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Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance.
- Source :
-
Journal of Controlled Release . Jun2016, Vol. 231, p94-102. 9p. - Publication Year :
- 2016
-
Abstract
- A poly( l -glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro , cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex. [ABSTRACT FROM AUTHOR]
- Subjects :
- *GLUTAMIC acid
*CISPLATIN
*DISULFIRAM
*CANCER cells
*LABORATORY mice
Subjects
Details
- Language :
- English
- ISSN :
- 01683659
- Volume :
- 231
- Database :
- Academic Search Index
- Journal :
- Journal of Controlled Release
- Publication Type :
- Academic Journal
- Accession number :
- 115366537
- Full Text :
- https://doi.org/10.1016/j.jconrel.2016.02.039