Co-reporter:Nicholas A. Williams, Jenna L. Bowen, Ghaith Al-Jayyoussi, Mark Gumbleton, Chris J. Allender, Jamie Li, Tim Harrah, Aditya Raja, and Hrishi B. Joshi
Molecular Pharmaceutics 2014 Volume 11(Issue 3) pp:673-682
Publication Date(Web):January 24, 2014
DOI:10.1021/mp400274z
Transurothelial drug delivery continues to be an attractive treatment option for a range of urological conditions; however, dosing regimens remain largely empirical. Recently, intravesical delivery of the nonsteroidal anti-inflammatory ketorolac has been shown to significantly reduce ureteral stent-related pain. While this latest development provides an opportunity for advancing the management of stent-related pain, clinical translation will undoubtedly require an understanding of the rate and extent of delivery of ketorolac into the bladder wall. Using an ex vivo porcine model, we evaluate the urothelial permeability and bladder wall distribution of ketorolac. The subsequent application of a pharmacokinetic (PK) model enables prediction of concentrations achieved in vivo. Ketorolac was applied to the urothelium and a transurothelial permeability coefficient (Kp) calculated. Relative drug distribution into the bladder wall after 90 min was determined. Ketorolac was able to permeate the urothelium (Kp = 2.63 × 10–6 cm s–1), and after 90 min average concentrations of 400, 141 and 21 μg g–1 were achieved in the urothelium, lamina propria and detrusor respectively. An average concentration of 87 μg g–1 was achieved across the whole bladder wall. PK simulations (STELLA) were then carried out, using ex vivo values for Kp and muscle/saline partition coefficient (providing an estimation of vascular clearance), to predict 90 min in vivo ketorolac tissue concentrations. When dilution of the drug solution with urine and vascular clearance were taken into account, a reduced ketorolac concentration of 37 μg g–1 across the whole bladder wall was predicted. These studies reveal crucial information about the urothelium’s permeability to agents such as ketorolac and the concentrations achievable in the bladder wall. It would appear that levels of ketorolac delivered to the bladder wall intravesically would be sufficient to provide an anti-inflammatory effect. The combination of such ex vivo data and PK modeling provides an insight into the likelihood of achieving clinically relevant concentrations of drug following intravesical administration.Keywords: intravesical; ketorolac; pharmacokinetics; stent; urothelium;
Co-reporter:Jenna L. Bowen, Marc A. Kelly, Mark Gumbleton, Philip R. Davies, Chris J. Allender
Tetrahedron Letters 2012 Volume 53(Issue 29) pp:3727-3730
Publication Date(Web):18 July 2012
DOI:10.1016/j.tetlet.2012.04.116
A straightforward method of creating a bifunctional support possessing pre-defined ratios of amine and chloromethyl groups based upon a controlled conversion of standard Merrifield resin is presented. It avoids the extensive optimisation of reactant concentrations and reaction conditions required by existing methods. Furthermore, it avoids increases in the spacer/linker length that lead to detrimental reductions in the rigidity of the grafted layer. The method will allow for efficient, predictable and reproducible co-immobilisation of molecular species.
Co-reporter:Oliver K. Castell;David A. Barrow;Ahmad R. Kamarudin;Chris J. Allender
Journal of Molecular Recognition 2011 Volume 24( Issue 6) pp:1115-1122
Publication Date(Web):
DOI:10.1002/jmr.1161
A contributing factor to the labored advance of molecularly imprinting as a viable commercial solution to molecular recognition needs is the absence of a standard and robust method for assessing and reporting on molecular imprinted polymer (MIP) performance. The diversity and at times inappropriateness of MIP performance indicators means that the usefulness of the literature back-catalogue, for predicting, elucidating or understanding patterns in MIP efficacy, remains largely inaccessible. We hereby put forward the case that the simple binding isotherm is the most versatile and useful method of assessing and reporting MIP function, allowing direct comparison between polymers prepared and evaluated in different studies. In this study we describe how to correctly plot and interpret a bound / free isotherm and show how such plots can be readily used to predict outcomes, retro-analyze data and optimize experimental design. We propose that by adopting the use of correctly constructed isotherms as the primary form of data representation researchers will enable inter-laboratory comparisons, promote good experimental design and encourage a greater collective understanding of molecular imprinting. Copyright © 2011 John Wiley & Sons, Ltd.
Co-reporter:Anna L. Hillberg;Keith R. Brain ;Chris J. Allender
Journal of Molecular Recognition 2009 Volume 22( Issue 3) pp:223-231
Publication Date(Web):
DOI:10.1002/jmr.935
Abstract
The aim of this work was to produce a thin, flexible and diffusion able molecularly imprinted polymeric matrix with good template accessibility. Membranes were prepared using a non-covalent molecular imprinting approach and their physical characteristics and binding capabilities investigated. Two materials were used, a poly(tri-ethyleneglycol dimethyacrylate-co-methyl methacrylate-co-methacrylic acid) copolymer containing 14% cross-linker and a monomer (g) to porogen (ml) ratio of 1:0.5 (A), and a blend of poly(TEGMA-co-MAA) and polyurethane (B). The polyurethane was added to improve membrane flexiblity and stability. The polymers were characterized using AFM, SEM and nitrogen adsorption, whilst binding was evaluated using batch-rebinding studies. For all membranes the specific surface area was low (<10 m2/g). MIP (A) films were shown to bind specifically at low concentrations but specific binding was masked by non-specific interactions at elevated concentrations. Selectivity studies confirmed specificity at low concentrations. KD approximations confirmed a difference in the population of binding sites within NIP and MIP films. The data also indicated that at low concentrations the ligand-occupied binding site population approached homogeneity. Scanning electron microscopy images of membrane (B) revealed a complex multi-layered system, however these membranes did not demonstrate specificity for the template. The results described here demonstrate how the fundamental parameters of a non-covalent molecularly imprinted system can be successfully modified in order to generate flexible and physically tolerant molecularly imprinted thin films. Copyright © 2009 John Wiley & Sons, Ltd.
Co-reporter:Chris Allender, Klaus Mosbach
Biosensors and Bioelectronics 2009 Volume 25(Issue 3) pp:539-542
Publication Date(Web):15 November 2009
DOI:10.1016/j.bios.2009.08.001
Co-reporter:Oliver K. Castell, Christopher J. Allender, David A. Barrow
Biosensors and Bioelectronics 2006 Volume 22(Issue 4) pp:526-533
Publication Date(Web):15 October 2006
DOI:10.1016/j.bios.2006.07.017
Molecularly imprinted polymers (MIPs) represent a class of artificial receptors that promise an environmentally robust alternative to naturally occurring biorecognition elements of biosensing devices and systems. However, in general, the performance of conventional MIPs in aqueous environments is poor. In the study reported here, this limitation has been addressed by the novel application of MIPs as a solvent extraction solid phase in a biphasic solvent system. This paper describes a previously unreported use of MIPs as solvent extraction reagents, their successful application to aqueous sample media and the opportunities for utilisation of this unique system in novel biosensing and separation procedures. This study demonstrates the development of a novel biphasic solvent system utilising MIP in the extracting phase to enhance both efficiency and selectivity of a simple two phase liquid extraction.Monodisperse propranolol imprinted polymer microspheres [p(divinylbenzene-co-methacrylic acid)] were prepared by precipitation polymerisation. Initially, the affinity of the polymers for (R,S)-propranolol was assessed by established techniques whereby the MIP demonstrated greater affinity for the template than did the non-imprinted control polymer (NIP). Importantly, MIP performance was also assessed using the novel dual solvent system. The depletion of (R,S)-propranolol from the aqueous phase into the polymer containing organic phase was determined. When compared to control extractions containing no polymer the presence of MIP in the extracting solvent phase resulted in an increased extraction of (R,S)-propranolol from the aqueous phase. Importantly, this extraction was significantly greater in the presence of MIP when compared to NIP.This unique principle generates opportunities for MIP based extractions and chemical enrichments in industrial applications, offering commercial, ecological and practical advantages to traditional solvent extraction techniques. The technique is readily transferable to analytical microsystems utilising MIP recognition elements generating promising opportunities for MIP based sensing of aqueous sample media.
Co-reporter:Nicholas A. Williams, Luke Barnard, Chris J. Allender, Jenna L. Bowen, ... Hrishi B. Joshi
The Journal of Urology (March 2016) Volume 195(Issue 3) pp:763-770
Publication Date(Web):1 March 2016
DOI:10.1016/j.juro.2015.10.066
PurposeWe compared the relative permeability of upper urinary tract and bladder urothelium to mitomycin C.Materials and MethodsEx vivo porcine bladder, ureters and kidneys were dissected out and filled with 1 mg ml–1 mitomycin C. At 60 minutes the organs were emptied and excised tissue samples were sectioned parallel to the urothelium. Sectioned tissue was homogenized and extracted mitomycin C was quantified. Transurothelial permeation across the different urothelia was calculated by normalizing the total amount of drug extracted to the surface area of the tissue sample. Average mitomycin C concentrations at different tissue depths (concentration-depth profiles) were calculated by dividing the total amount of drug recovered by the total weight of tissue.ResultsMitomycin C permeation across the ureteral urothelium was significantly greater than across the bladder and renal pelvis urothelium (9.07 vs 0.94 and 3.61 μg cm–2, respectively). Concentrations of mitomycin C in the ureter and kidney were markedly higher than those achieved in the bladder at all tissue depths. Average urothelial mitomycin C concentrations were greater than 6.5-fold higher in the ureter and renal pelvis than in the bladder.ConclusionsTo our knowledge we report for the first time that the upper urinary tract and bladder show differing permeability to a single drug. Ex vivo porcine ureter is significantly more permeable to mitomycin C than bladder urothelium and consequently higher mitomycin C tissue concentrations can be achieved after topical application. Data in this study correlate with the theory that mammalian upper tract urothelium represents a different cell lineage than that of the bladder and it is innately more permeable to mitomycin C.
