Figure 4.

Rapid release from SDDS and uptake by tumor cells of idarubicin (IDA) results in high local drug levels and a steep intratumoral gradient compared to doxorubicin (DXR). (A) Schematic illustration of intravital microcopy of mice undergoing hyperthermia in combination with SDDS. (B, C) Imaging of heat-triggered release in a window chamber fixed on eNOS-Tag-GFP mice showing green vessels. Eighteen µmol/kg of IDA-SDDS (B) or DXR-SDDS (C) was injected followed by 1 h local hyperthermia and 30 min normothermia, showing intravascular release of drug (red) and the subsequent drug diffusion into interstitial space of tumor. Scale bar, 200 µm. (D, E) A 3-dimensional representation of intratumoral drug concentration, as a factor of time and penetration distance into tumor tissue from the nearest vessel, shows higher tumor uptake of IDA (D) than DXR (E) during the treatment course (insert represents DXR concentration at a smaller scale). Maximum uptake was reached earlier for IDA showing higher drug accumulation close to tumor vessels compared to DXR (n = 3 mice per group). (F) Online IDA and DXR uptake rates are calculated starting from 10 to 30 min during HT, after which IDA uptake enters a saturation state (n = 3 mice per group, Nonparametric Mann-Whitney test: *p < 0.01). (F) Drug efflux is calculated from the peak concentration to the beginning of the steady concentration. IDA shows around 15 min of drug efflux after which a steady concentration was maintained. (H, I) At specified time points, release and diffusion profiles of IDA-SDDS (H) and DXR-SDDS are depicted (I). Data are presented as mean ± SD.