Medical student anxiety in caring for dying patients and their family: a cross-sectional study.

OBJECTIVES: To investigate the level of medical student anxiety in caring for a dying patient and their family and identify influencing factors. METHODS: We conducted a cross-sectional survey in a UK medical school to measure medical student anxiety using a validated Thanatophobia Scale questionnaire. RESULTS: In total, 332 questionnaires were completed. Mean thanatophobia score was 19.5 (SD 7.78, range 7-49). Most respondents were female (67.4%) and did not have a previous undergraduate degree (56%). Median student age was 22 years (IQR 20-24). Year of study influenced anxiety level, with second year students displaying an increase in mean thanatophobia score of 6.088 (95% CI 3.778 to 8.398, p<0.001). No significant differences were observed between final year and first year thanatophobia scores. For each 1-year increase in student age, mean thanatophobia score reduced by -0.282 (95% CI -0.473 to -0.091, p=0.004). Degree status and gender identity did not significantly affect thanatophobia score. CONCLUSION: A degree of thanatophobia exists among medical students, with no significant improvement observed by completion of training. Recognising this anxiety to care for the dying earlier in undergraduate curricula will give educators the opportunity to address students' fears and concerns and better prepare our future doctors for their role in caring for our dying patients and their families.

C2-linked alkynyl poly-ethylene glycol(PEG) adenosine conjugates as water-soluble adenosine receptor agonists.

A series of 12 novel polyethylene-glycol(PEG)-alkynyl C2-adenosine(ADN) conjugates were synthesized using a robust Sonogashira coupling protocol and characterized by NMR spectroscopy and mass spectrometry analysis. The ADN-PEG conjugates showed null to moderate toxicity in murine macrophages and 12c was active against Mycobacterium aurum growth (MIC = 62.5 mg/L). The conjugates were not active against Mycobacterium bovis BCG. Conjugates 10b and 11b exhibited high water solubility with solubility values of 1.22 and 1.18 mg/ml, respectively, in phosphate buffer solutions at pH 6.8. Further, 10b and 11b induced a significant increase in cAMP accumulation in RAW264.7 cells comparable with that induced by adenosine. Analogues 10c, 11c and 12c were docked to the A1 , A2A , A2B and A3 adenosine receptors (ARs) using crystal-structures and homology models. ADN-PEG-conjugates bearing chains with up to five ethyleneoxy units could be well accommodated within the binding sites of A1 , A2A and A3 ARs. Docking studies showed that compound 10b and 11b were the best A2A receptor binders of the series, whereas 12c was the best binder for A1 AR. In summary, introduction of hydrophilic PEG substituents at the C2 of adenine ring significantly improved water solubility and did not affect AR binding properties of the ADN-PEG conjugates.

Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators.

This is the first study investigating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO-1 in Hepa-1c1c7 cells. The compounds disrupted the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1's Kelch domain. The compounds exhibited anti-inflammatory activity in Escherichia coli Lipopolysaccharide (LPSEc )-stimulated RAW 264.7 cells. The anti-inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IFN-γ) and inflammatory mediators (PGE2, COX-2, and NF-κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half-life (T1/2 ) and intrinsic clearance (Clint ). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.

Triazole-substituted phenylboronic acids as tunable lead inhibitors of KPC-2 antibiotic resistance.

Inhibition of ß-lactamases is a promising strategy to overcome antimicrobial resistance to commonly used ß-lactam antibiotics. Boronic acid derivatives have proven to be effective inhibitors of ß-lactamases due to their direct interaction with the catalytic site of these enzymes. We synthesized a series of phenylboronic acid derivatives and evaluated their structure-activity relationships as Klebsiella pneumoniae carbapenemase (KPC-2) inhibitors. We identified potent KPC-2 inhibitors 2e & 6c (Ki = 0.032 µM and 0.038 µM, respectively) that enhance the activity of cefotaxime in KPC-2 expressing Escherichia coli. The measured acid dissociation constants (pKa) of selected triazole-containing phenylboronic acids was broad (5.98-10.0), suggesting that this is an additional property of the compounds that could be tuned to optimize the target interaction and/or the physicochemical properties of the compounds. These findings will help to guide the future development of boronic acid compounds as inhibitors of KPC-2 and other target proteins.

Care of the dying - medical student confidence and preparedness: mixed-methods simulation study.

OBJECTIVES: Of all doctors, Foundation Year 1 trainees spend the most time caring for dying patients yet report poor preparation and low confidence in providing this care. Despite documented effectiveness of simulation in teaching end-of-life care to undergraduate nurses, undergraduate medicine continues to teach this subject using a more theoretical, classroom-based approach. By increasing undergraduate exposure to interactive dying patient scenarios, simulation has the potential to improve confidence and preparedness of medical students to care for dying patients. The main study objective was to explore whether simulated experience of caring for a dying patient and their family can improve the confidence and preparedness of medical students to provide such care. METHODS: A mixed-methods interventional study simulating the care of a dying patient was undertaken with serial measures of confidence using the Self Efficacy in Palliative Care (SEPC) tool. Significance testing of SEPC scores was undertaken using paired t-tests and analysis of variance. Post-simulation focus groups gathered qualitative data on student preparedness. Data were transcribed using NVivo software and interpreted using Thematic Analysis. RESULTS: Thirty-eight 4th-year students participated. A statistically significant post-simulation increase in confidence was seen for all SEPC domains, with sustained confidence observed at 6 months. Focus group data identified six major themes: current preparedness, simulated learning environment, learning complex skills, patient centredness, future preparation and curriculum change. CONCLUSION: Using simulation to teach medical students how to care for a dying patient and their family increases student confidence and preparedness to provide such care.

Cancer centre supportive oncology service: health economic evaluation.

OBJECTIVES: There have been many models of providing oncology and palliative care to hospitals. Many patients will use the hospital non-electively or semielectively, and a large proportion are likely to be in the last years of life. We describe our multidisciplinary service to treatable but not curable cancer patients at University Hospitals Sussex. The team was a mixture of clinical nurse specialists and a clinical fellow supported by dedicated palliative medicine consultant time and oncology expertise. METHODS: We identified patients with cancer who had identifiable supportive care needs and record activity with clinical coding. We used a baseline 2019/2020 dataset of national (secondary uses service) data with discharge code 79 (patients who died during that year) to compare a dataset of patients seen by the service between September 2020 and September 2021 in order to compare outcomes. While this was during COVID-19 this was when the funding was available. RESULTS: We demonstrated a reduction in length of stay by an average of 1.43 days per admission and a reduction of 0.95 episodes of readmission rates. However, the costs of those admissions were found to be marginally higher. Even with the costs of the service, there is a clear return on investment with a benefit cost ratio of 1.4. CONCLUSIONS: A supportive oncology service alongside or allied to acute oncology but in conjunction with palliative care is feasible and cost-effective. This would support investment in such a service and should be nationally commissioned in conjunction with palliative care services seeing all conditions.

Dose-escalated radiotherapy to 82 Gy for prostate cancer following insertion of a peri-rectal hydrogel spacer: 3-year outcomes from a phase II trial.

BACKGROUND: Dose-escalation to above 80 Gy during external beam radiotherapy for localised prostate cancer leads to improved oncological outcomes but also substantially increased rectal toxicity. The aim of this study was to demonstrate the safety and efficacy of escalating the dose to 82 Gy following insertion of a peri-rectal hydrogel spacer (HS) prior to radiotherapy. METHODS: This was a single arm, open-label, prospective study of men with localised prostate cancer who were prescribed a course of intensity modulated radiotherapy escalated to 82 Gy in 2 Gy fractions following insertion of the SpaceOAR™ HS (Boston Scientific, Marlborough, MA). Patients were prescribed a standard course of 78 Gy in 2 Gy fractions where rectal dose constraints could not be met for the 82 Gy plan. The co-primary endpoints were the rate of grade 3 gastrointestinal (GI) and genitourinary (GU) adverse events (CTCAE, v4), and patient-reported quality of life (QoL) (EORTC QLQ-C30 and PR25 modules), up to 37.5 months post-treatment. RESULTS: Seventy patients received treatment on the study, with 64 (91.4%) receiving an 82 Gy treatment course. The median follow-up time post-treatment was 37.4 months. The rate of radiotherapy-related grade 3 GI and GU adverse events was 0% and 2.9%, respectively. There were 2 (2.9%) grade 3 adverse events related to insertion of the HS. Only small and transient declines in QoL were observed; there was no clinically or statistically significant decline in QoL beyond 13.5 months and up to 37.5 months post-treatment, compared to baseline. No late RTOG-defined grade ≥ 2 GI toxicity was observed, with no GI toxicity observed in any patient at 37.5 months post-treatment. Nine (12.9%) patients met criteria for biochemical failure within the follow-up period. CONCLUSIONS: Dose-escalation to 82 Gy, facilitated by use of a hydrogel spacer, is safe and feasible, with minimal toxicity up to 37.5 months post-treatment when compared to rates of rectal toxicity in previous dose-escalation trials up to 80 Gy. Trials with longer follow-up of oncological and functional outcomes are required to robustly demonstrate a sustained widening of the therapeutic window. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12621000056897 , 22/01/2021. Retrospectively registered.

The C-terminal head domain of Burkholderia pseudomallei BpaC has a striking hydrophilic core with an extensive solvent network.

Gram-negative pathogens like Burkholderia pseudomallei use trimeric autotransporter adhesins such as BpaC as key molecules in their pathogenicity. Our 1.4 Å crystal structure of the membrane-proximal part of the BpaC head domain shows that the domain is exclusively made of left-handed parallel ß-roll repeats. This, the largest such structure solved, has two unique features. First, the core, rather than being composed of the canonical hydrophobic Ile and Val, is made up primarily of the hydrophilic Thr and Asn, with two different solvent channels. Second, comparing BpaC to all other left-handed parallel ß-roll structures showed that the position of the head domain in the protein correlates with the number and type of charged residues. In BpaC, only negatively charged residues face the solvent-in stark contrast to the primarily positive surface charge of the left-handed parallel ß-roll "type" protein, YadA. We propose extending the definitions of these head domains to include the BpaC-like head domain as a separate subtype, based on its unusual sequence, position, and charge. We speculate that the function of left-handed parallel ß-roll structures may differ depending on their position in the structure.

Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode.

Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's and Parkinson's diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein-protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct "peptidomimetic" conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.

Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis.

Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.

Simulation to improve medical student confidence and preparedness to care for the dying: a feasibility study.

BACKGROUND: Undergraduate teaching currently fails to adequately prepare doctors to deliver 'end-of-life' care. Despite much evidence supporting simulation-based teaching, its use in medical undergraduate palliative and 'end-of-life' care curricula remain low. AIM: This study assesses whether simulation can improve the confidence and preparedness of medical students to provide holistic care to dying patients and their families, from clinical assessment to symptom management, communication and care after death. METHODS: Six fourth-year medical students undertook individual simulations involving a dying patient (high-fidelity simulator) and family member (actor). Intentional patient death occurred in four of the six scenarios (although unexpected by students). Pre-simulation/post-simulation thanatophobia questionnaires measured student attitudes towards providing care to dying patients. Thematic analysis of post-simulation focus group transcripts generated qualitative data regarding student preparedness, confidence and value of the simulations. RESULTS: Thematic analysis revealed that students felt the simulations were realistic, and left them better prepared to care for dying patients. Students coveted the 'safe' exposure to dying patient scenarios afforded by the simulations. Observed post-simulation reduction in mean thanatophobia scores was not found to be statistically significant (p=0.07). CONCLUSIONS: Results suggest a feasible potential for simulations to influence undergraduate medical student teaching on the care of a dying patient and their family. We believe that this study adds to the limited body of literature exploring the value of simulation in improving the confidence and preparedness of medical students to provide 'end-of-life' care. Further research into the cost-effectiveness of simulation is required to further support its application in this setting.

Understanding the impact of academic difficulties among medical students: A scoping review.

BACKGROUND: Many medical students may encounter a range of academic and personal challenges during their course of study, but very little is known about their experiences. Our aim was to review the literature to inform future scholarship and to inform policy change. METHODS: A scoping review was conducted searching PubMed, MEDLINE, EMBASE, PsycInfo, British Education Index, Web of Science and ERIC for English language primary research with no date limits. This retrieved 822 papers of which eight met the requirements for inclusion in the review. Data were independently reviewed by two researchers and underwent thematic analysis by the research team. RESULTS: Three major themes emerged. Theme 1: 'Identity preservation' addressed students' aim to preserve their sense of self in the face of academic difficulty and their tendency to seek support. This connected the apprehension many students expressed about their educational institutions to Theme 2: 'The dual role of the medical school'-medical schools are required to support struggling students but are predominantly seen as a punitive structure acting as the gatekeeper to a successful career in medicine. Students' apprehension and attempts to protect their identities within this complex landscape often resulted in 'maladaptive coping strategies' (Theme 3). CONCLUSION: Understanding and exploring the academic challenges faced by medical students through their own experiences highlight the need for the development of more individualised remediation strategies. Educators may need to do more to bridge the gap between students and institutions. There is a need to build trust and to work with students to enhance their sense of self and remediate approaches to engagement with learning, rather than focusing efforts on success in assessments and progression.

Intelligent resolution: Integrating Cryo-EM with AI-driven multi-resolution simulations to observe the severe acute respiratory syndrome coronavirus-2 replication-transcription machinery in action.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g., cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.

Atomic force microscopy-A tool for structural and translational DNA research.

Atomic force microscopy (AFM) is a powerful imaging technique that allows for structural characterization of single biomolecules with nanoscale resolution. AFM has a unique capability to image biological molecules in their native states under physiological conditions without the need for labeling or averaging. DNA has been extensively imaged with AFM from early single-molecule studies of conformational diversity in plasmids, to recent examinations of intramolecular variation between groove depths within an individual DNA molecule. The ability to image dynamic biological interactions in situ has also allowed for the interaction of various proteins and therapeutic ligands with DNA to be evaluated-providing insights into structural assembly, flexibility, and movement. This review provides an overview of how innovation and optimization in AFM imaging have advanced our understanding of DNA structure, mechanics, and interactions. These include studies of the secondary and tertiary structure of DNA, including how these are affected by its interactions with proteins. The broader role of AFM as a tool in translational cancer research is also explored through its use in imaging DNA with key chemotherapeutic ligands, including those currently employed in clinical practice.

Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism.

The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

Medical student confidence in care of the dying and their family: a systematic review.

BACKGROUND: The General Medical Council expects medical graduates to care for dying patients with skill, clinical judgement and compassion. UK surveys continually demonstrate low confidence and increasing distress amongst junior doctors when providing care to the dying. AIM: This systematic review aims to determine what has been evidenced within worldwide literature regarding medical undergraduate confidence to care for dying patients. DESIGN: A systematic electronic search was undertaken. Data extraction included measurements of baseline confidence, associated assessment tools and details of applied educational interventions. Pre/postintervention confidence comparisons were made. Factors influencing confidence levels were explored. DATA SOURCES: MEDLINE, CINAHL, EMBASE, ISI Web of Science, ERIC, PsycINFO, British Education Index and Cochrane Review databases were accessed, with no restrictions on publication year. Eligible studies included the terms 'medical student', 'confidence' and 'dying', alongside appropriate MeSH headings. Study quality was assessed using the Mixed Methods Appraisal Tool. RESULTS: Fifteen eligible studies were included, demonstrating a diversity of assessment tools. Student confidence was low in provision of symptom management, family support, and psycho-spiritual support to dying patients. Eight interventional studies demonstrated increased postinterventional confidence. Lack of undergraduate exposure to dying patients and lack of structure within undergraduate palliative care curricula were cited as factors responsible for low confidence. CONCLUSION: This review clarifies the objective documentation of medical undergraduate confidence to care for the dying. Identifying where teaching fails to prepare graduates for realities in clinical practice will help inform future undergraduate palliative care curriculum planning. PROSPERO REGISTRATION NUMBER: CRD42019119057.

A Good Death - Can the Concept Be Applied to Anatomy?

The importance of patient-centered decisions is embedded throughout clinical practice. The principle that the patient is at the center of all decisions has helped form the contemporary approach to death and dying. The concept of a "good death" will naturally mean different things to different individuals, but is based on the foundation of being pain free, comfortable, and able to make informed decisions. Potential donors are faced with many personal, ethical, and often spiritual considerations when they come to think about their wishes after death. One consideration is that of a "good death." This article explores how the concept of a "good death" may be applied to anatomy. Where first-person consent is in place, the motivating factors frequently include the wish for others to learn from the donation, and this notion may form part of the "good death" for the donor. Such motivations may impact positively on how students feel about dissecting and may provide comfort, assuaging feelings of discomfort, and allowing students to focus on anatomical learning. For donors where second-person consent is in place, the concept of a "good death" must depend on whether the individual wanted to donate their body in the first instance. The notion of a "bad death" may also be considered with body donation where no consent for donation is in place. This article proposes that there is ultimately a place for the concept that a "good death" may involve an individual donating their body to medical education.

Protein Encapsulation of Experimental Anticancer Agents 5F 203 and Phortress: Towards Precision Drug Delivery.

INTRODUCTION: Advancement of novel anticancer drugs into clinical use is frequently halted by their lack of solubility, reduced stability under physiological conditions, and non-specific uptake by normal tissues, causing systemic toxicity. Their progress to use in the clinic could be accelerated by the development of new formulations employing suitable and complementary drug delivery vehicles. METHODS: A robust method for apoferritin (AFt)-encapsulation of antitumour benzothiazoles has been developed for enhanced activity against and drug delivery to benzothiazole-sensitive cancers. RESULTS: More than 70 molecules of benzothiazole 5F 203 were encapsulated per AFt cage. Post-encapsulation, the size and integrity of the protein cages were retained as evidenced by dynamic light scattering. ToF-SIMS depth profiling using an argon cluster beam confirmed 5F 203 exclusively within the AFt cavity. Improved encapsulation of benzothiazole lysyl-amide prodrugs was achieved (~130 molecules of Phortress per AFt cage). Transferrin receptor 1, TfR1, was detected in lysates prepared from most cancer cell lines studied, contributing to enhanced anticancer potency of the AFt-encapsulated benzothiazoles (5F 203, Phortress, GW 610, GW 608-Lys). Nanomolar activity was demonstrated by AFt-formulations in breast, ovarian, renal and gastric carcinoma cell lines, whereas GI50 >50 µM was observed in non-tumourigenic MRC-5 fibroblasts. Intracellular 5F 203, a potent aryl hydrocarbon receptor (AhR) ligand, and inducible expression of cytochrome P450 (CYP) 1A1 were detected following exposure of sensitive cells to AFt-5F 203, confirming that the activity of benzothiazoles was not compromised following encapsulation. CONCLUSION: Our results show enhanced potency and selectivity of AFt-encapsulated 5F 203 against carcinomas derived from breast, ovarian, renal, colorectal as well as gastric cancer models, and offer realistic prospects for potential refinement of tumour-targeting and treatment, and merit further in vivo investigations.

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

Development of novel apoferritin formulations for antitumour benzothiazoles.

BACKGROUND: The benzothiazole structure is important in medicinal chemistry, and 5-fluoro-2-(3,4-dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite promising activity, poor water solubility limits its applications. The apoferritin (AFt) protein cage has been proposed as a robust and biocompatible drug delivery vehicle. AIMS: Here, we aim to enhance solubility of GW 610 by developing amino acid prodrug conjugates and utilizing the AFt capsule as drug delivery vessel. METHODS AND RESULTS: The potent experimental antitumour agent, GW 610, has been successfully encapsulated within AFt with more than 190 molecules per AFt cage. The AFt-GW 610 complex exhibits dose-dependent growth inhibition and is more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous solubility and encapsulation efficiency, a series of amino acid esters of GW 608 prodrug were synthesized via N,N'-dicyclohexylcarbodiimide ester coupling to produce molecules with different polarity. A dramatic increase in encapsulation efficiency was achieved, with more than 380 molecules of GW 608-Lys molecules per AFt cage. Release studies show sustained release of the cargo over 12 hours at physiologically relevant pH. The AFt-encapsulated amino acid modified GW 608 complexes are sequestered more rapidly and exhibit more potent anticancer activity than unencapsulated agent. CONCLUSION: These results indicate that AFt-encapsulation of GW 610 prodrug provides a biocompatible delivery option for this potent, selective experimental antitumour agent and for amino acid-modified GW 608. Of particular interest is the encapsulation efficiency and in vitro antitumour activity of AFt-GW 608-Lys, which warrants further preclinical evaluation.