SMA-raloxifene for the management of castrate-resistant prostate cancer
|Institution:||University of Otago|
|Keywords:||castrate-resistant prostate cancer; raloxifene; nanomedicine; biodistribution|
|Full text PDF:||http://hdl.handle.net/10523/5683|
Castrate-resistant prostate cancer (CRPC) has a poor prognosis, and these tumours are refractory to conventional androgen deprivation therapy. In addition to androgen, oestrogen alone or combined with androgen induces abnormal growth and neoplastic transformation of the prostate, therefore, providing a secondary target. The selective oestrogen receptor modulator raloxifene elicits disease stabilisation in a small number of CRPC patients, and the encapsulation of raloxifene into a styrene copoly(maleic acid) micelle (SMA-raloxifene) shows the potential to improve its efficacy. Further investigation in the current study determined the greater in vitro cytotoxicity of SMA-raloxifene (5 μM) is a result of the higher intracellular internalisation compared to the free drug. This resulted in a 75% higher intracellular raloxifene concentration after 48 h in PC-3 cells. Additionally, raloxifene (10 μM) elicited a reduction in phosphorylation of proteins involved in cell proliferation, survival, and migration including Met, Akt, FAK, and Src to 29, 14, 17, and 45% of control expression, respectively, as evaluated by western blot. SMA-raloxifene elicited an even greater reduction in Met and Akt phosphorylation, reducing expression to 1 and 5% of control, respectively. The efficacy of SMA-raloxifene was then examined in a CRPC xenograft model with the hypothesis that the micelle would accumulate and be retained within the tumour for longer as a result of the enhanced permeability and retention effect. Male SCID mice (7-8 weeks) were subcutaneously implanted with PC-3 cells (1 x 106) bilaterally into the lower flank, and randomly allocated into treatment groups (n=8). Mice were treated weekly for 4 weeks via intravenous tail vein injection with the vehicle control, 1 or 5 mg/kg of free raloxifene, or 1 mg/kg of SMA-raloxifene. At the end of the treatment period, mice treated with 1 mg/kg of free raloxifene exhibited a reduction in tumour progression by 20%, and an equivalent dose of SMA-raloxifene reduced progression by 39%. 1 mg/kg of SMA-raloxifene reduced tumour progression equivalently to a dose of free raloxifene 5-fold higher (i.e. 5 mg/kg). Despite this reduction in tumour progression, treatment did not induce disease stabilisation. A biodistribution study was then conducted in a CRPC xenograft model as described above. It was concluded that SMA-raloxifene (5 mg/kg, i.v.) increased the retention of raloxifene within the tumour compared to the free drug, resulting in 69% higher intratumoural raloxifene concentration 24 h post-injection. This is likely to be a result of the higher internalisation of drug as demonstrated in vitro, as well as an increased stability and reduced metabolism of the drug within micelles. Overall, SMA-raloxifene significantly improved the drug’s efficacy towards CRPC cells in vitro and in vivo; however, optimisation of SMA-raloxifene is required to further potentiate treatment efficacy for the management of CRPC.