Small interfering RNA (
siRNA) targeted
therapeutics (STT) offers a compelling alternative to tradition medications for treatment of
genetic diseases by providing a means to silence the expression of specific aberrant
proteins, through interference at the expression level. The perceived advantage of
siRNA therapy is its ability to target, through synthetic
antisense oligonucleotides, any part of the genome. Although STT provides a high level of specificity, it is also hindered by poor intracellular uptake, limited blood stability, high degradability and non-specific immune stimulation. Since
serum proteins has been considered as useful vehicles for targeting
tumors, in this study we investigated the effect of incorporation of
human serum albumin (HSA) in branched
polyethylenimine (bPEI)-
siRNA polyplexes in their internalization in epithelial and endothelial cells. We observed that introduction of HSA preserves the capacity of bPEI to complex with
siRNA and
protect it against extracellular
endonucleases, while affording significantly improved internalization and silencing efficiency, compared to bPEI-
siRNA polyplexes in endothelial and metastatic
breast cancer epithelial cells. Furthermore, the uptake of the HSA-bPEI-
siRNA ternary polyplexes occurred primarily through a caveolae-mediated endocytosis, thus providing evidence for a clear role for HSA in polyplex internalization. These results provide further impetus to explore the role of
serum proteins in delivery of
siRNA.