Targeting of aluminum (III) phthalocyanine tetrasulfonate by use of internalizing monoclonal antibodies: Improved efficacy in photodynamic therapy

Maarten B. Vrouenraets, Gerard W M Visser, Marijke Stigter, Hugo Oppelaar, Gordon B. Snow, Guus A M S Van Dongen

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The use of monoclonal antibodies (MAbs) directed against tumor-associated antigens for targeting of photosensitizers is an interesting option to improve the selectivity of photodynamic therapy (PDT). Hydrophilic photosensitizers are most suitable for conjugation to MAbs because of their water solubility. The photosensitizer aluminum (III) phthalocyanine tetrasulfonate [AIPc(SO3H)4] has many ideal photochemical properties; however, because of its hydrophilicity, the free form of this sensitizer does not readily reach the critical intracellular target and, therefore, is ineffective in PDT. On the basis of our previous studies, we hypothesized that AIPc(SO3H)4 might be suitable for PDT when coupled to internalizing tumor-selective MAbs. In this study, a reproducible procedure is presented for coupling of AIPc(SO3H)4 to MAbs via the tetra-glycine derivative AIPc(SO2Ngly)4. Conjugation was performed to chimeric MAb (cMAb) U36 and murine MAbs (mMAb) E48 and 425 using a labile ester. Conjugates showed preservation of integrity and immunoreactivity and full stability in serum in vitro. At molar ratios >4, the solubility of the conjugates decreased. Data on the in vitro efficacy of PDT showed that in the chosen experimental setup the internalizing AIPc(SO2Ngly)4-mMAb 425 conjugate was about 7500 times more toxic to A431 cells than the free sensitizer (IC50s, 0.12 nM versus 900 nM). The AIPc(SO2Ngly)4-mMAb 425 conjugate was also more toxic than meta-tetrahydroxyphenylchlorin-mMAb 425 conjugates and free meta-tetrahydroxyphenylchlorin that had been tested previously (M. B. Vrouenraets et al., Cancer Res., 59: 1505-1513, 1999) in the same system (IC50s, 7.3 nM and 2.0 nM, respectively). Biodistribution analysis of AIPc(SO2Ngly)4-125I-labeled cMAb U36 conjugates with different sensitizer:MAb ratios in squamous cell carcinoma-bearing nude mice revealed selective accumulation in the tumor, although to a lesser extent than for the unconjugated 125I-labeled cMAb U36, whereas tumor:blood ratios were similar. These findings indicate that AIPc(SO3H)4 has high potential for use in PDT when coupled to internalizing tumor-selective MAbs.

Original languageEnglish
Pages (from-to)1970-1975
Number of pages6
JournalCancer Research
Issue number5
Publication statusPublished - 1 Mar 2001

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