Journal
JOURNAL OF DRUG TARGETING
Volume 24, Issue 5, Pages 441-449Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/1061186X.2015.1086360
Keywords
raloxifene; nanomedicine; Biodistribution; enhanced permeability and retention effect; castrate resistant prostate cancer
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Funding
- Otago Medical Research Foundation
- Genesis Oncology Trust
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Background: Castrate-resistant prostate cancer (CRPC) patients are characterised by a 5-year relative survival rate of similar to 25-33%. Recently, our laboratory encapsulated a selective oestrogen receptor modulator, raloxifene, into poly(styrene-co-maleic acid) (SMA-raloxifene), which demonstrated superior in vitro cytotoxicity compared with free drug against several CRPC cell lines. Purpose: To validate SMA-raloxifene for the management of CRPC using a mouse xenograft model. Methods: The internalisation and retention of micellar and free raloxifene in vitro were measured by HPLC. A PC3-CRPC xenograft model was used to compare the biodistribution of both raloxifene formulations, as well as their effect on tumour progression where mice received free raloxifene (1 or 5 mg/kg, i.v.) or SMA-raloxifene (1 mg/kg, i.v.) weekly for 4 weeks. Results: SMA-raloxifene exhibited 75% higher intracellular content compared to free drug after 48 h in PC3 cells. Biodistribution of raloxifene was 69% higher in tumours following SMA-raloxifene compared with free raloxifene. Weekly administration of 1 mg/kg free raloxifene reduced tumour progression by 20% after 4 weeks, whereas 1 mg/kg SMA-raloxifene and 5 mg/kg free raloxifene reduced progression by 40%. Conclusion: Encapsulation of raloxifene increased its therapeutic potential for the management of CRPC.
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