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Targeting of a hydrophilic photosensitizer by use of internalizing monoclonal antibodies: A new possibility for use in photodynamic therapy
Author(s) -
Vrouenraets Maarten B.,
Visser Gerard W.M.,
Loup Christophe,
Meunier Bernard,
Stigter Marijke,
Oppelaar Hugo,
Stewart Fiona A.,
Snow Gordon B.,
van Dongen Guus A.M.S.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20001001)88:1<108::aid-ijc17>3.0.co;2-h
Subject(s) - conjugate , photosensitizer , photodynamic therapy , monoclonal antibody , in vitro , internalization , biodistribution , chemistry , porphyrin , cytotoxicity , cell culture , biochemistry , conjugated system , antibody , verteporfin , pharmacology , biophysics , cell , biology , immunology , photochemistry , organic chemistry , polymer , retinal , mathematical analysis , genetics , mathematics , choroidal neovascularization
Coupling of photosensitizers to tumor‐selective monoclonal antibodies (MAbs) is an attractive option for improving the selectivity of photodynamic therapy (PDT). For this purpose, hydrophilic sensitizers would be most suitable because of their solubility in water. However, such sensitizers are known to be ineffective in PDT, probably because they cannot readily pass the cell membrane and reach the critical intracellular target. We used the model compound TrisMPyP‐ΦCO 2 H, a hydrophilic porphyrin derivative, to test the hypothesis that hydrophilic photosensitizers might become of therapeutic value when directed into the tumor cell by use of internalizing MAbs. TrisMPyP‐ΦCO 2 H was conjugated using a labile ester. Conjugates showed no impairment of integrity on SDS‐PAGE, full stability in serum in vitro , and optimal immunoreactivity when the sensitizer:MAb ratio was ≤3. At higher molar ratios, the solubility of the conjugates decreased. In vitro internalization experiments showed that TrisMPyP‐ΦCONH– 125 I‐cMAb U36 and TrisMPyPΦCONH– 125 I‐mMAb 425 conjugates were internalized by A431 cells, in contrast to TrisMPyP‐ΦCONH– 125 I‐mMAb E48 conjugates. Data on the in vitro efficacy of PDT with MAb‐conjugated TrisMPyP‐ΦCO 2 H showed that the internalizing cMAb U36 and mMAb 425 conjugates were phototoxic to A431 cells, while the non‐internalizing E48 conjugate and the unconjugated sensitizer were not. Biodistribution data of conjugates with sensitizer: 125 I‐cMAb U36 ratios varying from 1:1 to 3:1 in tumor‐bearing nude mice revealed selective accumulation in the tumor. Conjugates with higher molar ratios were cleared more rapidly from the blood than the unconjugated 125 I‐cMAb U36, resulting in lower tumor uptake but similar tumor‐to‐blood ratios. Our data suggest that hydrophilic photosensitizers might have therapeutic value when targeted to tumors by internalizing MAbs. Int. J. Cancer 88:108–114, 2000. © 2000 Wiley‐Liss, Inc.