Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis

Abstract

The disruption of polynucleotide kinase/phosphatase (PNKP) in colorectal cancer (CRC) cells deficient in phosphatase and tensin homolog (PTEN) is expected to lead to the loss of cell viability by a process known as synthetic lethality. In previous studies, we have reported on the encapsulation of a novel inhibitor of PNKP, namely, A83B4C63, in polymeric micelles and its activity in slowing the growth of PTEN-deficient CRC cells as well as subcutaneous xenografts. In this study, to enhance drug delivery and specificity to CRC tumors, the surface of polymeric micelles carrying A83B4C63 was modified with GE11, a peptide targeting epidermal growth factor receptor (EGFR) overexpressed in about 70% of CRC tumors. Using molecular dynamics (MD) simulations, we assessed the binding site and affinity of GE11 for EGFR. The GE11-modified micelles, tagged with a near-infrared fluorophore, showed enhanced internalization by EGFR-overexpressing CRC cells in vitro and a trend toward increased primary tumor homing in an orthotopic CRC xenograft in vivo . In line with these observations, the GE11 modification of polymeric micelles was shown to positively contribute to the improved therapeutic activity of encapsulated A83B4C63 against HCT116-PTEN –/– cells in vitro and that of orthotopic CRC xenograft in vivo . In conclusion, our results provided proof of principle evidence for the potential benefit of EGFR targeted polymeric micellar formulations of A83B4C63 as monotherapeutics for aggressive and metastatic CRC tumors but at the same time highlighted the need for the development of EGFR ligands with improved physiological stability and EGFR binding.

Advances in active targeting of ligand-directed polymeric nanomicelles via exploiting overexpressed cellular receptors for precise nanomedicine

“…In another study, the outer shell of the nanomicelles was grafted with dodecapeptide GE11 to exploit EGFR so as to ameliorate deep tumor tissue internalization and retention. 28 Fabricated nanomicelles comprising-polyethylene oxide- block -polycaprolactone (PEO/ b /PCL) amphiphilic copolymer and PEO/ block /(α-benzyl carboxylate-ε-caprolactone)(PEO/ b /PBCL) amphiphilic copolymer were prepared via ring-opening polymerization. GE11-grafted nanomicelles were then conjugated with NIR dye Cy5.5 via azide–alkyne click chemistry 34 to form GE11-PEO/ b /PCL-Cy5.5 and GE11-PEO/ b /PBCL-Cy5.5 nanomicelles.…”

Recent Advances in Polycaprolactones for Anticancer Drug Delivery

“…Another study led by de Paiva et al on modifying the surface of polymeric micelles to improve the delivery and specificity of a new inhibitor of polynucleotide kinase/phosphatase (PNKP) to colorectal cancer (CRC) tumors [ 152 ]. To achieve this, a peptide called GE11 was used to target the epidermal growth factor receptor (EGFR) that is commonly overexpressed in about 70% of CRC tumors.…”

“…These results suggest the potential benefit of EGFR-targeted polymeric micellar formulations as monotherapeutics for aggressive and metastatic CRC tumors. However, they also highlight the need for the development of EGFR ligands with improved physiological stability and binding to EGFR [152]. Li et al have developed a cutting-edge solution to deliver doxorubicin and cypate to cancer cells [143].…”

EGFR-Targeted Cellular Delivery of Therapeutic Nucleic Acids Mediated by Boron Clusters

“…In normal cells, EGFR expression ranges from 4 × 10 4 to 10 5 receptors per cell [ 36 ], whereas epidermoid cell carcinoma lines (A431) express up to 2 × 10 6 EGFR molecules per cell [ 37 ]. Because of these properties, EGFR has been widely used for EGFR-mediated delivery of various medical agents, as demonstrated for nanoformulated photosensitizers [ 38 ], anticancer drugs [ 39 ], polyplexes [ 40 ], and other compounds. For example, Kim and others have shown that coupling cetuximab, an antibody against EGFR, to the liposomal surface enhances delivery of siRNA to target mice with SK-OV-3 tumor xenografts.…”