PEGylated dendritic polyglycerol conjugate targeting NCAM-expressing neuroblastoma: Limitations and challenges

• Published in: Nanomedicine Vol. 14; no. 4; pp. 1169 - 1179
• Main Authors: Vossen, Laura Isabel, Markovsky, Ela, Eldar-Boock, Anat, Tschiche, Harald Rune, Wedepohl, Stefanie, Pisarevsky, Evgeny, Satchi-Fainaro, Ronit, Calderón, Marcelo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018
• Subjects: Neural cell adhesion molecule; Neuroblastoma; Paclitaxel; Polyglycerol; Polymer-drug conjugates; Polymeric nanomedicines; Neural cell adhesion molecule; Neuroblastoma; Polymer-drug conjugates; Polyglycerol; Polymeric nanomedicines; Paclitaxel
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2018.02.009

Neural cell adhesion molecule (NCAM) is found to be a stem-cell marker in several tumor types and its overexpression is known to correlate with increased metastatic capacity. To combine extravasation- and ligand-dependent targeting to NCAM overexpressing-cells in the tumor microenvironment, we developed a PEGylated NCAM-targeted dendritic polyglycerol (PG) conjugate. Here, we describe the synthesis, physico-chemical characterization and biological evaluation of a PG conjugate bearing the mitotic inhibitor paclitaxel (PTX) and an NCAM-targeting peptide (NTP). PG-NTP-PTX-PEG was evaluated for its ability to inhibit neuroblastoma progression in vitro and in vivo as compared to non-targeted derivatives and free drug. NCAM-targeted conjugate inhibited the migration of proliferating endothelial cells, suggesting it would be able to inhibit tumor angiogenesis. The targeting conjugate provided an improved binding and uptake on IMR-32 cells compared to non-targeted control. However, these results did not translate to our in vivo model on orthotopic neuroblastoma bearing mice. Neural cell adhesion molecule (NCAM) is a stem-cell marker overexpressed in several tumor types. Amongst them is neuroblastoma, the deadliest tumor of childhood malignancies. A PEGylated dendritic polyglycerol conjugate bearing the mitotic inhibitor paclitaxel and an NCAM-targeting peptide was developed to target and eradicate neuroblastoma. Despite an improvement of the targeting conjugate in cell culture, the targeting peptide showed no advantage in vivo. [Display omitted]