title: Tumor penetrability and anti-angiogenesis using iRGD-mediated delivery of doxorubicin-polymer conjugates.
abstract: Tumor-penetrating peptide, iRGD (internalizing RGD, CRGDK/RGPD/EC) with the similar affinity to αv integrins as conventional RGD cyclopeptide could enhance the tumor penetrability of drugs by binding to neuropilin-1 (NRP-1) that over-expressed on both angiogenic blood vessels and tumor cells. Comparing with our previous study, in which a RGD cyclopeptide (RGDyC) was bound to PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) by acid-sensitive cis-aconityl linkage (PEG-PAMAM-cis-aconityl-DOX, PPCD), the present study selected iRGD instead of previous RGD to produce iRGD-PPCD conjugate. The effect of iRGD-mediated PPCD on tumor penetration was compared with the conventional RGD ones via administration of RGDs-modified PPCD (iRGD/RGDs-PPCD) and co-administration of RGDs and PPCD (iRGD/RGD + PPCD). C6 cells were selected as the cell model owing to the highest expression of αv integrins and NRP-1 among four tumor cell lines. In vitro cytotoxicity and cellular uptake showed no significant difference between RGD-PPCD and iRGD-PPCD, but glioma spheroid penetration study showed that RGD-PPCD, iRGD-PPCD and iRGD + PPCD penetrated into C6 spheroids with a depth of 115 μm, 144 μm and 150 μm, respectively, indicating that the iRGD-mediated PPCD delivery system had a stronger penetrating ability than the RGD ones. In vivo results also demonstrated the superiority of iRGD system over RGD ones. After systemic administration, iRGD-mediated PPCD increased tumor vascular permeability, decreased tumor vascular density and average vascular diameter. Correspondingly, the iRGD system exhibited stronger penetration ability, higher accumulation in brain tumor. The median survival time of iRGD + PPCD, iRGD-PPCD and RGD-PPCD treatment groups were 61, 57.5 and 43.5 days. The present findings strongly suggested that the iRGD-mediated drug delivery system could significantly improve the efficacy of tumor therapy through enhancing tumor accumulation and penetration as compared to the conventional RGD ones.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: wangkefdu@163.com.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jiangbh@simm.ac.cn.
authors.forename: Baohong
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: yanyanjiang@shmu.edu.cn.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019540:Area Under Curve; D002199:Capillary Permeability / Q000187:drug effects; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D050091:Dendrimers / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D057846:Cell-Penetrating Peptides; D050091:Dendrimers; D009842:Oligopeptides; C522249:PEG-PAMAM; D011108:Polymers; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin
keywords: Co-administration; Conjugates; Tumor vascular permeability; Tumor-penetrating peptide; iRGD