Question:

Tumors often show an immature and insufficient vascular network characterized by a loss of vessel hierarchy and an enhanced vascular permeability. These properties led to the idea of using nanoscaled drug carriers which show a forced extravasation in tumor vessel (EPR - enhanced permeability and retention effect). This study addresses to the question of how molecular properties of these drug carriers affect the uptake into the tumor cell.

Methods:

Fluorescence labeled HPMA-based polymers were synthetized with different molecular structures (hydrophilic HPMA homopolymers, amphiphilic HPMA-ran-LMA copolymers and HPMA- LMA block copolymers) and weights (low: ~10 kDa; high: 21-50 kDa). In addition, the large block copolymers were tagged with different amounts (1-11%) of PEG-2000 segments. The uptake in two different tumor cell lines (AT1 R-3327 prostate carcinoma, Walker-256 mammary carcinoma) was determined.

Results:

Pronounced differences of the uptake were seen between the two tumor lines with the Walker-256 cells taking up 5-10-times more than AT1 cells. In both cell lines the large polymers were accumulated stronger than the low molecular weight counterparts. Most prominently the uptake of the high molecular weight HPMA-ran-LMA copolymers was highest of all tested polymers. Finally, block copolymers containing 1% PEG-2000 showed much better uptake than the same polymer containing either none or more than 1% PEG.

Conclusions:

The study clearly indicates that the molecular structures of nanoscale drug carriers determine the cellular uptake probably due to differences in lipophilic segments. The data also show that the accumulation depends on the individual tumor cell line indicating that polymer drug carriers have to be adapted to individual tumors of each patient.