Abstract
Selective delivery of drugs to tumor cells can increase potency and reduce toxicity. In this study, we describe a novel recombinant chimeric protein, dsRBEC, which can bind polyIC and deliver it selectively into EGFR over-expressing tumor cells. dsRBEC, comprises the dsRNA binding domain (dsRBD) of human PKR (hPKR), which serves as the polyIC binding moiety, fused to human EGF (hEGF), the targeting moiety. dsRBEC shows high affinity towards EGFR and triggers ligand-induced endocytosis of the receptor, thus leading to the selective internalization of polyIC into EGFR over-expressing tumor cells. The targeted delivery of polyIC by dsRBEC induced cellular apoptosis and the secretion of IFN-β and other pro-inflammatory cytokines. dsRBEC-delivered polyIC is much more potent than naked polyIC and is expected to reduce the toxicity caused by systemic delivery of polyIC.
Highlights
Selective delivery of drugs to tumor cells can improve efficacy and reduce toxicity
We designed a chimeric protein vector, dsRBEC, for the targeted delivery of polyIC to Epidermal Growth Factor Receptor (EGFR) over-expressing tumor cells. This vector comprised the dsRNA binding domain (dsRBD) of human PKR fused via a linker to human EGF
In the present study we present the development of a novel, recombinant protein carrier, dsRBEC, to selectively deliver polyIC into EGFR over-expressing tumors. dsRBEC is a bifunctional protein, with a dsRBD to bind polyIC and an EGF domain to deliver the polyIC into EGFR over-expressing cells. dsRBEC effectively and selectively induced polyIC internalization into EGFR over-expressing cells, inducing cell death and cytokine secretion
Summary
Selectivity can be obtained by utilizing a drug vehicle that can distinguish between the targeted malignant cells and untargeted non-malignant cells. High specificity towards cancer can be programmed into recombinant proteins by fusing targeting moieties and drug binding moieties. One appropriate target is the Epidermal Growth Factor Receptor (EGFR), which is over-expressed in multiple types of human cancer and is usually associated with aggressive disease and low survival rate [1]. EGFR over-expression can be utilized to selectively deliver high quantities of polyinosine/polycytosine (polyIC) into tumor cells, while leaving normal cells unaffected, due to the low amounts of polyIC delivered. PolyIC is an attractive antitumor agent, as it can induce cancer cell apoptosis by activating Toll Like Receptor 3 (TLR3) in cancer cells [2,3,4,5,6]. TLR3 activation by polyIC triggers the induction of cytokines, PLOS ONE | DOI:10.1371/journal.pone.0162321 September 6, 2016
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