WMS » Publications

Good clocks in breast tumours are bad news for patients

Wed, 18 Mar 2026 20:55:00 GMT

Vadim's magnum opus now online as a preprint. 7 years after the initial preprint, 2 PhD students working on it. A coolaboration with David Rand and also including input Francis Lévi and with data from George Bjarnasson and Tami Martino.

We show in over 1200 patients that TimeTeller predicted functional tumour clocks have a negative effect on 10-year survival in breast cancer patients. Also, the tumour clocks are "off" compared to wall clock time, which we speculate might be a feature of tumour evading detection by the patients immune system.

In Situ Lipid Interactions of an Anticancer Metal Complex

Tue, 24 Feb 2026 14:20:00 GMT

Ed Lant's paper on cool molecular helicopters that also fluoresc entitled: "In Situ Lipid Interactions of an Anticancer Metal Complex". A big collaboration with Peter Sadler's lab and collaborators from Diamond (Maria Harkiolaki) and others.

In this paper, Ed uses an integrated multimodal imaging workflow of cryogenic super-resolution fluorescence microscopy and soft X-ray tomography, Orbitrap secondary ion mass spectrometry, and inductively coupled mass spectrometry to reveal unexpected targeting of a half-sandwich cyclopentadienyl Rh(III) phenylazopyridine anticancer complex to cellular lipid membranes and lipid droplets.

The complex accumulates in plasma membranes with a surprisingly intense switch-on luminescence in living cancer cells, drives remodelling of lipid droplet architecture, and penetrates deeply into lipid-rich tissue environments. DFT modelling shows strong supramolecular interactions between the complex and glycerophosphorylcholine lipids.

How to safeguard against the low hanging fruit being rotten?

Fri, 31 Oct 2025 00:10:00 GMT

Recent clinical results suggest that early immunotherapy is more efficacious than late immunotherapy. In a commentary lead by Seline Ismail-Sutton, we argue that "Personalising chronotherapy of immune checkpoint blockade" is important. Chronotype as a factor should be looked at in pragmatic chrono-immunotherapy trials.

Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro

Thu, 09 Oct 2025 23:10:00 GMT

Now out as paper in Biomacromolecules. Led by Sophie Laroque from the Perrier Lab in Warwick and in collaboration with Katherine Locock at CSIRO Australia, we show the anti-inflammatory effects of novel cationic co-polymers that also show anti-microbial activity. Win-win for sepsis patients.

Cyclic Peptide – Polymer Conjugate Nanotubes for Delivery of SN-38 in Treatment of Colorectal Cancer Model

Tue, 30 Sep 2025 23:00:00 GMT

New paper by Sophie Hill reporting on her drug delivery work during her PhD in the Perrier lab.

Cyclic peptide-polymer conjugate nanotubes have been shown to be powerful drug delivery vectors, due to their propensity for dynamic self-assembly, high aspect ratio morphology and structural interchangeability. Building upon previous studies that demonstrate the shielding abilities of the polymeric corona of nanotubes to enhance pro-drug bond stabilities and modulate hydrolysis, we utilise here the concept of a hydrophobic core building block with multiple drug units to improve drug loading capacity and overall efficiency of the nanotube carriers. By leveraging the intermolecular features of the drug core to strengthen assembly, we hypothesise that these nanotubes have the potential as a responsive supramolecular delivery system whereby upon full hydrolysis of the labile drug, these core forming interactions disappear, and nanotubes can fall apart and undergo clearance. Herein, we explore the self-assembly, in vitro efficacy and in vivo pharmacokinetic and anti-tumour pharmacodynamics of these nanotubes in colorectal cancer models, comparing the potent topoisomerase inhibitor SN-38 with its clinically-used parent pro-drug irinotecan.

Machine learning assisted classification of cell and brain penetrating peptides

Fri, 29 Aug 2025 11:28:00 GMT

Great collaboration with Seb Perrier and Gabriele Sosso from Warwick Chemistry. Vito's first paper from his PhD work in the IBR MRCDTP.

Crossing the blood-brain barrier (BBB) remains a major obstacle for central nervous system therapeutics. Short peptides have emerged as promising vectors, including cell-penetrating peptides (CPPs) and brain-penetrating peptides (BPPs). However, the structural and physicochemical features that distinguish CPPs from BPPs remain poorly understood, limiting rational design. Here, we systematically analysed their amino acid composition, sequence distribution, and physicochemical descriptors. Our findings suggest that BBB penetration is not a simple extension of cell penetration but requires finely tuned physicochemical properties. This study provides mechanistic insights into BPP design and highlights machine learning as a valuable tool for engineering next-generation BBB-penetrating peptides and peptide-mimetic materials.

Organometallic Anticancer Complexes with Activated Ligands

Mon, 12 May 2025 08:45:00 GMT

New study from Ed Lant's PhD project, entitled "Tuning Ligand Substituents for Enhanced Catalytic Activity and Antiproliferative Effects in Rh(III) Azopyridine Complexes".

We report the synthesis and characterisation of ten novel half-sandwich Rh(III) azopyridine complexes as potential anticancer agents, with the general formula [Rh(η5-Cpx)(4-R2-phenylazopy-5-R1)Cl]PF6, where Cpx = Cp*, CpxPh or CpxPhPh, R1 = H, Br, or CF3, and R2 = H, OH or NMe2. X-ray crystallographic data for complex 2 (R1 = Br, R2 = OH, Cpx = CpxPh) and complex 3 (R1 = CF3, R2 = OH, Cpx = CpxPh) confirm their typical half-sandwich “piano-stool” geometry. The substituents have a major effect on the cytotoxicity of these complexes towards human ovarian (A2780 and cisplatin-resistant A2780cis), lung (A549), prostate (PC-3) and breast (MCF-7) cancer cells, and non-cancerous human lung fibroblasts (MRC5). Potencies range from sub-micromolar to inactive within the concentration range investigated (<100 µM). Selectivity for cancer cells over non-cancerous cell is strongly dependent on the nature of the bidentate ligand. The nano-molar active, highly lipophilic complex 2 was strongly accumulated by cells, and catalyzed the oxidation of NADH to NAD+, and GSH to GSSG. Notably, complex 2 is almost an order of magnitude less toxic in vivo than cisplatin. These complexes appear to have an unusual mechanism of anticancer activity, associated not only with Rh(III) but also the azo bond and activated cyclopentadienyl methyl groups.

A clock in mammalian cells modulates bacterial cellular entry

Tue, 06 May 2025 21:10:00 GMT

Title:

The cellular mammalian clock regulates Staphylococcus aureus invasion in epithelial cells

Authors:

Pooja Agarwal, Giridhar Chandrasekharan, Jaspreet Grewal, Robert Dallmann, and Meera Unnikrishnan

An endogenous biological clock, the circadian clock, coordinates life with the 24-hour day/night cycle of the environment. The unit of this circadian clock is the cell but in multicellular organisms, such as mammals, a circadian timing system (CTS) with a central pacemaker orchestrates peripheral clocks and the overall finely tuned temporal order. For example, the CTS changes immune responses to infections depending on time-of-day, however, its role in controlling bacterial infections at a cellular level is not understood.

In this study, we investigated the role of the host cellular clock during infection by Staphylococcus aureus, a highly drug-resistant, facultatively intracellular human pathogen. Our findings revealed that S. aureus invasion into epithelial cells is dependent on the cellular circadian phase. Interestingly, in BMAL1, an essential clock protein, deficient cells bacterial uptake was significantly higher compared to parental A549 cells. RNA sequencing of BMAL1 knockdown (KD) cells showed a significant upregulation of GP340, coding for the receptor of SraP, an S. aureus adhesin. An S. aureus mutant lacking SraP did not exhibit a circadian rhythm of uptake into A549 cells nor an increased uptake into BMAL1 KD compared to the parental A549 cells. Of note, bacterial mutants for other adhesins continued to show a rhythmic and higher uptake in BMAL1 KD cells.

Hence, we report that S. aureus invasion of epithelial cells is clock-modulated and mediated through S. aureus SraP, suggesting potential for host clock-directed therapy against this pathogen.

Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro

Wed, 09 Apr 2025 18:41:00 GMT

Great collaboration with Seb Perrier's group characterising the anti-inflammatory properties of anti-microbial polymers led by Sophie Laroque.

Antimicrobial polymers, which have emerged as a promising alternative to antibiotics in the fight against antimicrobial resistance, are based on the design of cationic host defence peptides (CHDPs). Being a part of the mammalian innate immune system, CHDPs possess both antimicrobial and immunoregulatory effects to manage bacterial infections. However, the immunomodulatory effects of antimicrobial polymers remain largely unexplored. Within this work, a library of 15 copolymers were synthesised by reversible addition-fragmentation chain transfer (RAFT) polymerisation and their abilities to modulate pro-inflammatory pathways in LPS-activated murine and human macrophages were investigated. We found that two diblock copolymers with cationic units copolymerised with either apolar or hydrophilic comonomers appeared to have anti-inflammatory activity through suppression of the activation of the NF-κB signalling pathway, scavenging of reactive oxygen species and reduced production of the pro-inflammatory cytokine IL-6. Furthermore, the cationic-apolar copolymer exhibits
significant antimicrobial activity against P. aeruginosa. Thus, this promising copolymer holds potential as a dual-action therapeutic, effectively combating bacterial infections while curbing prolonged inflammation and thereby preventing sepsis at the site of infection.

Chronopharmacokinetics of the antidepressant paroxetine: an in vitro and in vivo approach

Tue, 01 Apr 2025 23:00:00 GMT

Led by the fantastic Soraia Silva as part of her PhD work in Ana Fortuna's lab at Coimbra University, this collaboration was published in Neuropharmacology now.

Soraia shows how time of day significantly influences how much of the antidepressant SSRI paroxetine gets into the brain after intranasal application.

The circadian rhythm influences homeostatic functions such as sleep, physical activity and food intake as well as pharmacotherapy, namely pharmacokinetics. To investigate the impact of the circadian rhythm on the pharmacokinetics of paroxetine, in vitro synchronized permeability studies were carried out in a tri-culture blood-brain barrier model. Paroxetine demonstrated lower apparent permeability when the cells were incubated at 24 h post-synchronization than at 36 h. Additionally, in vivo chronopharmacokinetic studies were performed in CD-1 female mice administered with paroxetine (5 mg/kg) by intranasal route in the early morning or evening. Paroxetine exposure in the brain was higher when it was administered at the beginning of the active phase (ZT13) compared with the rest phase (ZT1) (p<0.001), probably owing to the lower levels of P-glycoprotein expressed in the brain at the active phase (p<0.05). Since melatonin production depends on serotonin, its plasma concentrations were also assessed in vivo. The results demonstrated that melatonin concentrations increased 12 h after paroxetine nasal instillation at ZT13 (p<0.05), but remained unchanged at ZT1, suggesting that the drug effect is influenced by administration time.

In conclusion, the circadian rhythm impacted the pharmacokinetics of paroxetine, especially its distribution into the brain, the target organ. This emphasizes the importance of the time of administration in antidepressant dosing, highlighting its relevance for future studies.