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In vitro and in vivo matrix metalloproteinase expression after photodynamic therapy with a liposomal formulation of aminolevulinic acid and its methyl ester

Abstract

Photodynamic therapy (PDT) is a well-known method for the treatment of malignant tumors, and its principles have been well established over the past 30 years. This therapy involves the application of a chemical called a photosensitizer and its subsequent excitation with light at the appropriate wavelength and energy. Topical photodynamic therapy with aminolevulinic acid (5-ALA) is an alternative therapy for many malignant processes, including nonmelanoma skin cancers such as basal-cell carcinoma (BCC). Our novel approach for this study was to use a liposomal formulation of 5-ALA and its methyl ester (commercially available as metvix) both in vitro and in vivo, and to check whether the liposome-entrapped precursors of photosensitizers can induce the expression of metalloproteinases (MMPs) in animal tumor cells and in other tissues from tumor-bearing rats and in selected cell lines in vitro. We also checked whether the application of tissue inhibitors of matrix metalloproteinases (TIMPs) has any effect on MMPs in the above-mentioned experimental models, and if they can cause complete inhibition of MMP expression. Immunohistochemical studies revealed that after the PDT, the intensity of expression of MMPs in healthy animals was very low and seen in single cells only. After the PDT in tumor-bearing rats, MMP-3 was expressed in the tumor cells with the highest intensity of staining in the tissues directly adjacent to the tumors, while MMP-2 and -9 were not found. In the control groups, there was no observed expression of MMPs. In vitro studies showed that MMP-3 was expressed in MCF-7 cells after PDT, but MMP-9 was not observed and MMP-2 was only seen in single cases. Our studies confirmed that the application of an MMP-3 inhibitor may block an induction of MMP-3 expression which had previously been initiated by PDT. The preliminary data obtained from cancer patients revealed that new precursors are effective in terms of PDT, and that using MMP inhibitors should be considered as a potential enhancing factor in clinical PDT.

Abbreviations

5-ALA:

aminolevulinic acid

BCC:

basal cell carcinoma

CNV:

choroidal neo-vascularization

CPI:

coproporphyrin I

GM-CSF:

granulocyte-macrophage colony stimulating factor

HNSCC:

head and neck squamous cell carcinoma

IL-1:

interleukin-1

met-ALA:

methyl ester of aminolevulinic acid

MMPs:

matrix metalloproteinases

m-THPC:

meso-tetra(hydroxyphenyl)chlorine

PDT:

photodynamic therapy

PPIX:

protoporphyrin IX

ROS:

reactive oxygen species

TIMPs:

tissue inhibitors of matrix metalloproteinases

VEGF:

vascular endothelial growth factor

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Correspondence to Piotr Ziółkowski.

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Key words

  • Photodynamic therapy
  • Aminolevulinic acid
  • Methyl aminolevulinate
  • Liposomes
  • Metalloproteinases