The use of nanoparticulate delivery systems in metronomic chemotherapy.

Abstract

Metronomic chemotherapy aiming at inhibiting tumor angiogenesis with conventional chemotherapeutics is a promising strategy for antiangiogenic cancer therapy. However, current metronomic chemotherapy mainly focuses on free small-molecule drugs, without any effort to achieve tumor-specific biodistribution, which may lead to long-term toxicity concerns. Metronomic chemotherapy using nanoparticulate drug delivery system (DDS) offers significant upside to reduce off-target side effects, decrease accumulated dose, and enhance the efficacy of tumor vessel targeting without compromising antitumor efficacy; but there has been a lack of thorough experimental data describing the targeted metronomic chemotherapy. Here, we develop a new nanoparticulate DDS, SP5.2 peptide conjugated, Flt-1 (VEGFR-1) targeted nanoparticles for docetaxel (SP5.2-DTX-NP), as a model for the investigation of targeted metronomic chemotherapy with respect to both antitumor efficacy and toxicity. The results demonstrate that metronomic SP5.2-DTX-NP exerts antitumor activity mainly through the antiangiogenic effect of docetaxel, which is specifically delivered into the tumor vascular endothelial cells through the nanoparticle internalization mediated by the interaction of SP5.2 and over-expressed Flt-1 receptors on tumor vessels. Moreover, the antitumor efficacy of targeted metronomic chemotherapy is better than that of the treatment with the DDS given in the maximum tolerated dose (MTD) regimen, which is shown in significantly prolonged mice survival and minimal drug-associated toxicity (bone marrow suppression, hematological toxicity, and mucosal injury of small intestine). The present research reveals and highlights the significance of targeted metronomic therapy with nanoparticulate DDS in antiangiogenic cancer therapy.

• Authors: De-Hong Yu, Fu-Qiang Ban, Mei Zhao, Qin Lu, Jonathan F Lovell, Fan Bai, Chao Wang, Ying-Yun Guan, Xin Luan, Ya-Rong Liu, Chao Fang, Hong-Zhuan Chen
• Journal: Biomaterials (Biomaterials) Vol. 34 Issue 16 Pg. 3925-3937 (May 2013) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 23465835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Peptides
• Platelet Endothelial Cell Adhesion Molecule-1
• Taxoids
• Docetaxel
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Administration, Metronomic
• Animals
• Antineoplastic Agents (pharmacology)
• Bone Marrow (drug effects, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Docetaxel
• Drug Delivery Systems
• Endocytosis (drug effects)
• Female
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Mucous Membrane (drug effects, pathology)
• Nanoparticles (chemistry, toxicity, ultrastructure)
• Neoplasms (blood supply, pathology)
• Neovascularization, Physiologic (drug effects)
• Peptides (chemistry, metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Taxoids (administration & dosage, pharmacology)
• Tissue Distribution (drug effects)
• Treatment Outcome
• Vascular Endothelial Growth Factor Receptor-1 (chemistry, metabolism)