Polymer-
drug conjugates are growing in interest as novel
anticancer agents for targeted
cancer therapy. The aim of this study was to synthesize a poly(
ethylene glycol) (PEG) conjugated anticancer
drug for
neuroblastoma, which is the most common extracranial solid
tumor of childhood and the deadliest
tumor of infancy. In our previous studies, we designed and synthesized a dual targeting agent using
benzylguanidine (BG) conjugated with the high affinity thyrointegrin αvβ3 antagonist
TriAzole Tetraiodothyroacetic acid (TAT) via non-cleavable bonding to PEG400 to make BG-P400-TAT and its derivatives as agents against
neuroblastoma. Here, we improved the pharmacodynamic properties and increased the solubility by changing the
polymer length to 1600 molecular weight. The TAT group, which acts as an
integrin αvβ3 antagonist, and the BG group, which can be taken up by
neuroblastoma cells through the
norepinephrine transporter (NET) system, are conjugated to PEG1600 to make BG-PEG1600-TAT. The binding affinity of BG-PEG1600-TAT was 40-fold higher to
integrin αvβ3 versus BG-P400-TAT and was associated with greater anticancer activities against
neuroblastoma cells (SK-N-F1 and SKNAS) implanted in SCID mice along with broad spectrum anti-angiogenesis activities versus the FDA approved anti-
Vascular Endothelial Growth Factor (
VEGF)
monoclonal antibody Avastin (
bevacizumab). In conclusion, our novel dual targeting of NET and αvβ3 receptor antagonist, BG-P1600-TAT demonstrated broad spectrum anti-angiogenesis and anti-
cancer activities in suppressing
neuroblastoma tumor progression and
metastasis. Thus, BG-PEG1600-TAT represents a potential clinical candidate for targeted
therapy in
neuroblastoma management.