Development of Novel Nanomedicines for Treatment of Primary and Metastatic Prostate Cancer.

Prostate cancer is the 2nd most common cancer among men worldwide. This thesis addresses current issues of prostate cancer therapy as focusing on development of novel therapeutic approaches for focal ablation of primary prostate cancer and ii) targeted chemotherapeutics of metastatic lesion in bone. We developed perfluorocarbon-loaded nanodroplets (NDs; average diameter 500µm in < 1microsececond when exposed to therapeutic ultrasound before they collapse, which proved to mechanically fractionate neighboring cells with high precision. The results show that 3D Prostate Cancer spheroids can be ablated with perfluorocarbon-loaded NDs below the pressure of the intrinsic gas pockets in in-vitro conditions. Successful development of these targeted NDs will be a significant paradigm shift in current treatment methods of prostate cancer as it will eliminate the need for surgical resection of the whole gland. We have developed “smart” particles that proved to deliver their chemotherapeutic cargo into the cytoplasm of prostate cancer cells in vitro. These particles were functionalized with two targeting ligands (pVTK-peptide and bisphosphonate (BP)) to actively target mineralizing or hydrolyzing bone surfaces in prostate cancer lesions, respectively. We characterized the size of the bone targeted particles (60-90 nm) and confirmed their binding affinity towards bone hydroxyapatite powder. Further, we examined both bone-targeted nanoparticles uptake profiles into prostate cancer cell lines (PC-3 and C4-2B) and bone cell lines (MC3T3, RAW264.7 bone-macrophages, and RANKL-activated RAW264.7) on regular tissue culture plates as well as on bone-like surfaces (BLS). Results showed that increasing the number of BP-targeting copolymer in the particle formulation was able to augment the normalized particle fluorescence intensity in macrophages on a regular culture plate. Additionally, the results indicate that C4-2B and MC3T3 cells were effectively targeted by pVTK bone-targeted nanoparticles. While BP bone-targeted nanoparticles are capable of targeting PC-3 and RAW 264.7 cells. These results collectively indicate that pVTK-/BP-based bone targeting strategies can facilitate selective delivery of chemotherapeutic agents to metastatic prostate cancer in bone and the cross-talk between cancer cells and bone cells could be inhibited by using a specific targeting strategy (pVTK or BP), which opens doors to new personal bone metastasis therapies.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135816/1/biomer_1.pd