title: The effects of subcellular localization of N-(2-hydroxypropyl)methacrylamide copolymer-Mce(6) conjugates in a human ovarian carcinoma.
abstract: Photosensitizers, light-sensitive compounds, become activated upon illumination with a specific wavelength of light generating cytotoxic oxygen species. Due to the short half-life of singlet oxygen, the subcellular site of localization and excitation affects the type of cellular damage produced as well as cellular responses to different types of photodamage created within the cell. Here, we investigated the effects of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-mesochlorin e(6) monoethylenediamine (Mce(6)) conjugates localized to different subcellular compartments. Temperature was utilized to achieve subcellular localization of conjugates and subcellular fractionation was performed to confirm localization patterns of HPMA copolymer-Mce(6) conjugates. Cytotoxicity studies suggest plasma membrane and late endosomes were more sensitive to photodamage than lysosomal compartments as observed by an approximate 2-fold decrease in the IC(50) compared to lysosomally accumulated conjugate. Releasing Mce(6) from the polymer backbone within lysosomal compartments significantly lowered the IC(50) when compared to HPMA copolymer conjugates with Mce6 bound via a nondegradable linkage. These differences will prove useful in the future design of HPMA copolymer-Mce(6) conjugates for the treatment of ovarian cancer.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Room 301, Salt Lake City, UT 84112, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tijerina
authors.forename: P
authors.initials: P
authors.lastname: Kopecková
authors.forename: J
authors.initials: J
authors.lastname: Kopecek
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006801:Humans; D008652:Mesoporphyrins; D008689:Methacrylates / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011166:Porphyrins / Q000008:administration & dosage / Q000627:therapeutic use*; D017382:Reactive Oxygen Species; D013347:Subcellular Fractions / Q000378:metabolism*; D013696:Temperature; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008652:Mesoporphyrins; D008689:Methacrylates; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; C088297:meso-chlorin e(6) monoethylene diamine; C032802:hydroxypropyl methacrylate