Current treatments for
prostate cancer are still not satisfactory, often resulting in
tumor regrowth and
metastasis. One of the main reasons for the ineffective anti-
prostate cancer treatments is the failure to deplete
cancer stem-like cells (CSCs) - a subset of
cancer cells with enhanced tumorigenic capacity. Thus, combination of agents against both CSCs and bulk
tumor cells may offer better therapeutic benefits. Several molecules with anti-
cancer stem/progenitor cell activities have been under preclinical evaluations. However, their low solubility and nonspecific toxicity limit their clinical translation. Herein, we designed a combination macromolecular
therapy containing two
drug conjugates:
HPMA copolymer-
cyclopamine conjugate (P-CYP) preferentially toxic to
cancer stem/progenitor cells, and
HPMA copolymer-
docetaxel conjugate (P-DTX) effective in debulking the
tumor mass. Both conjugates were synthesized using RAFT (reversible addition-fragmentation chain transfer) polymerization resulting in narrow molecular weight distribution. The killing effects of the two conjugates against bulk
tumor cells and CSCs were evaluated in vitro and in vivo. In PC-3 or RC-92a/hTERT
prostate cancer cells, P-CYP preferentially kills and impairs the function of CD133+
prostate cancer stem/progenitor cells; P-DTX was able to kill bulk
tumor cells instead of CSCs. In a PC-3 xenograft mice model, combination of P-DTX and P-CYP showed the most effective and persistent
tumor growth inhibitory effect. In addition,
residual tumors contained less CD133+
cancer cells following combination or P-CYP treatments, indicating selective killing of
cancer cells with stem/progenitor cell properties.