Abstract
Recombinant MrNV capsid protein has been shown to effectively deliver plasmid DNA and dsRNA into Sf9 insect cells and shrimp tissues. To extend its application to cancer cell-targeting drug delivery, we created three different types of chimeric MrNV virus-like particles (VLPs) (R-MrNV, I-MrNV, and E-MrNV) that have specificity toward the epidermal growth factor receptor (EGFR), a cancer cell biomarker, by incorporating the EGFR-specific GE11 peptide at 3 different locations within the host cell recognition site of the capsid. All three chimeric MrNV-VLPs preserved the ability to form a mulberry-like VLP structure and to encapsulate EGFP DNA plasmid with an efficiency comparable to that previously reported for normal MrNV (N-MrNV). Compared to N-MrNV, the chimeric R-MrNV and E-MrNV carrying the exposed GE-11 peptide showed a significantly enhanced binding and internalization abilities that were specific towards EGFR expression in colorectal cancer cells (SW480). Specific targeting of chimeric MrNV to EGFR was proven by both EGFR silencing with siRNA vector and a competition with excess GE-11 peptide as well as the use of EGFR-negative colorectal cells (SW620) and breast cancer cells (MCF7). We demonstrated here that both chimeric R-MrNV and E-MrNV could be used to encapsulate cargo such as exogenous DNA and deliver it specifically to EGFR-positive cells. Our study presents the potential use of surface-modified VLPs of shrimp virus origin as nanocontainers for targeted cancer drug delivery.
Highlights
Among several delivery systems at the nanoscale, virus-like particles (VLPs) designed from capsid proteins of many non-enveloped viruses are considered the most outstanding biomaterials that that surpass other biological containers[1]
It is probable that this protruded GE11 peptide may impair the general cellular binding of the Macrobrachium rosenbergii nodavirus (MrNV) in some circumstances. Overall these results showed that replacing a portion of the P-domain with GE11 peptide or adding the GE11 as an extension to the P-domain can enhance the ability of MrNV VLPs to bind to cancer cells
For the epidermal growth factor receptor (EGFR)-knockdown cells treated with EGFP-loaded R-MrNV and E-MrNV, the levels EGFP-positive cells reduced markedly (p < 0.001), with 60% less EGFP- expressing cells than the siLuc control counterpart (Fig. 6D). These results clearly demonstrated that the chimeric R-MrNV and E-MrNV VLPs delivered the cargo with high specificity to EGFR-positive cancer cells
Summary
Among several delivery systems at the nanoscale, virus-like particles (VLPs) designed from capsid proteins of many non-enveloped viruses are considered the most outstanding biomaterials that that surpass other biological containers[1] This is due to their excellent physical properties such as self-assembling to form nano-sized symmetrical particles, controllable disassembly/reassembly, and practical surface functionality modifications through either chemical modification or genetic reengineering[2]. Exterior modification is aimed for either triggering immune response of the host cells or enhancing specific recognition of VLPs towards the desirable targeted cells or tissues[3]. The latter has been extensively reported with the objective to deliver therapeutic compounds into the targeted cancer cells[4]. The resulting chimeric EGFR-targeting MrNV VLPs that we created exhibited great potential as nano-containers for targeted delivery of therapeutic compounds to cancer cells
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