Chemotherapy commonly used in the treatment of advanced
bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize
bladder cancer-specific nanometer-scale
micelles loaded with the chemotherapeutic drug
paclitaxel (PTX) and determine the anti-
tumor activity and toxicity.
Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight
cholic acid units at one terminus of
polyethylene glycol (PEG) and a
bladder cancer-specific targeting
peptide named PLZ4 at the other terminus. To synthesize
disulfide-crosslinked PLZ4 nanomicelles (DC-PNM),
cysteine was introduced between the
cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a
solution containing
sodium docecyl
sulfate (SDS). It was stable in a SDS
solution, but dissolved within 5 min after the addition of
glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-
tumor activity were determined in immunodeficient mice carrying patient-derived
bladder cancer xenografts (PDXs). After
intravenous administration, DC-PNM specifically targeted the
bladder cancer PDXs, but very little to the
lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame
cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d (p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS
solution, specifically targeted the
bladder cancer xenografts in vivo, and improved the anti-
cancer efficacy of PTX.