1 research outputs found
Tumor-Penetrating Nanosystem Strongly Suppresses Breast Tumor Growth
Antiangiogenic
and vascular disrupting compounds have shown promise
in cancer therapy, but tend to be only partially effective. We previously
reported a potent theranostic nanosystem that was highly effective
in glioblastoma and breast cancer mouse models, retarding tumor growth
and producing some cures [Agemy, L. et
al. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 17450ā17455. Agemy, L. et
al. Mol. Ther. 2013, 21, 2195ā2204.]. The nanosystem consists of iron oxide NPs (ānanowormsā)
coated with a composite peptide with tumor-homing and pro-apoptotic
domains. The homing component targets tumor vessels by binding to
p32/gC1qR at the surface or tumor endothelial cells. We sought to
further improve the efficacy nanosystem by searching for an optimally
effective homing peptide that would also incorporate a tumor-penetrating
function. To this effect, we tested a panel of candidate p32 binding
peptides with a sequence motif that conveys tumor-penetrating activity
(CendR motif). We identified a peptide designated as Linear TT1 (Lin
TT1) (sequence: AKRĀGARĀSTA) as most effective in causing
tumor homing and penetration of the nanosystem. This peptide had the
lowest affinity for p32 among the peptides tested. The low affinity
may have moderated the avidity effect from the multivalent presentation
on nanoparticles (NPs), such that the NPs avoid getting trapped by
the so-called ābinding-site barrierā, which can hinder
tissue penetration of compounds with a high affinity for their receptors.
Treatment of breast cancer mice with the LinTT1 nanosystem showed
greatly improved efficacy compared to the original system. These results
identify a promising treatment modality and underscore the value of
tumor penetration effect in improving the efficacy tumor treatment