Abstract
Abstract Cisplatin (DDP) has been widely used in the treatment of different cancers. However, resistance to DDP limits its clinical application. Since reduced intracellular DDP accumulation is one of the main causes for DDP resistance, increasing the accumulation of DDP may overcome drug resistance. The folate receptor (FR) is overexpressed on the surface of many human tumors including breast, ovarian and lung cancer, but is found at low levels in normal tissues. In this study, folic acid (FA) was conjugated to heparin-DDP (FHDDP) nanoparticles to target FR. In vitro cellular uptake experiments showed that the accumulation of FHDDP nanoparticles in FR-expressing DDP-resistant KB-CP.5 cancer cells (selected from KB3-1 cells, and showing a 36-fold increase in resistance to DDP compared with KB3-1) was significantly higher than that of free DDP (9.31±2.2 ng Pt/106 cells vs 0.98±0.25 ng Pt/106 cells, Pt:0.5ug/ml, 4 hrs at 37°C). Further, the level of platinum DNA-adducts in the resistant cells treated with FHDDP nanoparticles was about 4-fold greater than in cells treated with free DDP (24.21±5.32 pg Pt/ug DNA vs 97.9±22.5 pg Pt/ug DNA). Nude mice bearing KB-CP.5 cell tumors receiving FHDDP nanoparticles (2.5mg/kg, tail vein injection, twice weekly, 5 times) showed enhanced antitumor effects as compared with mice treated with free DDP (tumor volume: 823±221mm3 vs 1450±392mm3, 21 days after treatment), while non-targeted heparin-DDP nanoparticles did not show significant difference compared with free DDP. Our results suggest that FHDDP nanoparticles have the potential to be used for overcoming DDP resistance.(This research was supported by the National Cancer Institute award 5 P50 CA128613) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4750. doi:1538-7445.AM2012-4750
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