title: 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: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: De-Hong
authors: DH
authors: Yu
authors: Vancouver Prostate Center, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors: Fu-Qiang
authors: FQ
authors: Ban
authors: Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to Shanghai Jiao Tong University School of Medicine, 279 Zhouzhu Road, Shanghai 201318, China.
authors: Mei
authors: M
authors: Zhao
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Qin
authors: Q
authors: Lu
authors: Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
authors: Jonathan F
authors: JF
authors: Lovell
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Fan
authors: F
authors: Bai
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Chao
authors: C
authors: Wang
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Ying-Yun
authors: YY
authors: Guan
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Xin
authors: X
authors: Luan
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors: Ya-Rong
authors: YR
authors: Liu
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: fangchao100@hotmail.com.
authors: Chao
authors: C
authors: Fang
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: hongzhuan_chen@hotmail.com.
authors: Hong-Zhuan
authors: HZ
authors: Chen
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009092:Mucous Membrane / Q000187:drug effects / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D043823:Taxoids; D000077143:Docetaxel; D040281:Vascular Endothelial Growth Factor Receptor-1