Metastatic bone disease is a detrimental stage in prostate cancer for which no satisfying treatment options exist to date. Prostate cancer progression is strongly promoted by tumour-associated inflammation in which tumour-associated macrophages (TAM) play a prominent role by the secretion of growth-, inflammatory- and angiogenic factors. Angiogenic factors induce tumour angiogenesis and these chaotically organised blood vessels are typically characterised by enhanced vascular leakage. This characteristic can be exploited by the use of nanomedicinal drug delivery systems (i.e. liposomes). The long circulation time of liposomes, in combination with the leaky tumour vasculature, leads to efficient localisation and retention of these nanoparticles at the metastatic microenvironment, which is also referred to as the enhanced permeability and retention (EPR)-effect. After extravasation to the tumour microenvironment, liposomes are typically taken up by pro-inflammatory TAM. In this study, we evaluated the antitumor efficacy of liposomal encapsulated dexamethasone, a glucocorticoid receptor-agonist with strong anti-inflammatory activity, in a preclinical in vivo model for prostate cancer bone metastasis (intra-tibial growth of luciferase-expressing PC-3M-Pro4 cells in 6-week old male Balb-c nu/nu mice). We found that liposomes localise efficiently at malignant bone lesions. Intravenous administration of both free- and liposomal dexamethasone displayed potent antitumour efficacy, suggesting that dampening the tumour-associated inflammation, presumably via silencing of pro-inflammatory TAM, leads to inhibition of tumour growth. Interestingly, we found that the liposomal formulation of dexamethasone significantly outperforms administration of free (non-encapsulated) dexamethasone. It is important to note that liposomal dexamethasone was found to be well-tolerated at therapeutically-active dosages in both tumour-bearing mice and healthy CD Sprague Dawley rats. Taken together, our findings warrant further clinical evaluation of liposomal dexamethasone in patients with advanced, metastatic, prostate cancer. Phase I clinical trials are now in preparation.
Disclosure: JMB is the CEO of Enceladus Pharmaceuticals, a company that produces liposomal dexamethasone. GS in member of the advisory board of Enceladus Pharmaceuticals. This study was supported by a grant from the NanoNextNL Drug Delivery programme 03D.01 and by the European Research Council (ERC Starting Grant-309494:NeoNaNo). JTB was supported by NWO (VENI-grant-916.131.10). GH and MM were supported by the Dutch Cancer Society (UL-2011-4030). HC was supported by PRONET (International innovation grant).