Antitumor activity of nanosponge-encapsulated camptothecin in human prostate tumors

Antitumor activity of nanosponge-encapsulated camptotechin in human prostate tumors Rosalba Minelli, Roberta Cavalli, Roberto Fantozzi, Chiara Dianzani, Piergiorgio Pettazzoni, Leigh Ellis, Li Shen and Roberto Pili Drug delivery technologies are new and powerful approaches to enhance the pharmacological properties of drugs by improving their availability and stability and by reducing their side effects. Camptothecin (CPT) is a potent DNA Topoisomerase I inhibitor that presents strong antitumoral efficacy in both hematological and epithelial malignancies. However, its use is limited because of its high degradability and weak solubility. Indeed, the structure of camptothecin presents a lactone ring that is subjected to hydrolysis in physiological conditions with consequent inactivation of the topoisomerase binding activity. In the present study a new formulation of CPT embedded in cyclodextrin-based nanosponges (CN-CPT) has been evaluated in vitro and in vivo on prostate cancer models. CN-CPT manifested a strong antitumoral efficacy revealed by MTT and colony forming assay on hormonal independent PC-3 and DU145 cells, significantly higher as compared to the same dose of free CPT. Moreover, cell cycle analysis and annexin V/PI staining showed that CN-CPT treatments induced significant apoptotic cell death at 1 nM (61.7% apoptotic cell death; p<<0.001), where free CTP (4.36% apoptotic cell death) was not effective. The efficacy of CN-CPT has been tested in vivo in PC3 and DU145 xenograft experiments that have confirmed a significant improvement of antitumoral activity of CN-CPT as compared to CPT. To evaluate possible antimetastatic activity of CPT, in vitro experiments of tumor cell adhesion to HUVECs as a model of endothelium and cell motility were performed. Results showed that CN-CPT is effective at lower doses compared to CPT in inducing inhibition of adhesion and motility. In order to evaluate whether androgen receptor signaling could affect the responsiveness to either CPT or CN-CPT the AR expressing murine models of prostate cancer (MYC-AD, PTEN8 and PTEN CAP8) have been used. Results showed that expression of functional AR diminished the efficacy of both CPT and CN-CPT. However the latter still exerted greater effects compared to CN-CPT. Taken together these results support the use of CPT and the development of nanotechnologies for drug delivery in the treatment of castrate refractory prostate cancer.