Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging

Our plain-English summary of Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging, by S. Giordano, M. Zucchetti, A. Decio, et al (Scientific Reports, 2016).

The study

• Authors: S. Giordano, M. Zucchetti, A. Decio, M. Cesca, I. Fuso Nerini, M. Maiezza, M. Ferrari, S.A. Licandro, R. Frapolli, R. Giavazzi, D. Maurizio, E. Davoli, L. Morosi
• Journal: Scientific Reports
• Published: 2016;6:39284
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors.

In plain English

This was a laboratory experiment in mice, not an asbestos study. The authors tested an imaging method (MALDI mass spectrometry imaging) showing where the cancer drug paclitaxel goes in tumors. Female nude mice carried one of six human tumor models: three ovarian (HOC84, A2780-1A9, IGROV1), one colon, one breast (MDA-MB-231) and one malignant pleural mesothelioma (MPM484). Treated mice received one intravenous paclitaxel dose of 60 mg/kg, controls received vehicle only, and animals were euthanized 4 hours later. In the images, HOC84 had the most even spread of the drug, and MPM484 and MDA-MB-231 had the least even. Drug-positive pixels made up 82.17% of HOC84 images and 38.81% of MPM484 images. Measuring drug in ground-up tumor (HPLC) did not detect these differences. Only MDA-MB-231 was reported as significantly lower, but the one p-value given is labelled 'versus MDA 484', which matches no model name. Areas with little or no drug mainly matched dead (necrotic) and scarred (fibrotic) tissue. In the mesothelioma model, the highest-signal areas had 4.76 times more drug per square millimetre than the lowest-signal areas. The authors concluded that tumor structure seemed to influence drug distribution.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: human tumors grown in nude mice (xenografts), analyzed by MALDI mass spectrometry imaging, HPLC and histology
• Who was studied: Six- to eight-week-old female NCr-Nu/Nu nude mice bearing one of six human tumor models: ovarian HOC84, A2780-1A9 and IGROV1; colon HCT116; breast MDA-MB-231; and malignant pleural mesothelioma MPM484. Three to five tumors per group and three sections per tumor were analyzed, at the Mario Negri Institute, Milan, Italy.
• Exposure: The anticancer drug paclitaxel, given as a single 60 mg/kg intravenous dose to treated mice. Control mice received vehicle. Animals were euthanized 4 hours after treatment. No asbestos exposure was studied.
• Main results:
  • In the imaging, HOC84 showed the most even paclitaxel distribution. A2780-1A9, IGROV1 and HCT116 were uneven. The mesothelioma model MPM484 and the breast model MDA-MB-231 had the least uniform distribution.
  • Image analysis confirmed these differences. The percentage of pixels above background was 82.17% (n = 5) in HOC84, 68.75% (n = 5) in A2780-1A9, 64.83% (n = 4) in IGROV1, 60.42% (n = 3) in HCT116, 39.93% (n = 3) in MDA-MB-231 and 38.81% (n = 3) in MPM484. Each of the other models was significantly lower than HOC84.
  • HPLC of whole tumor homogenates did not detect the uneven distribution. Paclitaxel concentrations did not differ significantly among HOC84 (17.14 μg/g), A2780-1A9 (20.98 μg/g), IGROV1 (20.30 μg/g), HCT116 (21.86 μg/g) and MPM484 (16.19 μg/g). Only MDA-MB-231 (8.67 μg/g, n = 3) was reported as significantly lower. The single p-value given (0.014) is labelled 'versus MDA 484'. No model in the article has that name, so which comparison it refers to is not clear from the text.
  • In MDA-MB-231, drug penetration was both scant and irregular.
  • Comparing the images with stained adjacent sections, areas with scarce or absent drug signal corresponded mainly to necrotic and fibrotic regions in the models other than HOC84. In HOC84, fibrosis did not seem to prevent drug distribution at a macroscopic level.
  • In the mesothelioma model MPM484, the estimated amount of paclitaxel per mm2 in the highest-signal (red) zones was 4.76 times that in the lowest-signal (blue) zones and 2.09 times that in the intermediate (green) zones.
  • Normalizing the drug signal to a sprayed deuterated paclitaxel standard improved the linearity of the calibration curve. The R2 rose from 0.915 to 0.997.
• The authors' conclusion: The authors concluded that they had presented an accurate and reproducible imaging method for paclitaxel in tumor tissue. They found wide differences in how the drug spread within tumors, and the tumor's tissue structure (necrotic or fibrotic regions) seemed to influence where the drug went.
• Limitations the authors state:
  • The authors note that mass spectrometry imaging in general works only for molecules that can be ionized by the process, that quantitative interpretation is often complex, and that its sensitivity is limited compared with autoradiography.

Topics

Medical terms in this study, explained in our Lexicon: Ovarian Cancer, Colorectal Cancer, Pleural Mesothelioma.

Related studies

• 3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors — S. Giordano, L. Morosi, et al. (2016)
• Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma — M.D. Schulz, K.A. Zubris, et al. (2011)
• Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles — A.H. Colby, R. Liu, et al. (2016)
• Paclitaxel for malignant pleural mesothelioma: a phase II study of the EORTC Lung Cancer Cooperative Group — J. van Meerbeeck, C. Debruyne, et al. (1996)
• Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids — H. Lei, S.C. Hofferberth, et al. (2015)
• Unusually favorable outcome of 6 consecutive patients with diffuse malignant peritoneal mesothelioma treated with repeated doses of intraperitoneal paclitaxel. A case series — P.H. Sugarbaker, O.A. Stuart (2020)

Browse more research in Scientific Reports, or return to medical research.