title: Novel approach of MALDI drug imaging, immunohistochemistry, and digital image analysis for drug distribution studies in tissues.
abstract: Drug efficacy strongly depends on the presence of the drug substance at the target site. As vascularization is an important factor for the distribution of drugs in tissues, we analyzed drug distribution as a function of blood vessel localization in tumor tissue. To explore distribution of the anticancer drugs afatinib, erlotinib, and sorafenib, a combined approach of matrix-assisted laser desorption/ionization (MALDI) drug imaging and immunohistochemical vessel staining was applied and examined by digital image analysis. The following two xenograft models were investigated: (1) mice carrying squamous cell carcinoma (FaDu) xenografts (ntumor = 13) were treated with afatinib or erlotinib, and (2) sarcoma (A673) xenograft bearing mice (ntumor = 8) received sorafenib treatment. MALDI drug imaging revealed a heterogeneous distribution of all anticancer drugs. The tumor regions containing high drug levels were associated with a higher degree of vascularization than the regions without drug signals (p < 0.05). When correlating the impact of blood vessel size to drug abundance in the sarcoma model, a higher amount of small vessels was detected in the tumor regions with high drug levels compared to the tumor regions with low drug levels (p < 0.05). With the analysis of coregistered MALDI imaging and CD31 immunohistochemical data by digital image analysis, we demonstrate for the first time the potential of correlating MALDI drug imaging and immunohistochemistry. Here we describe a specific and precise approach for correlating histological features and pharmacokinetic properties of drugs at microscopic level, which will provide information for the improvement of drug design, administration formula or treatment schemes.
authors.affiliation: Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health , 85764 Neuherberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Huber
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Borgmann
authors.forename: Zhoulei
authors.initials: Z
authors.lastname: Li
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D000069347:Erlotinib Hydrochloride; D005260:Female; D007150:Immunohistochemistry / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D012509:Sarcoma / Q000188:drug therapy; D000077157:Sorafenib; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D009536:Niacinamide; D000077716:Afatinib; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride