کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1426759 986827 2008 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Cellular accumulation and cytotoxicity of macromolecular platinum complexes in cisplatin-resistant tumor cells
موضوعات مرتبط
مهندسی و علوم پایه مهندسی مواد بیومتریال
پیش نمایش صفحه اول مقاله
Cellular accumulation and cytotoxicity of macromolecular platinum complexes in cisplatin-resistant tumor cells
چکیده انگلیسی

The development of resistance is one of the major limitations for the use of platinum (Pt) complexes in cancer chemotherapy. As reduced cellular uptake is a well-known resistance mechanism of cisplatin we explored the potential to overcome resistance in cisplatin-resistant A2780 ovarian carcinoma cells by means of macromolecular prodrugs exploiting endocytosis as alternative uptake mechanism.Two Pt–albumin (PL04–HSA, PL07–HSA) complexes and one Pt–polyethylene glycol complex (PEG10k-(Mal-Pt-DACH)2) were investigated. Intracellular platinum accumulation was quantified by FAAS. Cytotoxic activity was measured using the MTT assay. Endocytosis mechanisms were investigated by co-incubation experiments with bafilomycin A1 and methyl-β-cyclodextrin, inhibitors of the clathrin-mediated and caveolae-mediated endocytosis, respectively.Whereas the intracellular accumulation of the low molecular precursors PL04 and PL07 was reduced in the resistant cell variant, no difference between sensitive and resistant cells was observed for the three macromolecular complexes. In the presence of bafilomycin A1 intracellular accumulation of all investigated macromolecular complexes was decreased whereas methyl-β-cyclodextrin only affected the Pt–PEG complex. The Pt–PEG complex exhibited a higher cytotoxic activity than the albumin conjugates but also showed cross-resistance with cisplatin.In conclusion, cellular accumulation of macromolecular platinum complexes is not altered in cisplatin-resistant A2780 cells as these complexes enter the cells mainly via endocytotic pathways. Macromolecular platinum complexes specially designed to circumvent reduced cellular accumulation may be a promising approach to overcome cisplatin resistance.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Controlled Release - Volume 131, Issue 2, 21 October 2008, Pages 100–106
نویسندگان
, , , , ,