title: Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer.
abstract: Anticancer drug resistance is a common intractable obstacle in clinical cancer chemotherapy. Here, we hypothesize that antiangiogenic cancer therapy through the targeted delivery of antiangiogenic agents to the tumor endothelial cells (EC), not the resistant cancer cells, may have the potential of combating multidrug resistant cancer. The K237 peptide-conjugated paclitaxel loaded nanoparticles (K237-PTX-NP), which can target KDR receptors highly expressed in the tumor vasculature, were fabricated for this investigation and the human colorectal adenocarcinoma HCT-15 with naturally expressed P-gp on the cell surface was adopted as the resistant tumor model. The human umbilical vein endothelial cells (HUVEC, a classical cell model mimicking tumor EC) were much more sensitive, in the cytotoxicity and apoptosis test, to K237-PTX-NP than Taxol and non-targeted PTX-NP. The enhanced antiangiogenic feature of K237-PTX-NP can be ascribed to the active internalization mediated by the interaction of K237 and KDR specifically highly expressed on the HUVEC, and the significantly extended intracellular drug retention. The tumor vessel targeting of K237-PTX-NP led to increased nanoparticle accumulation in HCT-15 tumors, and more importantly, induced significant apoptosis of tumor vascular EC and necrosis of tumor tissues. Low dose paclitaxel formulated in K237-PTX-NP (1 mg/kg) achieved significant anticancer efficacy of inhibiting the growth of HCT-15 tumors, but the same efficacy could be only obtained with 8 fold dose paclitaxel (8 mg/kg) in Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of K237-PTX-NP was well related with the improved antiangiogenic effect shown in the dramatically decreased intratumoral microvessel density and pronouncedly increased apoptotic tumor cells, and such approach did not lead to obvious toxicity in the mice. These results suggest that the nanoparticles targeting drug to tumor neovasculature may be a promising strategy for the treatment of multidrug resistant cancer.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Bai
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Ban
authors.forename: De-Hong
authors.initials: DH
authors.lastname: Yu
authors.forename: Ying-Yun
authors.initials: YY
authors.lastname: Guan
authors.forename: Xin
authors.initials: X
authors.lastname: Luan
authors.forename: Ya-Rong
authors.initials: YR
authors.lastname: Liu
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D010455:Peptides; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel