Human serum albumin (HSA) is the most abundant
plasma protein. The main reason for using HSA as a versatile tool for drug delivery is based on its ability to accumulate in
tumors. However, the mechanism of
albumin accumulation in
tumors is not yet clear. Many researchers using HSA as a
drug-carrier have focused on the passive
tumor targeting by enhanced permeability and retention (EPR) effect, while other investigators proposed that
albumin binding proteins mediate
albumin accumulation in
tumors. We investigated whether HSA accumulation in
tumors is mediated by the EPR effect or by secreted
protein acidic and rich in
cysteine (SPARC), which is known to be an
albumin-
binding protein. Methods: To investigate the role of SPARC on HSA accumulation in
tumors, we compared HSA uptake in U87MG
glioblastoma cells with different SPARC expression. U87MG cells generally express high levels of SPARC and were, therefore, used as SPARC-rich cells. SPARC-less U87MG (U87MG-shSPARC) cells were established by viral-shSPARC transduction. We detected cellular uptake of fluorescence-labeled HSA by confocal microscopy in U87MG and U87MG-shSPARC cells. To demonstrate the mechanism of HSA accumulation in
tumors, we injected FNR648-labeled HSA and
FITC-labeled
dextran in U87MG and U87MG-shSPARC
tumor-bearing mice and observed their micro-distribution in
tumor tissues. Results: HSA was internalized in cells by binding with SPARC in vitro. HSA accumulation in U87MG
glioma was associated with SPARC expression in vivo.
FITC-dextran was distributed in U87MG
tumors in the vicinity of blood vessels. The distribution of HSA, on the other hand, was observed in the regions remote from blood vessels of U87MG
tumor tissues but not in U87MG-shSPARC
tumor tissues. Conclusion: Our results demonstrate that the
tumor-distribution of HSA is affected not only by the EPR-effect but also by SPARC expression. SPARC enhances HSA accumulation in U87MG
glioma and mediates active targeting of HSA in
tumors.