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

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 devel...

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Published inNanomedicine 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
LanguageEnglish
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
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Abstract 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]
AbstractList 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]
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.
Author Pisarevsky, Evgeny
Markovsky, Ela
Calderón, Marcelo
Tschiche, Harald Rune
Satchi-Fainaro, Ronit
Wedepohl, Stefanie
Eldar-Boock, Anat
Vossen, Laura Isabel
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Keywords Neural cell adhesion molecule
Neuroblastoma
Polymer-drug conjugates
Polyglycerol
Polymeric nanomedicines
Paclitaxel
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Snippet 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...
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SubjectTerms Neural cell adhesion molecule
Neuroblastoma
Paclitaxel
Polyglycerol
Polymer-drug conjugates
Polymeric nanomedicines
Title PEGylated dendritic polyglycerol conjugate targeting NCAM-expressing neuroblastoma: Limitations and challenges
URI https://dx.doi.org/10.1016/j.nano.2018.02.009
https://www.ncbi.nlm.nih.gov/pubmed/29471169
https://search.proquest.com/docview/2007984010
Volume 14
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