| Prostate cancer is the most common malignancy and second leading cause of cancer-related deaths in men in the United States. Despite improved management of patients with early stage prostate cancer, the mortality rate is still high due to frequent relapse, progression and metastasis following current antiprostate cancer therapies. Recently, research evidences support the presence of a subpopulation of cancer stem cells (CSCs) with infinite self-renewal and differentiation abilities. These drug-resistant CSCs, surviving following traditional anticancer therapies, contribute to cancer recurrence and metastasis. Therefore, to overcome the failure of current therapies and improve prostate cancer patient outcomes, it is necessary to not only shrink the tumor mass, but also inhibit CSC growth and maintenance. To this end, we designed the combination macromolecular therapeutics containing two types of HPMA copolymer-drug conjugates: one effectively killing non-CSC bulk tumor cells, the other preferentially killing prostate CSCs.;Docetaxel, a first line chemotherapeutic agent for advanced prostate cancer, is employed in the bulk tumor cell-killing HPMA copolymer-drug conjugate. Cyclopamine (a hedgehog pathway inhibitor) or GDC-0980 (a PI3K/mTOR dual inhibitor), with antiprostate CSC activity, is incorporated in the CSC-killing conjugate. The two types of HPMA copolymer-drug conjugates were synthesized by RAFT (reverse addition-fragmentation chain-transfer) copolymerization, with well controlled molecular weight and narrow molecular weight distribution. The anti-CSC and antibulk tumor effects of individual and combination of the two HPMA copolymer-drug conjugates were evaluated in vitro and in vivo. The in vitro evaluations show that the CSC-killing conjugate decreased the relative amount of CD133+ prostate CSC enriched population and impaired prostasphere forming ability. On the other hand, HPMA copolymer-docetaxel conjugate failed to decrease the relative amount of CD133+ cancer cells. The combination treatment led to the strongest tumor growth inhibition in long-term. For the in vivo evaluations, single and combination treatment all inhibited tumor growth immediately in PC-3 prostate tumor bearing mice. However, only the combination therapy led to sustained tumor growth inhibition in long-term. The characterizations of residual tumor cells suggest a decreased proportion of CD133+ cells following combination therapy. |
