Stabilization of pluronic P-105 micelles for targeted nanoparticle drug delivery

Pluronic P-105 self assembles into micelles and can sequester hydrophobic drugs at concentrations above its critical micellar concentration (CMC). Pluronic micelles have also been shown to release drugs upon exposure to low frequency ultrasound. The relatively high CMC of Pluronic reduces its value as a drug carrier because the micelles dissolve upon dilution and release the sequestered drug. In this study a cross-linked, interpenetrating network of cross-linked N,N′-diethylacrylamide was used to stabilize the Pluronic micelles at concentrations below their CMC. The stabilized micelles, called “Plurogels”, provided an increased hydrophobic environment, compared to Pluronic, at sub-CMC concentrations as measured by the fluorescent probe diphenylhexatriene Pluronic P-105 and Plurogels were loaded with the anti-cancer drug Doxorubicin, which is fairly hydrophobic and partitions preferentially into the micellar cores. Low concentrations (0.1 to 0.4 wt%) of Pluronic provided no protection to human leukemia cells (HL-60), while the same concentrations of Plurogels temporarily protected the cells from Doxorubicin-mediated killing as measured by the trypan blue exclusion assay. The protection only lasted about 12 hours after which the rate of cell death was similar for Doxorubicin solutions containing low concentrations of either Pluronic P-105 or Plurogel solutions.; Exposure to low-frequency (70 kHz) ultrasound was found to substantially increase the killing of human leukemia cells (HL-60) in the presence of Doxorubicin loaded Plurogels and Pluronic P-105 micelles.; In-vitro cell studies and in-vivo rat studies revealed that the Plurogels were well tolerated by HL-60 cells and red blood cells in suspension and were not toxic to rats at concentrations up to 200 mg/kg of rat body weight.