3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors

Our plain-English summary of 3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors, by S. Giordano, L. Morosi, P. Veglianese, et al (Scientific Reports, 2016).

The study

• Authors: S. Giordano, L. Morosi, P. Veglianese, S.A. Licandro, R. Frapolli, M. Zucchetti, G. Cappelletti, L. Falciola, V. Pifferi, S. Visentin, M. D'Incalci, E. Davoli
• Journal: Scientific Reports
• Published: 2016;6:37027
• Cited by: 68 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse.

In plain English

This laboratory study in mice developed a method to map, in three dimensions, where the cancer drug paclitaxel goes inside tumors. It did not study asbestos exposure. The authors grew a human malignant pleural mesothelioma tumor line, MPM487, which came from patient cells, under the skin of female nude mice. When tumors reached about 1000 mg, the mice received either a single intravenous dose of paclitaxel (60 mg/kg) or a drug-free control, and were killed 4 hours later. Each tumor was split in two. One half was cut into thin slices, imaged by mass spectrometry, and stacked into a 3D model. The other half was measured by a standard chemical method (HPLC). The drug was unevenly spread. It collected mostly at tumor edges, with less in scarred (fibrotic) and dead (necrotic) areas. In the tumor analyzed in detail, imaging estimated an average of 2.58 μg/g, compared with 6.09 μg/g by HPLC. The highest concentration range covered 0.21% of the tumor volume, and 37.67% had levels below detection (under 0.2 μg/g). The authors concluded that tumor structure shapes drug distribution and can limit therapy. They described their imaging concentrations as estimates rather than absolute measurements.

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 and laboratory methods development: 3D mass spectrometry imaging (MALDI MSI) of drug distribution in human mesothelioma tumors grown in mice, compared with HPLC measurement
• Who was studied: Female nude mice (NCr-Nu/Nu), six to seven weeks old, carrying MPM487, a human malignant pleural mesothelioma xenograft of biphasic type derived from patient cells, at the Mario Negri Institute, Milan, Italy. The number of mice and tumors is not stated. Table 1 reports one tumor.
• Exposure: The chemotherapy drug paclitaxel (not asbestos), given as a single intravenous dose of 60 mg/kg, or vehicle as a control, when tumors weighed about 1000 mg. Tumors were removed 4 hours after treatment.
• Main results:
  • In the 3D reconstructions, paclitaxel localized mainly at the edges of the tumors rather than in the core.
  • Lower drug signal matched fibrotic and necrotic regions of the tumor sections.
  • In the MPM487 tumor analyzed in Table 1, the mean paclitaxel concentration estimated by imaging was 2.58 μg/g. HPLC gave 6.09 μg/g in the other half of the same tumor. The authors described these as the same order of magnitude.
  • In that tumor, the highest concentration range was reached in only 0.21% of the tumor volume.
  • In that tumor, 37.67% of the tissue had concentrations below the detection limit of 0.2 μg/g.
  • Drug concentration in some tumor volumes appeared about 500 times higher than in volumes not reached by the drug.
• The authors' conclusion: The authors concluded that the structural heterogeneity of the tumor microenvironment plays a role in drug distribution that can limit the success of therapy. They proposed 'pseudo-resistance' (cells not reached by enough drug) as a further explanation for treatment failure and relapse.
• Limitations the authors state:
  • Absolute quantification of paclitaxel was beyond the scope of the work. The imaging concentrations were estimates (semi-quantitative).

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm.

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