Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models

Abstract

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.

Structure of the Complex of an Iminopyridinedione Protein Tyrosine Phosphatase 4A3 Phosphatase Inhibitor with Human Serum Albumin

“…Albumin is an endogenous carrier of many nutrients that are required to fulfil the needs of rapidly growing cancer cells and the energy demands of the tumor microenvironment (Hoogenboezem and Duvall, 2018;Park et al, 2019). Tumors are thought to accumulate consderable quantities of albumin as a consequence of at least two mechanisms: (a) the enhanced permeability and retention effect (Hoogenboezem and Duvall, 2018) and (b) albumin-binding protein and receptor-mediated accretion (Park et al, 2019). The fundamental principle involved in the enhanced permeability and retention effect is tumor vasculature hyperpermeability that allows albumin to extravasate and accumulate in the tumor interstitial space, which lacks fully functional lymphatic drainage.…”

“…the tumor vascular endothelium and endocytosis into tumor cells using an assortment of albumin-binding proteins, including SPARC, megalin, calreticulin, and albondin, which also contributes to the movement of nutrients and drugs into tumors. An important role for albumin-binding proteins has been illustrated, for example, by using short hairpin RNA to reduce SPARC in human cancer cells, which attenuates HSA accumulation (Park et al, 2019). The transcytosis and endocytosis of albumin requires functional caveolae and the protein caveolin-1, which is highly expressed in many tumor types (Hoogenboezem and Duvall, 2018).…”

Ceria-based nanotheranostic agent for rheumatoid arthritis

“…In the pathology of RA, various types of cells, including inflammatory cells (e.g., macrophages and T cells) and vascular endothelial cells, are activated and with an associated change expression of cell surface receptors, including those for scavenging albumin (gp18, gp30, SPARC, FcRn, gp60, the Megalin/Cubilin complex) 25 - 26 —these receptors increase endocytosis, transcytosis, and catabolism of albumin. Elevated gp60 and SPARC in the synovium fluid of RA patients and murine CIA model work to transports albumin across the endothelial barrier into the interstitium (Gp60) and SPARC enhances the uptake of albumin into immune cells in the RA synovium 24 , 26 . Albumin-based NPs can be taken up via the SPARC-mediated mechanism 60 and directly internalized by phagocytic cells via interactions with FcRn receptors, or after opsonization by IgG, and eventually sequestered within the endo-lysosomal compartment.…”

“…For example, gp60, glycoprotein 60, is overexpressed in the sera of patients with RA (RA mean concentration is 97 µg/mL relative to the normal mean concentration of 34 µg/mL), along with the Fc receptors being present at high levels in the phagocytic cells (macrophage, monocytes, dendritic cells) that are abundant at sites of inflammation 23 . Another albumin-binding protein, the secreted protein acidic and rich in cysteine (SPARC), also known as a glycoprotein of the extracellular matrix that binds albumin 24 , is overexpressed in RA synovial fluid and in murine collagen-induced arthritis (CIA) 25 - 27 . Gp60 and SPARC work in conjunction to transport albumin across the endothelial barrier to the interstitium and then translocate the protein into immune cells and cells of the synovium.…”

Albumin-Modified Melanin-Silica Hybrid Nanoparticles Target Breast Cancer Cells via a SPARC-Dependent Mechanism

“…SPARC is a secreted protein that binds albumin (albumin-binding protein) and is highly expressed in many cancers. Some studies have proposed the involvement of SPARC in the uptake of albumin in tumors ( Frei, 2011 ; Liu et al, 2015 ; Chlenski et al, 2016 ; Park et al, 2019 ) and in NPs internalization via HSA in cancer cells ( Hoang et al, 2015 ). Thanks to this feature, SPARC represents a good molecular target for the active NPs delivery.…”