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Abstract
Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a chemotherapeutic drug widely used against many solid tumors. A pharmacokinetics study found that CDDP can bind to human serum albumin (HSA), which is the most abundant plasma protein in serum. HSA has the advantage of being a nanocarrier and can accumulate in tumors by passive targeting and active targeting mediated by the secreted protein acidic and rich in cysteine (SPARC). In this study, we investigated the possibility of using a CDDP-HSA complex (HSA-CDDP) as a SPARC-mediated therapeutic agent. To investigate the HSA-dependent therapeutic effect of HSA-CDDP, we used two types of U87MG glioma cells that express SPARC differently. HSA-CDDP was highly taken up in SPARC expressing cells and this uptake was enhanced with exogenous SPARC treatment in cells with low expression of SPARC. The cytotoxicity of HSA-CDDP was also higher in SPARC-expressing cells. In the tumor model, HSA-CDDP showed a similar tumor growth and survival rate to CDDP only in SPARC-expressing tumor models. The biosafety test indicated that HSA-CDDP was less nephrotoxic than CDDP, based on blood markers and histopathology examination. Our findings show that HSA-CDDP has the potential to be a novel therapeutic agent for SPARC-expressing tumors, enhancing the tumor targeting effect by HSA and reducing the nephrotoxicity of CDDP.

Affiliations

Cho Rong Park  1   2   3 , Hyo Young Kim  1   2 , Myung Geun Song  1   2   4 , Yun-Sang Lee  1   5 , Hyewon Youn  1   2   6 , June-Key Chung  1   2   3   4 , Gi Jeong Cheon  1   2   4   5   7 , Keon Wook Kang  1   2   3   4   5   6   8
1 Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea.
2 Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul 03080, Korea.
3 Department of Biomedical Sciences, Seoul National University Graduate School, Biomedical Science Building, Seoul 03080, Korea.
4 Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
5 Radiation Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
6 Cancer Imaging Center, Seoul National University Hospital, Seoul 03080, Korea.
7 Institute on Aging, Seoul National University, Seoul 08826, Korea.
8 Bio-MAX Institute, Seoul National University, Seoul 08826, Korea.