Theranostics for MRI‐guided therapy: Recent developments

Recent advances in bioimaging, biochemistry, and bioinformatics have facilitated the development of personalized and precision medicine. Theranostics, combining imaging modalities and therapeutic agents, have garnered a lot of attention in this context, owing to their potential to monitor and control treatment for individual patients. A promising strategy to achieve this goal involves the development of therapy guided by magnetic resonance imaging (MRI). MRI has a high degree of soft tissue contrast, low invasiveness, high depth of penetration and good spatial resolution. MRI-guided therapy could thus allow precise and time-resolved assessment of disease conditions and therapeutic progression. This article will give a brief introduction to the principles of MRI, and describe recently developed strategies to produce MRI-guided therapies. A number of theranostics based on T1, T2, or chemical exchange saturation transfer (CEST) MRI have been explored to track the route of drug carriers in vivo and image diseased tissue so as to enhance bioavailability, overcome complex delivery barriers, and assess therapeutic responses. In addition, the integration of thermal therapy and MRI imaging offers a strategy to noninvasively identify target areas, plan treatment, and provide real-time assessment of the efficacy of tumor ablation. We also discuss advances in intelligent nanoparticles combining small molecule drugs, thermal treatment and multimodal imaging, arguing that these multifunctional agents can further improve therapeutic outcomes

The implications of model-informed drug discovery and development for tuberculosis

Despite promising advances in the field and highly effective first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokinetic–pharmacodynamic (PK/PD) relations. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development. The aim of the consortium is to develop new preclinical tools in concert with an in silico model-based approach, grounded in PKPD principles. Here, we highlight the potential impact of such an integrated framework on various stages in TB drug development and on the dose rationale for drug combinations

The effect of formulation morphology on stimuli-triggered co-delivery of chemotherapeutic and MRI contrast agents

Most conventional chemotherapeutics have narrow therapeutic windows, and thus their delivery remains challenging and often raises safety and efficacy concerns. Theranostic platforms, with simultaneous encapsulation of therapeutic and diagnostic agents, have been proposed as next-generation formulations which can overcome this issue. In this work, we fabricated core@shell formulations comprising a pH responsive Eudragit L100 shell embedded with superparamagnetic iron oxide nanoparticles (SPIONs), and a thermo-responsive poly(N-isopropylacrylamide) (PNIPAM)/ethyl cellulose core loaded with the model drug carmofur. The key aim was to explore the effect of morphology (particles/fibres) on stimuli-responsive release. By varying the weight ratio of core polymer to shell polymer, the morphology of PNIPAM/ethyl cellulose@Eudragit L100 microparticles changed from concave microparticles to spherical particles. Smooth cylindrical fibres could also be generated. All the formulations exist as amorphous solid dispersions of drug-in-polymer, with distinct core@shell architectures. The fibres have clear thermo-responsive drug release profiles, while no thermo-responsive properties can be seen with the particles. All the formulations can protect SPIONs from degradation in gastric fluids (pH ∼ 1.5), and around the physiological pH range the materials offer effective and pH-responsive relaxivity. The r2 values also display clear linear relationships with drug release data, suggesting the potential of using MRI signals to track drug release in vivo. Mathematical equations were established to track drug release in vitro, with very similar experimental and predicted release profiles obtained

pH-responsive nanocomposite fibres allowing MRI monitoring of drug release

Magnetic resonance imaging (MRI) is one of the most widely-used non-invasive clinical imaging tools, producing detailed anatomical images whilst avoiding side effects such as trauma or X-ray radiation exposure. In this article, a new approach to non-invasive monitoring of drug release from a drug delivery vehicle via MRI was developed, using pH-responsive Eudragit L100 and S100 fibres encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) and carmofur (a drug used in the treatment of colon cancer). Fibres were prepared by electrospinning, and found to be smooth and cylindrical with diameters of 645 ± 225 nm for L100 and 454 ± 133 nm for S100. The fibres exhibited pH responsive dissolution behaviour. Around the physiological pH range, clear pH-responsive proton relaxation rate changes due to matrix swelling/dissolution can be observed: r2 values of L100 fibres increase from 29.3 ± 8.3 to 69.8 ± 2.5 mM-1s-1 over 3 h immersion in a pH 7.4 medium, and from 13.5 ± 2.0 mM-1 s-1 to 42.1 ± 3.0 mM-1 s-1 at pH 6.5. The r2 values of S100 fibres grow from 30.4 ± 4.4 to 64.7 ± 1.0 mM-1 s-1 at pH 7.4, but at pH 6.5, where the S100 fibres are not soluble, r2 remains very low ( 0.94) between the two. Mathematical equations were developed to predict carmofur release in vitro, with very similar experimental and predicted release profiles obtained. Therefore, the formulations developed herein have the potential to be used for non-invasive monitoring of drug release in vivo, and could ultimately result in dramatic reductions to off-target side effects from interventions such as chemotherapy

Christian Counsellors' Views on Working with Gay and Lesbian Clients:Integrating Religious Beliefs with Counselling Ethics

Thirty-one counsellors who identified themselves as practising, committed Christians, returned completed questionnaires that investigated how they integrate their Christian beliefs with their professional ethical code when counselling gay and lesbian clients. It was found that although most respondents believed that they were able to accept gay and lesbian clients, a minority demonstrated incongruence in relation to members of this client group, and were judgmental about perceived gay/lesbian behavious. Counsellors who took a rational stance in their understanding of the Bible and Christianity expressed more open and accepting views. Counsellors with a literalist approach to the Bible appeared to be lacking in acceptance and were unaware that they may not be offering the core condition of respect to their gay or lesbian clients. These findings are discussed in terms of their implications for supervision, research and practice

Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial

Introduction Drug-resistant tuberculosis (TB) remains a global health threat, with little over 50% of patients successfully treated. Novel regimens like the ones being studied in the TB-PRACTECAL trial are urgently needed. Understanding anti-TB drug exposures could explain the success or failure of these trial regimens. We aim to study the relationship between the patients’ exposure to anti-TB drugs in TB-PRACTECAL investigational regimens and their treatment outcomes. Methods and analysis Adults with multidrug-resistant TB randomised to investigational regimens in TB-PRACTECAL will be recruited to a nested pharmacokinetic-pharmacodynamic (PKPD) study. Venous blood samples will be collected at 0, 2 and 23 hours postdose on day 1 and 0, 6.5 and 23 hours postdose during week 8 to quantify drug concentrations in plasma. Trough samples will be collected during week 12, 16, 20 and 24 visits. Opportunistic samples will be collected during weeks 32 and 72. Drug concentrations will be quantified using liquid chromatography-tandem mass spectrometry. Sputum samples will be collected at baseline, monthly to week 24 and then every 2 months to week 108 for MICs and bacillary load quantification. Full blood count, urea and electrolytes, liver function tests, lipase, ECGs and ophthalmology examinations will be conducted at least monthly during treatment. PK and PKPD models will be developed for each drug with nonlinear mixed effects methods. Optimal dosing will be investigated using Monte-Carlo simulations. Ethics and dissemination The study has been approved by the Médecins sans Frontières (MSF) Ethics Review Board, the LSHTM Ethics Committee, the Belarus RSPCPT ethics committee and PharmaEthics and the University of Witwatersrand Human Research ethics committee in South Africa. Written informed consent will be obtained from all participants. The study results will be shared with public health authorities, presented at scientific conferences and published in a peer-reviewed journal. Trial registration number NCT04081077; Pre-results

SiO₂-coated layered gadolinium hydroxides for simultaneous drug delivery and magnetic resonance imaging

Layered gadolinium hydroxides (LGdH) have significant potential in simultaneous drug delivery and magnetic resonance imaging (MRI). In this work, we synthesized LGdH nanocomposites surface functionalised with SiO₂ nanodots (LGdH@SiO₂). We find these to have good dispersibility in cell culture medium, and a reduced tendency to aggregate compared to their uncoated analogue. Under the optimal reaction conditions, SiO₂ nanodots were evenly spread across the surface of the LGdH particles. We further intercalated ibuprofen (Ibu) and 5-fluorouracil (5FU) into LGdH@SiO₂, and explored the use of the resultant composites for drug delivery in vitro. While the SiO₂ coating could effectively reduce aggregation of the Ibu intercalate prepared by ion exchange from the parent LGdH, it was noted to increase aggregation in the case of the 5FU-loaded systems produced by coprecipitation. With a SiO₂ coating, 5FU release from the composite was almost zero-order at pH 7.4. The LGdH-5FU@SiO₂ composites can effectively inhibit the growth of A549 cells (a human adenocarcinoma cell line). In contrast, the Ibu-loaded materials are highly biocompatible. After SiO₂ modification, LGdH-5FU@SiO₂ retains the same proton relaxivity properties as LGdH-5FU, while LGdH-Ibu@SiO₂ ecomes suitable for use as a negative contrast agent in MRI. Overall, we find the LGdH@SiO₂ nanocomposites are promising materials for theranostic applications

Discovery, activity and characterisation of an AA10 lytic polysaccharide oxygenase from the shipworm symbiont Teredinibacter turnerae

Background: The quest for novel enzymes for cellulosic biomass-degradation has recently been focussed on lytic polysaccharide monooxygenases (LPMOs/PMOs), Cu-containing proteins that catalyse the oxidative degradation of otherwise recalcitrant polysaccharides using O2 or H2O2 as a co-substrate. Results: Although classical saprotrophic fungi and bacteria have been a rich source of lytic polysaccharide monooxy genases (LPMOs), we were interested to see if LPMOs from less evident bio-environments could be discovered and assessed for their cellulolytic activity in a biofuel context. In this regard, the marine shipworm Lyrodus pedicellatus represents an interesting source of new enzymes, since it must digest wood particles ingested during its natural tunnel boring behaviour and plays host to a symbiotic bacterium, Teredinibacter turnerae, the genome of which has revealed a multitude of enzymes dedicated to biomass deconstruction. Here, we show that T. turnerae encodes a cellulose-active AA10 LPMO. The 3D structure, at 1.4 Å resolution, along with its EPR spectrum is distinct from other AA10 polysaccharide monooxygenases insofar as it displays a “histidine-brace” catalytic apparatus with changes to the surrounding coordination sphere of the copper. Furthermore, TtAA10A possesses a second, surface accessible, Cu site 14 Å from the classical catalytic centre. Activity measurements show that the LPMO oxidises cellulose and thereby signifcantly augments the rate of degradation of cellulosic biomass by classical glycoside hydrolases. Conclusion: Shipworms are wood-boring marine molluscs that can live on a diet of lignocellulose. Bacterial sym bionts of shipworms provide many of the enzymes needed for wood digestion. The shipworm symbiont T. turnerae produces one of the few LPMOs yet described from the marine environment, notably adding to the capability of shipworms to digest recalcitrant polysaccharides

Thermal Behavior of Benzoic Acid/lsonicotinamide Binary Cocrystals

A comprehensive study of the thermal behavior of the 1:1 and 2:1 benzoic acid/isonicotinamide cocrystals is reported. The 1:1 material shows a simple unit cell expansion followed by melting upon heating. The 2:1 crystal exhibits more complex behavior. Its unit cell first expands upon heating, as a result of C–H···π interactions being lengthened. It then is converted into the 1:1 crystal, as demonstrated by significant changes in its X-ray diffraction pattern. The loss of 1 equiv of benzoic acid is confirmed by thermogravimetric analysis–mass spectrometry. Hot stage microscopy confirms that, as intuitively expected, the transformation begins at the crystal surface. The temperature at which conversion occurs is highly dependent on the sample mass and geometry, being reduced when the sample is under a gas flow or has a greater exposed surface area but increased when the heating rate is elevated