Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature.
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.
Yu
De-Hong
DH
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
Lu
Qin
Q
Xie
Jing
J
Fang
Chao
C
Chen
Hong-Zhuan
HZ
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D002465:Cell Movement; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
D000447:Aldehydes; D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D004337:Drug Carriers; D010455:Peptides; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D017239:Paclitaxel