Publications
A complete up-to-date list of publications of Robert can be found on Google Scholar and full-texts might be available from the Warwick Research Active Portal (WRAP).
Cyclic Peptide – Polymer Conjugate Nanotubes for Delivery of SN-38 in Treatment of Colorectal Cancer Model
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. |
Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro
 |
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. |
Machine learning assisted classification of cell and brain penetrating peptides
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
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
|
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. |
|||||