Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance

• Published in: Journal of controlled release 2016-06, Vol.231, p.94-102
• Main Authors: Song, Wantong, Tang, Zhaohui, Shen, Na, Yu, Haiyang, Jia, Yanjie, Zhang, Dawei, Jiang, Jian, He, Chaoliang, Tian, Huayu, Chen, Xuesi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; bcl-2-Associated X Protein - metabolism; Cell Line, Tumor; Cell Survival; Cisplatin; Cisplatin - chemistry; Cisplatin - pharmacology; Cisplatin - therapeutic use; Combination; Disulfiram; Disulfiram - chemistry; Disulfiram - pharmacology; Disulfiram - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Female; Glutathione - metabolism; Heterografts; Humans; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Nanoparticles - chemistry; NF-kappaB-Inducing Kinase; Polyglutamic Acid - chemistry; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.02.039

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. [Display omitted]