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Cellular accumulation and cytotoxicity of macromolecular platinum complexes in cisplatin-resistant tumor cells
- Source :
- Journal of Controlled Release. 131:100-106
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
Abstract
- 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 (PEG(10k)-(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 A(1) and methyl-beta-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 A(1) intracellular accumulation of all investigated macromolecular complexes was decreased whereas methyl-beta-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.
- Subjects :
- Organoplatinum Compounds
Cell Survival
Serum albumin
Pharmaceutical Science
Antineoplastic Agents
Endocytosis
Polyethylene Glycols
Cell Line, Tumor
medicine
Humans
MTT assay
Cytotoxicity
Serum Albumin
Cisplatin
Drug Carriers
Molecular Structure
biology
Chemistry
Hydrolysis
Spectrophotometry, Atomic
Serum Albumin, Bovine
DNA
In vitro
Biochemistry
Drug Resistance, Neoplasm
Cell culture
biology.protein
Fluorescein-5-isothiocyanate
Intracellular
medicine.drug
Subjects
Details
- ISSN :
- 01683659
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- Journal of Controlled Release
- Accession number :
- edsair.doi.dedup.....db6b4eeea31ce6ed78fbba75add5120d