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.
Highlights
Central nervous system (CNS) tumours are a major cause of cancer-related death in children and adults, with high grade invasive brain tumours showing a poor response and frequent high local recurrence rates despite multiple modes of therapy
OrbiSIMS has been applied to native brain analysis to detect the distribution of neurotransmitters [11], and we have recently demonstrated the ability of OrbiSIMS to identify metabolites which predict relapse in the malignant childhood brain tumour, ependymoma [12]
We have previously demonstrated a long-term survival benefit in high-grade glioma when etoposide is delivered interstitially post-surgery [3]; we have shown the feasibility of olaparib to be incorporated into nanoparticles within a sprayable hydrogel for interstitial brain tumour delivery [13]; vorinostat has recently shown to induce metabolic reprogramming in glioblastoma leading to extended animal survival [14]; gemcitabine significantly enhances glioblastoma survival in animals when delivered interstitially via a lipid nanocapsulebased hydrogel [15]; a recent genome sequencing data has proposed a patient stratification strategy for dasatanib, to potentially enhance therapeutic efficacy in clinical trials [16]
Summary
Central nervous system (CNS) tumours are a major cause of cancer-related death in children and adults, with high grade invasive brain tumours showing a poor response and frequent high local recurrence rates despite multiple modes of therapy. Conventional oral or intravenous chemotherapy distributes drugs to the whole body, whereby systemic toxicity to healthy parts of the body (e.g., bone marrow failure) limits the maximum dose that can be achieved in the brain. This presents a particular concern for CNS tumours where the blood–brain barrier (BBB) restricts drug influx from the circulation [1,2]. The ability to deliver chemotherapy locally at the tumour site offers the opportunity to target residual cancer cells post-surgery whilst minimising systemic toxicity. We have demonstrated that long-term survival benefits when chemotherapeutics are delivered interstitially post-neurosurgery, via incorporation into polymeric delivery systems [3–5].
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