Antiangiogenic
cancer therapy can be achieved through the targeted delivery of
antiangiogenic agents to the endothelial cells of
tumor neovasculature. In the present study, we developed a drug delivery system (DDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL)
peptides for
tumor neovasculature targeting drug delivery.
Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the
aldehyde poly(
ethylene glycol)-
poly(lactide) (
aldehyde-
PEG-PLA) block copolymer by ring opening polymerization. The nanoparticles loading
paclitaxel (PTX-NP) were fabricated using the O/W
emulsion and evaporation technique. K237
ligand, a
peptide that can bind to the KDR receptors predominantly expressed on the surface of
tumor neovasculature endothelial cells with high affinity and specificity and inhibit the
VEGF-KDR angiogenic signal pathway, was conjugated to the
aldehyde group of PEG chain using the N-terminal PEGylation technique. The K237 conjugated
paclitaxel-loaded nanoparticles (K237-PTX-NP) had a hydrodynamic diameter of 150 nm. The K237 density on nanoparticle surface was 474 and the mean distance between two neighboring PEG chains linked to
K237 peptide was 12 nm. The K237 conjugated nanoparticles could be significantly internalized by human umbilical vein endothelial cells (HUVEC) through the K237-KDR interaction, and this facilitated uptake led to the expected enhanced antiangiogenic activity shown by HUVEC proliferation, migration and tube formation compared to cells treated with the commercial formulation
Taxol and PTX-NP. The long-circulating property and the K237
ligand of K237-PTX-NP warranted rapid, long-term, and accurate in vivo
tumor neovasculature targeting, and thereafter the significant apoptosis of
tumor neovasculature endothelial cells and
necrosis of
tumor tissues of MDA-MB-231
breast tumors implanted in female BLAB/c nude mice. This nanoparticulate DDS offers a new strategy for
paclitaxel chemotherapy application and it could also be used to carry other chemotherapeutic drugs, genes, and
proteins with antiangiogenic activity for antiangiogenic
cancer therapy.