Tissue distribution and pharmacokinetics of an ATWLPPR-conjugated chlorin-type photosensitizer targeting neuropilin-1 in glioma-bearing nude mice.
Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). The PDT anti-vascular effect can be promoted by developing addressed photosensitizers localized preferentially to the tumor vascular compartment. A new photosensitizer conjugated to an heptapeptide [H-Ala-Thr-Trp-Leu-Pro-Pro-Arg-OH (ATWLPPR)] targeting neuropilin-1, a Vascular Endothelial Growth Factor (VEGF) co-receptor, has been synthesized. It was administered intravenously for an easier access to endothelial cells lining the vasculature in human malignant glioma-bearing nude mice. Plasma pharmacokinetic parameters were derived from plasma concentration-time data using a non-compartmental analysis and validated a relatively rapid elimination from the blood compartment with an elimination rate constant of 0.062 h(-1) and a biological half-life of 11.0 h. The photosensitizer was mainly concentrated in organs such as liver, spleen and kidneys, which are rich in reticuloendothelial cells. In these organs, the elimination profiles of the photosensitizer were comparable, with half-lives as short as 12.2, 15.1 and 19.7 h, respectively. The peptidic moiety of the conjugated photosensitizer was degraded to various rates depending on the organ considered, most of the degradation process occurred in organs of the reticuloendothelial system. A metabolic product resulting from the enzymatic cleavage of the peptide bond between Ala and Thr was detected in plasma at all the examined time points from 2 h post-injection. The conjugated photosensitizer accumulated rapidly and at high levels in the tumor, with 2.3% of injected dose per gram of tumor tissue at 1 h after injection. Taking into account the aspecific uptake of the degradation product, the tumor levels of total photoactivable compounds might exhibit an interesting photodynamic activity. On the contrary, levels of total photoactivable compounds remained low in the skin. This study provides essential information for the choice of the time interval not to exceed to activate the photosensitizer.
Thomas
Noémie
N
Centre de Recherche en Automatique de Nancy, Nancy-University, CNRS, Centre Alexis Vautrin, Brabois, Avenue de Bourgogne, F-54511, Vandoeuvre-lès-Nancy Cedex, France.
Tirand
Loraine
L
Chatelut
Etienne
E
Plénat
François
F
Frochot
Céline
C
Dodeller
Marc
M
Guillemin
François
F
Barberi-Heyob
Muriel
M
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D039942:Neuropilin-1 / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
D010455:Peptides; D017319:Photosensitizing Agents; D011166:Porphyrins; D039942:Neuropilin-1; C006969:chlorin