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TBRT allows the control of cyclisation within branched polymer architectures by simply changing dilution. Increased cyclisation leads to changes in physical properties, therefore, tunig of behaviour is available without changing starting materials.

This review outlines the importance of improving the treatment of preterm birth, summarises the use of nanomedicines for the delivery of active pharmaceutical ingredients and discusses the opportunities/challenges for enhancing future patient outcomes.

Nanogels are candidates for biomedical applications, and core-shell nanogels offer the potential to tune thermoresponsive behaviour with the capacity for extensive degradation. These properties were achieved by the combination of a core of poly(N-isopropylmethacrylamide) and a shell of poly(N-isopropylacrylamide), both crosslinked with the degradable crosslinker N,N′-bis(acryloyl)cystamine. In this work, the degradation behaviour of these nanogels was characterised using asymmetric flow field flow fractionation coupled with multi-angle and dynamic light scattering. By monitoring the degradation products of the nanogels in real-time, it was possible to identify three distinct stages of degradation: nanogel swelling, nanogel fragmentation, and nanogel fragment degradation. The results indicate that the core-shell nanogels degrade slower than their non-core-shell counterparts, possibly due to a higher degree of self-crosslinking reactions occurring in the shell. The majority of the degradation products had molecule weights below 10 kDa, which suggests that they may be cleared through the kidneys. This study provides important insights into the design and characterisation of degradable nanogels for biomedical applications, highlighting the need for accurate characterisation techniques to measure the potential biological impact of nanogel degradation products.

Core–shell nanogels with a poly(N-isopropylmethacrylamide) core and poly(N-isopropylacrylamide) shell display tuneable thermoresponsive behaviour and high degradability.

Three new synthesis strategies for branched statistical copolymers containing analogues of step-growth backbones are shown using free radical chemistries and transfer-dominated branching radical polymerisation (TBRT) conditions.

Transfer-dominated Branching Radical Telomerisation (TBRT) enables the production of branched polymers with step-growth backbones using radical telomerisation chemistry. By conducting identical TBRTs over a broad temperature range, the role of temperature in telomer formation and branching has been evaluated. Elevated temperature limits telomer length, thereby allowing a10% reduction in the amount of telogen required to produce near identical high molecular weight branched polymers.

Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use.

Amine functionality offers the modification of polymer properties to enable stimuli-responsive behaviour, and this feature has been utilised in numerous studies of self-assembly and disassembly. The ability to place amines as pendant groups along linear polymer backbones within distinct blocks, at chain ends or as statistical mixtures with other functionalities, has allowed fine tuning of responses to pH. Here we study and compare the placement of amines within the backbones or as pendant groups within polyesters synthesised by the newly reported transfer-dominated branching radical telomerisation (TBRT). Branched polymers with backbone amines are clearly shown to undergo dissolution that is determined by pH and telogen selection; they undergo nanoprecipitation only when hydrophilic telogens are present within their structure and provide nanoprecipitates that are highly sensitive to the addition of acid. In contrast, TBRT polymers with pendant amines form uniform nanoparticles with remarkable stability to pH changes, under identical nanoprecipitation conditions. The behaviour differences shown here open new avenues of synthetic flexibility for pH-responsive polymer design using TBRT.

New branched polymerisations offer previously inaccessible macromolecules and architectural understanding is important as it provides insight into the branching mechanism and enables the determination of structure–property relationships. Here we present a detailed inverse gated 13C NMR characterisation of materials derived from the very recently reported Transfer-dominated Branching Radical Telomerisation (TBRT) approach to quantify branching and provide an insight into cyclisation.

A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the LogP of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and LogP appeared to stongly influence rates of nucleation. Model drugs with high LogP were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form unifrom and stable lipid based nanoparticles of high drug loading- through manipulation of LogP are discussed.

Curcumin is widely used as a nutraceutical ingredient in food and beverage products. It has been reported that curcumin has a broad spectrum of biological activities such as anticancer, anti-inflammatory, antioxidant, and antibacterial effects. Despite the potent therapeutic effect of curcumin, its low aqueous solubility, stability, and oral bioavailability limits its effectiveness. In order to improve the physical and chemical properties of curcumin, we have formulated curcumin as a nanosuspension by using the emulsion templated freeze-drying technique. This approach produces a solid that can be dispersed as required to form a nanosuspension. The formulations were investigated in a screening process using various excipients, resulting in the identification of one curcumin nanosuspension sample which contained only polyethylene glycol (PEG) as the excipient. This formulation exhibited a small diameter (211 nm), low polydispersity (0.06) and zeta potential of −25 mV and was therefore chosen for further in vitro investigations. Various experimental parameters such as active agent and excipient concentrations, and sonication time were varied to tune the size and polydispersity of the chosen formulation. The resulting nanosuspension showed an improved chemical stability at pH values that mimic the gastrointestinal tract. An in vitro bioaccessibility experiment showed that the nanosuspension formulation resulted in more dissolution of the curcumin but this was also coupled with reduced stability. Cytotoxicity studies showed that the nanosuspension offered a reduced cytotoxicity profile compared to the solubilised curcumin on both cell lines investigated. This redispersible curcumin nanosuspension formulation may provide new opportunities for the oral dosing of curcumin.

Complex macromolecular architectures offer innovation opportunities through the formation of new polymers with novel physical and chemical behaviour. Optimally existing commercial feedstocks are used as the introduction of new small molecule chemistries may extend regulatory requirements at high expense. In a highly orthogonal synthesis strategy, we recently utilised telomerisation approaches, conventionally targeting small molecule dimerisation, to generate high molecular weight branched polymers. Transfer-dominated Branching Radical Telomerisation (TBRT) employs radical reactions, but yields branched polymers with extended backbones resembling those conventionally formed via step-growth polymerisation. Here we examine the impact of taxogen dimensions on the outcomes of TBRT using multi-vinyl taxogens ethylene glycol dimethacrylate (EGDMA), 1,6-hexanediol dimethacrylate (HDMA) and 1,12-dodecanediol dimethacrylate (LDMA). Marked differences in gelation behaviours were correlated to the dimensions of the taxogen, notably due to the shifting balance of intermolecular and intramolecular branching processes occuring during TBRT.

The commercial synthesis of polymers is generally limited to two main mechanisms that are typically considered to be mutually exclusive, namely step-growth and chain-growth polymerisation. This also defines the vast number of academic advances in macromolecular synthesis including the increasingly studied reversible deactivation radical polymerisation techniques (chain-growth) and complex polymer architectures such as dendrimers (step-growth). We report here a new synthetic strategy that utilises conventional free radical chain-growth chemistry, under modified telomerisation conditions, to form branched polymers containing chemistries conventionally formed under step-growth conditions. Telomerisation is typically limited to small molecule synthesis and employs addition across the unsaturated bond of a substrate, whilst minimising intermolecular reaction between substrates. Through the careful manipulation of reaction conditions, we have created a ‘transfer dominated branching radical telomerisation’ mechanism that creates branched polymers containing step-growth motifs from multi-vinyl monomers, with molecular weights in excess of 1000 kg mol−1, using industrially relevant free radical chain-growth chemistry. The scope of this approach is considerable, allowing access to entirely new macromolecular structures.

Successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention implementable alongside vaccination programmes. Camostat and nafamostat are serine protease inhibitors that inhibit SARS-CoV-2 viral entry in vitro but have not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and while camostat is orally available, both drugs have extremely short plasma half-lives. This study sought to determine whether intranasal dosing at 5 mg/kg twice daily was able to prevent airborne transmission of SARS-CoV-2 from infected to uninfected Syrian golden hamsters. SARS-CoV-2 viral RNA was above the limits of quantification in both saline- and camostat-treated hamsters 5 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, intranasal nafamostat-treated hamsters remained RNA negative for the full 7 days of cohabitation. Changes in body weight over the course of the experiment were supportive of a lack of clinical symptomology in nafamostat-treated but not saline- or camostat-treated animals. These data are strongly supportive of the utility of intranasally delivered nafamostat for prevention of SARS-CoV-2 infection and further studies are underway to confirm absence of pulmonary infection and pathological changes.

Currently nitazoxanide is being assessed as a candidate therapeutic for SARS-CoV-2. Unlike many other candidates being investigated, tizoxanide (the active metabolite of nitazoxanide) plasma concentrations achieve antiviral levels after administration of the approved dose, although higher doses are expected to be needed to maintain these concentrations across the dosing interval in the majority of patients. Here an LC-MS/MS assay is described that has been validated in accordance with Food and Drug Administration (FDA) guidelines. Fundamental parameters have been evaluated, and these included accuracy, precision and sensitivity. The assay was validated for human plasma, mouse plasma and Dulbeccos Modified Eagles Medium (DMEM) containing varying concentrations of Foetal Bovine Serum (FBS). Matrix effects are a well-documented source of concern for chromatographic analysis, with the potential to impact various stages of the analytical process, including suppression or enhancement of ionisation. Therefore, a robustly validated LC-MS/MS analytical method is presented capable of quantifying tizoxanide in multiple matrices with minimal impact of matrix effects. The validated assay presented here was linear from 15.6ng/mL to 1000ng/mL. Accuracy and precision ranged between 102.2% and 113.5%, 100.1% and 105.4%, respectively. The presented assay here has applications in both pre-clinical and clinical research and may be used to facilitate further investigations into the application of nitazoxanide against SARS-CoV-2.

The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate.

Favipiravir (FAV; T-705) has been approved for use as an anti-influenza therapeutic and has reports against a wide range of viruses (e.g., Ebola virus, rabies and norovirus). Most recently FAV has been reported to demonstrate activity against SARS-CoV-2. Repurposing opportunities have been intensively studied with only limited success to date. If successful, repurposing will allow interventions to become more rapidly available than development of new chemical entities. Pre-clinical and clinical investigations of FAV require robust, reproducible and sensitive bioanalytical assay. Here, a liquid chromatography tandem mass spectrometry assay is presented which was linear from 0.78-200 ng/mL Accuracy and precision ranged between 89% and 110%, 101% and 106%, respectively. The presented assay here has applications in both pre-clinical and clinical research and may be used to facilitate further investigations into the application of FAV against SARS-CoV-2.

Objectives To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19. Trial design This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial. Participants Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward. Inclusion criteria Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening. Intervention and comparator Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria. Main outcome measures Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs. Randomisation Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities. Blinding None, this is an open-label trial. Number to be randomised (sample size) 98 patients (49 per arm). Trial status Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021. Trial registration The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534. Full protocol The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry.MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load.ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups.ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Solid lipid nanoparticles (SLNs) have proved to be effective nanocarriers with many advantages over other non-lipid-based systems. The development of new SLN formulations is often hindered through poor drug loading capacity and time-consuming optimisation of lipid/stabiliser combinations. One challenge in the development of new SLN formulations is understanding the complex interactions between amphiphilic stabilisers and hydrophobic lipids; the nature of these interactions can significantly impact SLN properties, including the internal polarity within the nanoparticle core. Herein, we report the use of pyrene to probe the internal lipid microenvironment inside SLNs. We investigate the effect of using different poloxamer stabilisers on the internal polarity of SLNs formed using the common solid lipid, Compritol 888 ATO. We show that the polarity of the internal lipid environment is modified by the length of the poly(propylene oxide) (PPO) block of the poloxamer stabiliser, with longer PPO blocks producing SLNs with less polar lipid cores. Blending of stabilisers could also be used to tune the polarity of the core lipid environment, which may allow for adjusting the polarity of the lipid to assist the loading of different therapeutics.

The synthesis of complex polymer architectures using relatively facile experimental protocols provides access to materials with the opportunity to control functionality and physical behaviour. The scope of hyperbranched-polydendron chemistries has been expanded here to include primary chains comprising amine-functional ‘homopolymer’, ‘statistical copolymer’ and amphiphilic ‘block copolymer’ analogues using 2-(diethyl amino)ethyl methacrylate, 2-hydroxy propyl methacrylate and t-butyl methacrylate. The different primary chain chemistry and architectures leads to a marked variation in nanoprecipitation behaviour and the response of the resulting amine-functional nanoparticles to varying pH. When acid-sensitive and acid-stable branchers, 1,4-butanediol di(methacryoyloxy)-ethyl ether and ethylene glycol dimethacrylate respectively, are utilised, nanoparticles with encapsulation properties are formed and may be triggered to either release-and-disassemble or release-disassemble-degrade to form a solution of lower molecular weight constituent primary chains.

Poly(N-isopropylacrylamide) (pNIPAM) nanogels are a highly researched type of colloidal material. In this work, we establish a versatile asymmetric-flow field-flow fractionation (AF4) method that can provide high resolution particle sizing and also structural information on nanogel samples from 65–310 nm in hydrodynamic diameter and so different chemical compositions. To achieve this online multi-angle light scattering and dynamic light scattering detectors were used to provide measurement of the radius of gyration (Rg) and hydrodynamic radius (Rh) respectively. Two different eluents and a range of cross-flows were evaluated in order to provide effective fractionation and high recovery for the different nanogel samples. We found that using 0.1 M NaNO3 as the eluent and an initial cross-flow of 1 mL min−1 provided optimal separation conditions for all samples tested. Using this method, we analysed two types of samples, pNIPAM nanogels prepared by free radical dispersion polymerisation with increasing diameters and analysed poly(acrylic acid)-b-pNIPAM crosslinked nanogels prepared by reversible addition–fragmentation chain transfer dispersion polymerisation. We could determine that the differently sized free radical nanogels possessed differing internal structures; shape factors (Rg/Rh) ranged from 0.58–0.73 and revealed that the smallest nanogel had a homogeneous internal crosslinking density, while the larger nanogels had a more densely crosslinked core compared to the shell. The poly(acrylic acid)-b-pNIPAM crosslinked nanogels displayed clear core–shell structures due to all the crosslinking being contained in the core of the nanogel.

Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus.

Aim: A preclinical safety assessment of a novel nanoemulsion drug-delivery system, initially developed to improve the posology of efavirenz (EFV), was conducted with a specific focus on possible immunological and hematological complications. Materials & methods: Assessment of common acute toxicities, such as complement activation and cytokine secretion, was performed using validated assays known to have good correlation with in vivo end points. Results & conclusion: Compared with a standard aqueous solution of EFV, the EFV nanoemulsion showed no significant effect on immune cell function or phenotype. Prolongation of activated partial thromboplastin time was observed for EFV-loaded nanoemulsions (88% at 4 μg/ml) as well as unloaded nanoemulsions (52%) highlighting the potential for drug-free anticoagulant activity and warranting further investigation of the mechanism and utility of these materials.

Cu-Catalysed reversible-deactivation radical polymerisation of hydrophobic methacrylate monomers in anhydrous alcohols has been expanded to explore the scope of this unusual choice of solvent. A range of linear methacrylic homopolymers with well-targeted molecular weight and low dispersity (Đ = 1.12–1.53) have been generated in anhydrous methanol and isopropanol with relative ease. These solvents are normally considered antisolvents and employed to precipitate such polymers; therefore, our studies have assessed the polymerisation reaction mixture homogeneity and extent of reaction control. Statistical copolymerisations with the bi-functional monomer, ethylene glycol di-methacrlylate (EGDMA), has led to branched statistical copolymers with weight average molecular weights up to Mw = 1.76 × 106 g mol−1; subsequent triple-detection size exclusion chromatography studies have provided insight into the impact of monomer structure on the extent of branching within the final isolated polymers. The ability to control branched copolymer molecular weights under these conditions through variation of EGDMA concentrations was seen to be highly dependent on methacrylate monomer chemistry. A number of factors which are likely to effect branching reactions during the polymerisation of hydrophobic methacrylates in anhydrous alcohols are discussed.

The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.

There is a rapidly expanding literature on thein vitroantiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly,in vitroanti-SARS-CoV-2 activity data was digitised from all available publications up to 13thApril 2020 and used to recalculate an EC90value for each drug. EC90values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50as a better indicator of potential human efficacy (lung Cmax/EC90ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlungbut nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

Enhancing the activity of existing antimicrobial agents may help to address the emergence of resistant bacteria. Nanoparticles of antimicrobial agents have previously been shown to provide potential activity enhancements and here we report a high-throughput nanoprecipitation approach to identify viable nanosuspensions of the antimicrobial compound triclosan. Through careful choice of the components of the nanoprecipitation, amorphous nanosuspensions were created, freeze-dried and redispersed in water with z-average diameters varying from 170–290 nm. Particle size was shown to be controlled by a series of factors including polymer/surfactant concentration and concentration of triclosan solution prior to nanoprecipitation. A ten-fold decrease (i.e. higher activity) in the Escherichia coli (E. coli) inhibitory concentration (IC50) of triclosan, compared to an aqueous control, was observed for nanoparticles prepared using Pluronic® F68 and the cationic surfactant Hyamine. This overall approach offers a rapid route for identifying viable nanosuspensions and enhancing the properties of commercially available biologically active compounds with poor water-solubility.

Pharmaceutical excipients are no longer considered inert and have been shown to influence the activity of metabolic enzymes and transporters, resulting in altered pharmacokinetics of substrate drugs. In this study, the effect of 25 excipients commonly used in drug formulations were investigated for their effect on P-glycoprotein (P-gp) activity. The effect of excipients on P-gp were assessed by measuring the change in the cellular accumulation of a P-gp substrate, digoxin, in MDCK-MDR1 (Madin Darby canine kidney transfected with multidrug resistance 1 gene) cells. The cells were exposed to low (10 μM) and high (200 μM) concentrations of excipient along with 10 μM digoxin. Excipient concentrations were chosen to span the range of concentrations previously used for investigating activities in vitro. At 10 μM of excipient, an increase in the intracellular digoxin concentration was seen with d-α-tocopherol poly-(ethylene glycol) succinate (Vit-E-PEG; p = 0.002), poly(ethylene oxide)

Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic–pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field., Long-acting antimalarials could provide improved prophylaxis and treatment options in the field. Here, Bakshi et al. develop a long-acting injectable atovaquone nanomedicine that prevents malaria infection prophylactically for up to 4 weeks in mice with no evidence for generation of resistant parasites.

Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3–18 years) using physiologically-based pharmacokinetic modelling. Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.

The vast potential of these unique and complex materials has inspired scientists worldwide to construct dendritic architectures using various iterative chemistries, which has led to an array of well-established dendritic families that hold great promise in application-driven research. Despite a lack of products being made commercially available for real-world applications, interest in dendritic materials remains high and recent research has indicated a desire for more sophisticated functions that often require more intricate synthetic design. In this chapter we present a discussion of advances that use the highly efficient ‘click’ and multicomponent reactions to construct multifunctional dendritic scaffolds before highlighting the unique architectures of fullerodendrimers and hyperbranched polydendrons – the latter incorporating branched vinyl polymerisation strategies to enhance commercial viability. Finally, recent reports that describe the assembly of dendrimers and dendritic–linear polymer hybrids to form hierarchically larger assemblies will be discussed before reasoning why academic research is beginning to focus on simpler, albeit polydisperse, dendritic platforms. Throughout the discussion, there will be a sustainability awareness that highlights the number of reactions, the overall yields, the total reaction time, significant reagent excesses and the methods of purification involved – all of which contribute to the viability of large-scale manufacturing within a commercial setting.

Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio–nano papers, the community responds.

Colorectal cancer remains a significant cause of morbidity and mortality worldwide. Half of all patients develop liver metastases, presenting unique challenges for their treatment. The shortcomings of conventional chemotherapy has encouraged the use of nanomedicines; the application of nanotechnology in the diagnosis and treatment of disease. In spite of technological improvements in nanotechnology, the complexity of biological systems hinders the prospect of nanomedicines being applied in cancer therapy at the present time. This review highlights current biological barriers and discusses aspects of tumor biology together with the physicochemical features of the nanocarrier, that need to be considered in order to develop effective nanotherapeutics for colorectal cancer patients with liver metastases. It becomes clear that incorporating an interdisciplinary approach when developing nanomedicines should assure appropriate disease‐driven design and that this will form a critical step in improving their clinical translation. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease, A fundamental understanding of the tumor biology and its physiological features is necessary for the design and development of effective nanomedicines to target cancers.

Stimuli-responsive layer-by-layer (LbL) capsules are appealing drug carriers for oral drug delivery owing to their abilities to utilize environmental differences to trigger changes in particles properties. LbL capsules typically have micrometer diameter ranging between 1 and 5 µm. The opportunity to use LbL for the modification of particles in the nanorange may provide enhanced benefits and properties for drug delivery. In this work, we used multiple polyelectrolytes to prepare novel stimuli-responsive multi-layered nanocapsules with submicron diameters. A systematic study was conducted to investigate the influence of various experimental parameters on the formation of calcium carbonate nanoparticles (CaCO3) as nanocores. The resultant nanocores were then used for the assembly of LbL nanocapsules and the variables that influenced the diameter of capsules were investigated. Finally, novel stimuli-responsive multi-layered nanocapsules made of four polyelectrolytes including Eudragit L100, chitosan, sodium alginate, and poly-L-arginine were prepared and characterized. The stimuli-responsive multi-layered nanocapsules loaded with a model drug, curcumin, were assessed for drug release under pH conditions that mimic the gastrointestinal tract. These data demonstrate the potential for nanocapsules to be designed to protect the drug in the stomach and release it in the lower gastrointestinal tract.

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

Human Immunodeficiency Virus (HIV) is a global health concern to which nanomedicine approaches provide opportunities to improve the bioavailability of existing drugs used to treat HIV. In this article, lipid polymer hybrid nanoparticles (LPHNs) were developed as a system to provide a combination drug delivery of two leading antiretroviral drugs; darunavir (DRV) and its pharmacokinetic enhancer ritonavir (RTV). The LPHNs were designed with a poly(D, l -lactide-co-glycolide) (PLGA) core, and soybean lecithin (SBL) and Brij 78 as the stabilizers. The LPHNs were prepared by modified nanoprecipitation and the effect of synthetic conditions on the particle properties was studied, which included the Z-average diameter and polydispersity index of LPHNs in water and phosphate buffered saline, and the morphology of the particles. This investigation aimed to prepare a formulation that could be stored in its dry and redispersible form, therefore avoiding the challenges associated with storage of dispersions. The optimum ratio of stabilizer to polymer core was established at 20% w/w, and Brij 78 was found to be crucial in providing colloidal stability in physiological solutions; the minimum amount of Brij 78 required to provide stability in phosphate buffered saline was 70% w/w of the total stabilizer mass. Viable formulations of LPHNs containing DRV and RTV in the clinically used 8:1 ratio were prepared containing 20% w/w DRV with respect to the PLGA mass. The use of cryoprotectant, polyethylene glycol, combined with freeze-drying yielded LPHNs with a Z-average diameter of 150 nm when the particles were re-dispersed in water. The oral absorption behavior was assessed using an in vitro triple culture model. Whilst the use of cryoprotectant and freeze-drying led to no improvement of the transcellular permeability compared to the unformulated drugs, the non-freeze-dried samples with the highest soybean lecithin led to increased transcellular permeability, revealing the potential of LPHNs for enhancing HIV treatment.

International audience; A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative’s recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

Background Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations. Here we have conducted a preclinical evaluation of efavirenz SDN to assess their potential interaction with these systems. Platelet aggregation and activation, plasma coagulation, haemolysis, complement activation, T cell functionality and phenotype, monocyte derived macrophage functionality, and NK cell function were assessed in primary healthy volunteer samples treated with either aqueous efavirenz or efavirenz SDN. Results Efavirenz SDNs were shown not to interfere with any of the systems studied in terms of immunostimulation nor immunosuppression. Although efavirenz aqueous solution was shown to cause significant haemolysis ex vivo, efavirenz SDNs did not. No other interaction with haematological systems was observed. Efavirenz SDNs have been demonstrated to be immunologically and haematologically inert in the utilised assays. Conclusions Taken collectively, along with the recent observation that lopinavir SDN formulations did not impact immunological responses, these data indicate that this type of nanoformulation does not elicit immunological consequences seen with other types of nanomaterial. The methodologies presented here provide a framework for pre-emptive preclinical characterisation of nanoparticle safety. Electronic supplementary material The online version of this article (10.1186/s12951-018-0349-y) contains supplementary material, which is available to authorized users.

A synthetic strategy for generating branched polymer building blocks for the rapid construction of patchy nanoparticles is presented. Hyperbranched polydendrons containing a controlled mixture of PEG and thiol-functional chain ends, with different dendron generation (G0 and G3), were synthesised and nanoprecipitated (50–70 nm). The patchy isolation of thiol groups was confirmed through the binding of 4 nm gold particles and the quantification of clustering at the nanoprecipitate surface.