglycerol adipate) (PDGA) at different (di)glycerol:hex ratios (30:70; 50:50 and 70:30 mol/mol) and its effect on purification upon NPs formation. By varying the amphiphilicity of the backbone, we demonstrated that minor adjustments influence the NPs formation, NPs stability, drug encapsulation, and degradation of these polymers, despite the high chemical similarity. Moreover, the best performing materials have shown good biocompatibility in both in vitro and in vivo (whole organism) tests. As preliminary result, the sample containing diglycerol and Hex in a 70:30 ratio, named as PDGA-Hex 30%, has shown to be the most promising candidate in this small library analysed. It demonstrated comparable stability to the glycerol-based samples in various media but exhibited superior encapsulation efficiency of a model hydrophobic dye. This in-depth investigation provides new insights into the design and modification of biodegradable (di)glycerol-based polyesters, potentially paving the way for more effective and sustainable PEG-free drug delivery nano-systems in the pharmaceutical and biomedical fields

N-Hydroxyethyl acrylamide as a functional eROP initiator for the preparation of nanoparticles under “greener” reaction conditions

N-Hydroxyethyl acrylamide was used as a functional initiator for the enzymatic ring-opening polymerisation of ε-caprolactone and δ-valerolactone. N-Hydroxyethyl acrylamide was found not to undergo self-reaction in the presence of Lipase B from Candida antarctica under the reaction conditions employed. By contrast, this is a major problem for 2-hydroxyethyl methacrylate and 2-hydroxyethyl acrylate which both show significant transesterification issues leading to unwanted branching and cross-linking. Surprisingly, N-hydroxyethyl acrylamide did not react fully during enzymatic ring-opening polymerisation. Computational docking studies helped us understand that the initiated polymer chains have a higher affinity for the enzyme active site than the initiator alone, leading to polymer propagation proceeding at a faster rate than polymer initiation leading to incomplete initiator consumption. Hydroxyl end group fidelity was confirmed by organocatalytic chain extension with lactide. N-Hydroxyethyl acrylamide initiated polycaprolactones were free-radical copolymerised with PEGMA to produce a small set of amphiphilic copolymers. The amphiphilic polymers were shown to self-assemble into nanoparticles, and to display low cytotoxicity in 2D in vitro experiments. To increase the green credentials of the synthetic strategies, all reactions were carried out in 2-methyl tetrahydrofuran, a solvent derived from renewable resources and an alternative for the more traditionally used fossil-based solvents tetrahydrofuran, dichloromethane, and toluene

Glycerol-based sustainably sourced resin for volumetric printing

Volumetric Additive Manufacturing (VAM) represents a revolutionary advancement in the field of Additive Manufacturing, as it allows for the creation of objects in a single, cohesive process, rather than in a layer-by-layer approach. This innovative technique offers unparalleled design freedom and significantly reduces printing times. A current limitation of VAM is the availability of suitable resins with the required photoreactive chemistry and from sustainable sources. To support the application of this technology, we have developed a sustainable resin based on polyglycerol, a bioderived (e.g., vegetable origin), colourless, and easily functionisable oligomer produced from glycerol. To transform polyglycerol-6 into an acrylate photo-printable resin we adopted a simple, one-step, and scalable synthesis route. Polyglycerol-6-acrylate fulfils all the necessary criteria for volumetric printing (transparency, photo-reactivity, viscosity) and was successfully used to print a variety of models with intricate geometries and good resolution. The waste resin was found to be reusable with minimal performance issues, improving resin utilisation and minimising waste material. Furthermore, by incorporating dopants such as poly(glycerol) adipate acrylate (PGA-A) and 10,12-pentacosadyinoic acid (PCDA), we demonstrated the ability to print objects with a diverse range of functionalities, including temperature sensing probes and a polyester excipient, highlighting the potential applications of these new resins

Poly (diglycerol adipate) variants as enhanced nanocarrier replacements in drug delivery applications

Sustainably derived poly(glycerol adipate) (PGA) has been deemed to deliver all the desirable features expected in a polymeric scaffold for drug-delivery, including biodegradability, biocompatibility, self-assembly into nanoparticles (NPs) and a functionalisable pendant group. Despite showing these advantages over commercial alkyl polyesters, PGA suffers from a series of key drawbacks caused by poor amphiphilic balance. This leads to weak drug-polymer interactions and subsequent low drug-loading in NPs, as well as low NPs stability. To overcome this, in the present work, we applied a more significant variation of the polyester backbone while maintaining mild and sustainable polymerisation conditions. We have investigated the effect of the variation of both hydrophilic and hydrophobic segments upon physical properties and drug interactions as well as self-assembly and NPs stability. For the first time we have replaced glycerol with the more hydrophilic diglycerol, as well as adjusting the final amphiphilic balance of the polyester repetitive units by incorporating the more hydrophobic 1,6-n-hexanediol (Hex). The properties of the novel poly(diglycerol adipate) (PDGA) variants have been compared against known polyglycerol-based polyesters. Interestingly, while the bare PDGA showed improved water solubility and diminished self-assembling ability, the Hex variation demonstrated enhanced features as a nanocarrier. In this regard, PDGAHex NPs were tested for their stability in different environments and for their ability to encode enhanced drug loading. Moreover, the novel materials have shown good biocompatibility in both in vitro and in vivo (whole organism) experiments

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course