Publications

@article{Woodhouse2023-wp,

title = {Quantification of drugs in brain and liver mimetic tissue models 

 using Raman spectroscopy},

author = {Nathan Woodhouse and Jan Majer and Peter Marshall and Steve Hood and Ioan Notingher},

year  = {2023},

date = {2023-03-01},

journal = {Appl. Spectrosc.},

volume = {77},

number = {3},

pages = {246\textendash260},

publisher = {SAGE Publications},

abstract = {Quantitative analysis of drug delivery with in biological 

 systems is an integral challenge in drug development. Analytical 

 techniques are important for assessing both drug target 

 delivery, target action, and drug toxicology. Using mimetic 

 tissue models, we have investigated the efficacy of Raman 

 spectroscopy in quantitative detection of alkyne group and 

 deuterated drugs in rat brain and rat liver tissue models. 

 Lasers with 671 nm and 785 nm wavelengths were assessed for 

 their feasibility in this application due to opposing relative 

 benefits and disadvantages. Thin tissue sections have been 

 tested as a practical means of reducing autofluorescent 

 background by minimizing out-of-focus tissue and therefore 

 maximizing photobleaching rates. Alkyne-tagged drugs were 

 quantitatively measured at 18 $±$ 5 μg/g drug/tissue mass 

 ratio in rat brain and at 34 $±$ 6 μg/g in rat liver. 

 Quantification calibration curves were generated for a range of 

 concentrations from 0-500 μg/g. These results show the 

 potential of Raman spectroscopy as a diffraction-limited 

 spatially resolved imaging technique for assessing drug delivery 

 in tissue applications.},

keywords = {Drug delivery, drug quantification, microscopy, Raman spectroscopy},

pubstate = {published},

tppubtype = {article}

}

@article{Rahman2023-fy,

title = {Childhood brain tumors: A review of strategies to translate 

 CNS drug delivery to clinical trials},

author = {Ruman Rahman and Miroslaw Janowski and Clare L Killick-Cole and William G B Singleton and Emma Campbell and Piotr Walczak and Soumen Khatua and Lukas Faltings and Marc Symons and Julia R Schneider and Kevin Kwan and John A Boockvar and Steven S Gill and J Miguel Oliveira and Kevin Beccaria and Alexandre Carpentier and Michael Canney and Monica Pearl and Gareth J Veal and Lisethe Meijer and David A Walker},

year  = {2023},

date = {2023-01-01},

journal = {Cancers (Basel)},

volume = {15},

number = {3},

pages = {857},

publisher = {MDPI AG},

abstract = {Brain and spinal tumors affect 1 in 1000 people by 25 years of 

 age, and have diverse histological, biological, anatomical and 

 dissemination characteristics. A mortality of 30-40% means the 

 majority are cured, although two-thirds have life-long 

 disability, linked to accumulated brain injury that is acquired 

 prior to diagnosis, and after surgery or chemo-radiotherapy. 

 Only four drugs have been licensed globally for brain tumors in 

 40 years and only one for children. Most new cancer drugs in 

 clinical trials do not cross the blood-brain barrier (BBB). 

 Techniques to enhance brain tumor drug delivery are explored in 

 this review, and cover those that augment penetration of the 

 BBB, and those that bypass the BBB. Developing appropriate 

 delivery techniques could improve patient outcomes by ensuring 

 efficacious drug exposure to tumors (including those that are 

 drug-resistant), reducing systemic toxicities and targeting 

 leptomeningeal metastases. Together, this drug delivery strategy 

 seeks to enhance the efficacy of new drugs and enable 

 re-evaluation of existing drugs that might have previously 

 failed because of inadequate delivery. A literature review of 

 repurposed drugs is reported, and a range of preclinical brain 

 tumor models available for translational development are 

 explored.},

keywords = {blood-brain barrier, brain tumor model, childhood brain tumors, companion animal, Drug delivery, drug repurposing, preclinical, xenograft},

pubstate = {published},

tppubtype = {article}

}

@article{McCrorie2022-ls,

title = {Detection of label-free drugs within brain tissue using orbitrap 

 secondary ion mass spectrometry as a complement to 

 neuro-oncological drug delivery},

author = {Phoebe McCrorie and Jonathan Rowlinson and David J Scurr and Maria Marlow and Ruman Rahman},

year  = {2022},

date = {2022-03-01},

journal = {Pharmaceutics},

volume = {14},

number = {3},

pages = {571},

publisher = {MDPI AG},

abstract = {Historically, pre-clinical neuro-oncological drug delivery 

 studies have exhaustively relied upon overall animal survival as 

 an exclusive measure of efficacy. However, with no adopted 

 methodology to both image and quantitate brain parenchyma 

 penetration of label-free drugs, an absence of efficacy 

 typically hampers clinical translational potential, rather than 

 encourage re-formulation of drug compounds using nanocarriers to 

 achieve greater tissue penetration. OrbiSIMS, a next-generation 

 analytical instrument for label-free imaging, combines the high 

 resolving power of an OrbiTrapTM mass spectrometer with the 

 relatively high spatial resolution of secondary ion mass 

 spectrometry. Here, we develop an ex vivo pipeline using 

 OrbiSIMS to accurately detect brain penetration of drug 

 compounds. Secondary ion spectra were acquired for a panel of 

 drugs (etoposide, olaparib, gemcitabine, vorinostat and 

 dasatinib) under preclinical consideration for the treatment of 

 isocitrate dehydrogenase-1 wild-type glioblastoma. Each drug 

 demonstrated diagnostic secondary ions (all present molecular 

 ions [M-H]− which could be discriminated from brain analytes 

 when spiked at \>20 µg/mg tissue. Olaparib/dasatinib and 

 olaparib/etoposide dual combinations are shown as exemplars for 

 the capability of OrbiSIMS to discriminate distinct drug ions 

 simultaneously. Furthermore, we demonstrate the imaging 

 capability of OrbiSIMS to simultaneously illustrate label-free 

 drug location and brain chemistry. Our work encourages the 

 neuro-oncology community to consider mass spectrometry imaging 

 modalities to complement in vivo efficacy studies, as an 

 analytical tool to assess brain distribution of systemically 

 administered drugs, or localised brain penetration of drugs 

 released from micro- or nano-scale biomaterials.},

keywords = {Drug delivery, Glioblastoma, mass spectrometry imaging, OrbiSIMS},

pubstate = {published},

tppubtype = {article}

}

@article{McCrorie2020-ag,

title = {Biomedical engineering approaches to enhance therapeutic 

 delivery for malignant glioma},

author = {Phoebe McCrorie and Catherine E Vasey and Stuart J Smith and Maria Marlow and Cameron Alexander and Ruman Rahman},

year  = {2020},

date = {2020-12-01},

journal = {J. Control. Release},

volume = {328},

pages = {917\textendash931},

publisher = {Elsevier BV},

abstract = {We review the challenges of next-generation therapeutics for 

 both systemic and localised delivery to brain tumours and 

 discuss how recent engineering advances may be used to enhance 

 brain penetration of systemic delivery therapies. The unmet 

 clinical need which drug delivery seeks to address is discussed 

 with reference to the therapy obstacles that the intra-tumour 

 heterogeneity of glioma present. The unmet chemistry and 

 biomedical engineering challenge to develop controlled release 

 therapeutics is appraised, with commentary on current 

 success/failures in systemic carrier-mediated delivery, 

 including receptor-targeted, cell-based, blood-brain-barrier 

 disrupting and MRI-guided focused ultrasound. Localised 

 therapeutic delivery is a relatively under-studied research 

 avenue and is discussed with reference to existing technologies 

 in preclinical development. These include convection-enhanced 

 delivery, alternative catheter delivery, and neuro-surgically 

 applied delivery systems such as polymeric hydrogels and 

 interstitial spray. A myriad of nano-scale therapeutic delivery 

 systems is emerging as potential future medicines for malignant 

 brain tumours. Such biomedically-engineered systems will 

 increasingly feature in next-generation neuro-oncological 

 clinical trials to deliver repurposed and experimental 

 therapeutics, aimed at achieving therapeutic drug concentrations 

 in the brain, with associated mortality and morbidity benefits 

 for patients.},

keywords = {blood-brain-barrier, brain tumour, Drug delivery, nanoparticles, Polymers, Receptor-targeting},

pubstate = {published},

tppubtype = {article}

}