The effects of subcellular localization of N-(2-hydroxypropyl)methacrylamide copolymer-Mce(6) conjugates in a human ovarian carcinoma

Photosensitizers, light-sensitive compounds. become activated upon illumina tion with a specific wavelength of light generating cytotoxic oxygen specie s. Due to the short half-life of singlet oxygen, the subcellular site of lo calization and excitation affects the type of cellular damage produced as w ell as cellular responses to different types of photodamage created within the cell, Here, we investigated the effects of N-(2-hydroxypropyl)methacryl amide (HPMA) copolymer-mesochlorin e(6) monoethylenediamine (Mce(6)) conjug ates localized to different subcellular compartments. Temperature was utili zed to achieve subcellular localization of conjugates and subcellular fract ionation was performed to confirm localization patterns of HPMA copolymer-M ce(6) conjugates. Cytotoxicity studies suggest plasma membrane and late end osomes were more sensitive to photodamage than lysosomal compartments as ob served by an approximate 2-fold decrease in the IC50 compared to lysosomall y accumulated conjugate. Releasing Mce(6) from the polymer backbone within lysosomal compartments significantly lowered the IC50 when compared to HPMA copolymer conjugates with Mce6 bound via a nondegradable linkage. These di fferences will prove useful in the future design of HPMA copolymer-Mce(6) c onjugates for the treatment of ovarian cancer. (C) 2001 Elsevier Science B. V. All rights reserved.