Biology subjects

Ferguson, E. L.

Publications and source records attributed to Ferguson, E. L..

5 recordsLinked to original sources

bioRxiv2026

Development of a nanomedicine approach to improve the therapeutic index of bexarotene.

Bexarotene (BEX), a retinoid X receptor (RXR) agonist, has demonstrated therapeutic potential in oncology, neurodegenerative diseases and inflammatory conditions, including multiple sclerosis (MS). However, its broader clinical application is limited by poor aqueous solubility, low bioavailability, and dose-limiting adverse effects, most notably hypertriglyceridaemia. In this study, we investigated whether conjugation of BEX to dextrin, a biodegradable polysaccharide, could improve its physicochemical properties and therapeutic index. A dextrin-BEX conjugate was synthesised using succinoylated dextrin (30 mol%) and characterised by gel permeation chromatography (GPC), Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (1H-NMR) and dynamic light scattering (DLS). The effects of conjugation on solubility, aggregation behaviour and biological activity were evaluated using in vitro cytotoxicity assays in leukaemia, liver and fibroblast cell lines, alongside measurements of intracellular triglyceride levels. The impact on lipid metabolism and toxicity was further assessed in an in vivo murine model of hyperlipidaemia. Dextrin conjugation significantly increased the aqueous solubility of BEX (from <0.004 mg/mL to 9.88 mg/mL) and led to the formation of nanoscale aggregates in solution. This was associated with a marked increase in in vitro potency, with IC50 values reduced by up to 14-fold across multiple cell lines. However, the increased cytotoxicity was not selective for cancer cells and was also observed in normal fibroblast and hepatic cell models. The dextrin-BEX conjugate did not induce intracellular triglyceride accumulation in vitro. In vivo, dextrin conjugation did not mitigate BEX-associated lipid dysregulation, while serum triglyceride levels and markers of liver injury remained unchanged. However, although free BEX led to a significant increase in liver weight after 14 days, the dextrin-BEX conjugate did not produce a statistically significant effect. In conclusion, dextrin conjugation markedly improves the solubility and in vitro potency of BEX but does not enhance its selectivity or reduce its metabolic toxicity in vivo. These findings suggest that while polymer conjugation is an effective strategy for addressing physicochemical limitations, it is insufficient to overcome the inherent dyslipidaemia associated with systemic RXR activation. Future strategies should focus on integrating targeting and controlled release mechanisms, alongside approaches that address the underlying pharmacological drivers of lipid dysregulation.

pharmacology and toxicology↗

bioRxiv2023

Modification of the antibiotic, colistin, with dextrin causes enhanced cytotoxicity and triggers apoptosis in myeloid leukemia

Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different subtypes in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistins anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin-colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistins cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic. Our results identified a conjugate (containing 8,000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently-labelled compounds showed both free and dextrin-conjugated colistin were endocytosed and co-localized in lysosomes and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization. Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote AMR and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/565276v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1cb7aaorg.highwire.dtl.DTLVardef@15e3574org.highwire.dtl.DTLVardef@7577aorg.highwire.dtl.DTLVardef@eb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected /inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistins toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistins renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565265v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1ec6ac8org.highwire.dtl.DTLVardef@56a2b1org.highwire.dtl.DTLVardef@1d347fborg.highwire.dtl.DTLVardef@1ab7da_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

Virtually the same? Evaluating the effectiveness of remote undergraduate research experiences

In-person undergraduate research experiences (UREs) promote students integration into careers in life science research. In 2020, the COVID-19 pandemic prompted institutions hosting summer URE programs to offer them remotely, raising questions about whether undergraduates who participate in remote research can experience scientific integration. To address this, we investigated indicators of scientific integration for students who participated in remote life science URE programs in summer 2020. We found that these students experienced gains in their scientific self-efficacy and scientific identity similar to results reported for in-person UREs. We also found that these students perceived high benefits and low costs of doing research at the outset of their programs, and their perceptions did not change despite the remote circumstances. Yet, their perceptions differed by program, indicating that programs differentially affected students perceptions of the costs of doing research. Finally, we observed that students with prior research experience made greater gains in self-efficacy and identity, as well as in their perceptions of the alignment of their values with those of the scientific community, in comparison to students with no prior research experience. This finding suggests that additional programming may be needed for undergraduates with no prior experience to benefit from remote research.

scientific communication and education↗

bioRxiv2021

"How do we do this at a distance?!" A descriptive study of remote undergraduate research programs during COVID-19

The COVID-19 pandemic shut down undergraduate research programs across the U.S. Twenty-three sites offered remote undergraduate research programs in the life sciences during summer 2020. Given the unprecedented offering of remote research experiences, we carried out a study to describe and evaluate these programs. Using structured templates, we documented how programs were designed and implemented, including who participated. Through focus groups and surveys, we identified programmatic strengths and shortcomings as well as recommendations for improvements from the perspectives of participating students. Strengths included the quality of mentorship, opportunities for learning and professional development, and development of a sense of community. Weaknesses included limited cohort building, challenges with insufficient structure, and issues with technology. Although all programs had one or more activities related to diversity, equity, inclusion, and justice, these topics were largely absent from student reports even though programs coincided with a peak in national consciousness about racial inequities and structural racism. Our results provide evidence for designing remote REUs that are experienced favorably by students. Our results also indicate that remote REUs are sufficiently positive to further investigate their affordances and constraints, including the potential to scale up offerings, with minimal concern about disenfranchising students.

scientific communication and education↗