Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy.

The development of nanoparticle (NP)-based drug carriers has presented an exciting opportunity to address challenges in oncology. Among the 100,000 available possibilities, zirconium-based metal-organic frameworks (MOFs) have emerged as promising candidates in biomedical applications. Zr-MOFs can be easily synthesized as small-size NPs compatible with intravenous injection, whereas the ease of decorating their external surfaces with functional groups allows for targeted treatment. Despite these benefits, Zr-MOFs suffer degradation and aggregation in real, in vivo conditions, whereas the loaded drugs will suffer the burst effect-i.e., the fast release of drugs in less than 48 h. To tackle these issues, we developed a simple but effective bilayer coating strategy in a generic, two-step process. In this work, bilayer-coated MOF NU-901 remained well dispersed in biologically relevant fluids such as buffers and cell growth media. Additionally, the coating enhances the long-term stability of drug-loaded MOFs in water by simultaneously preventing sustained leakage of the drug and aggregation of the MOF particles. We evaluated our materials for the encapsulation and transport of pemetrexed, the standard-of-care chemotherapy in mesothelioma. The bilayer coating allowed for a slowed release of pemetrexed over 7 days, superior to the typical 48 h release found in bare MOFs. This slow release and the related performance were studied in vitro using both A549 lung cancer and 3T mesothelioma cells. Using high-resolution microscopy, we found the successful uptake of bilayer-coated MOFs by the cells with an accumulation in the lysosomes. The pemetrex-loaded NU-901 was indeed cytotoxic to 3T and A549 cancer cells. Finally, we demonstrated the general approach by extending the coating strategy using two additional lipids and four surfactants. This research highlights how a simple yet effective bilayer coating provides new insights into the design of promising MOF-based drug delivery systems.

Feedback that Lands: Exploring How Residents Receive and Judge Feedback During Entrustable Professional Activities.

Introduction: Receiving feedback from different types of assessors (e.g., senior residents, staff supervisors) may impact trainees' perceptions of the quantity and quality of data during entrustable professional activity (EPA) assessments. We evaluated the quality of EPA feedback provided by different assessors (senior residents, chief medical residents/subspecialty residents, and staff) and explored residents' judgements of the value of this feedback. Methods: From a database of 2228 EPAs, we calculated the frequency of contribution from three assessor groups. We appraised the quality of 60 procedure-related EPAs completed between July 2019 and March 2020 using a modified Completed Clinical Evaluation Report Rating (CCERR) tool. Next, we asked 15 internal medicine residents to sort randomly selected EPAs according to their judgements of value, as an elicitation exercise before a semi-structured interview. Interviews explored participants' perceptions of quality of written feedback and helpful assessors. Results: Residents completed over 60% of EPA assessments. We found no difference in modified-CCERR scores between the three groups. When judging EPA feedback value, residents described a process of weighted deliberation, considering perceived assessor characteristics (e.g., credibility, experience with EPA system), actionable written comments, and their own self-assessment. Discussion: Like other recent studies, we found that residents contributed most to procedure-related EPA assessments. To the established list of factors influencing residents' judgements of feedback value, we add assessors' adherence to, and their shared experiences of being assessed within, EPA assessment systems. We focus on the implications for how assessors and leaders can build credibility in themselves and in the practices of EPA assessments.

Assessing the Need for Mobile Health (mHealth) in Monitoring the Diabetic Lower Extremity.

BACKGROUND: Complications of the diabetic lower extremity (such as diabetic foot ulcers, DFUs) occur when monitoring is infrequent, and often result in serious sequelae like amputation or even death. OBJECTIVE: To evaluate the potential application of mobile health (mHealth) to diabetic foot monitoring. We surveyed the self-management routines of a group of diabetic patients, as well as patient and clinician opinions on the use of mHealth in this context. METHODS: Patients with DFUs in Toronto, Ontario, Canada completed a 25-item questionnaire addressing their foot care practices, mobile phone use, and views on mHealth. Wound care clinicians across Canada were also surveyed using a 9-item questionnaire. RESULTS: Of the patients surveyed, 59/115 (51.3%) spend less than a minute checking their feet, and 17/115 (15%) of patients find it difficult to see their doctor or get to the hospital regularly. Mobile phone use was widespread in our patient cohort (93/115, 80.9%). Of mobile phone users, 68/93 (73.1%) would use a device on their mobile phone to help them check their feet. Of the clinicians who completed the questionnaire, only 7/202 (3.5%) were familiar with mHealth; however, 181/202 (92%) of clinicians expressed interest in using mHealth to monitor their patients between visits. CONCLUSIONS: Patient education or motivation and clinician training were identified as the major barriers to mHealth use in the diabetic lower extremity, which may be a viable mechanism to improve DFU monitoring practices.

Comprehensive Experimental and Theoretical Study of the CO + NO Reaction Catalyzed by Au/Ni Nanoparticles.

The catalytic and structural properties of five different nanoparticle catalysts with varying Au/Ni composition were studied by six different methods, including in situ X-ray absorption spectroscopy and density functional theory (DFT) calculations. The as-prepared materials contained substantial amounts of residual capping agent arising from the commonly used synthetic procedure. Thorough removal of this material by oxidation was essential for the acquisition of valid catalytic data. All catalysts were highly selective toward N2 formation, with 50-50 Au:Ni material being best of all. In situ X-ray absorption near edge structure spectroscopy showed that although Au acted to moderate the oxidation state of Ni, there was no clear correlation between catalytic activity and nickel oxidation state. However, in situ extended X-ray absorption fine structure spectroscopy showed a good correlation between Au-Ni coordination number (highest for Ni50Au50) and catalytic activity. Importantly, these measurements also demonstrated substantial and reversible Au/Ni intermixing as a function of temperature between 550 °C (reaction temperature) and 150 °C, underlining the importance of in situ methods to the correct interpretation of reaction data. DFT calculations on smooth, stepped, monometallic and bimetallic surfaces showed that N + N recombination rather than NO dissociation was always rate-determining and that the activation barrier to recombination reaction decreased with increased Au content, thus accounting for the experimental observations. Across the entire composition range, the oxidation state of Ni did not correlate with activity, in disagreement with earlier work, and theory showed that NiO itself should be catalytically inert. Au-Ni interactions were of paramount importance in promoting N + N recombination, the rate-limiting step.

Temperature Treatment of Highly Porous Zirconium-Containing Metal-Organic Frameworks Extends Drug Delivery Release.

Utilizing metal-organic frameworks (MOFs) as a biological carrier can lower the amount of the active pharmaceutical ingredient (API) required in cancer treatments to provide a more efficacious therapy. In this work, we have developed a temperature treatment process for delaying the release of a model drug compound from the pores of NU-1000 and NU-901, while taking care to utilize these MOFs' large pore volume and size to achieve exceptional model drug loading percentages over 35 wt %. Video-rate super-resolution microscopy reveals movement of MOF particles when located outside of the cell boundary, and their subsequent immobilization when taken up by the cell. Through the use of optical sectioning structured illumination microscopy (SIM), we have captured high-resolution 3D images showing MOF uptake by HeLa cells over a 24 h period. We found that addition of a model drug compound into the MOF and the subsequent temperature treatment process does not affect the rate of MOF uptake by the cell. Endocytosis analysis revealed that MOFs are internalized by active transport and that inhibiting the caveolae-mediated pathway significantly reduced cellular uptake of MOFs. Encapsulation of an anticancer therapeutic, alpha-cyano-4-hydroxycinnamic acid (α-CHC), and subsequent temperature treatment produced loadings of up to 81 wt % and demonstrated efficacy at killing cells beyond the burst release effect.