Improved treatments for
prostate cancer are in great need to overcome lethal recurrence and
metastasis. Targeting the tumorigenic cancer stem cells (CSCs) with self-renewal and differentiation capacity appears to be a promising strategy. Blockade of the hedgehog (Hh) signaling pathway, an important pathway involved in stem cell self-renewal, by
cyclopamine leads to long-term
prostate cancer regression without recurrence, strongly suggesting the connection between Hh pathway and prostate CSCs. Here we designed an
HPMA (N-(2-hydroxypropyl)methacrylamide)-based
cyclopamine delivery system as a CSC-selective macromolecular
therapeutics with improved
drug solubility and decreased systemic toxicity. To this end,
HPMA and N-methacryloylglycylphenylalanylleucylglycyl
thiazolidine-2-thione were copolymerized using the RAFT (reversible addition-fragmentation chain transfer) process, followed by
polymer-analogous attachment of
cyclopamine. The selectivity of the conjugate toward CSCs was evaluated on RC-92a/hTERT cells, the human
prostate cancer epithelial cells with human
telomerase reverse transcriptase transduction. The use of RC-92a/hTERT cells as an in vitro CSC model was validated by stem cell marker expression and prostasphere culture. The bioactivity of
cyclopamine was retained after conjugation to the
polymer. Furthermore,
HPMA polymer-conjugated
cyclopamine showed anti-CSC efficacy on RC-92a/hTERT cells as evaluated by decreased stem cell marker expression and CSC viability.