title: LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics.
abstract: Lymphatic metastasis can be greatly promoted by metastases growth and lymphangiogenesis in lymph nodes (LNs). LyP-1, a cyclic peptide, is able to specifically bind with tumor cells and tumor lymphatics in metastatic LNs. This work aimed to use LyP-1-conjugated liposomes (L-LS) loaded with doxorubicin (DOX) (L-LS/DOX) to suppress lymphatic metastasis by inhibiting both metastases and tumor lymphatics in LNs. L-LS were prepared and exhibited sizes around 90 nm and spherical morphology as characterized by transmission electron microscopy. The in vitro cellular studies showed that LyP-1 modification obviously increased liposome uptake by MDA-MB-435 tumor cells and enhanced the cytotoxicity of liposomal DOX. A popliteal and iliac LN metastases model was successfully established by subcutaneous inoculation of tumor cells to nude mice. The immunofluorescence staining analysis indicated that LyP-1 modification enabled specific binding of liposome with tumor lymphatics and enhanced the destroying effect of liposomal DOX on tumor lymphatics. The in vivo fluorescence imaging and pharmacodynamic studies showed that LyP-1 modification increased liposome uptake by metastatic LNs and that L-LS/DOX significantly decreased metastatic LN growth and LN metastasis rate. These results suggested that L-LS/DOX were an effective delivery system for suppressing lymphatic metastasis by simultaneously inhibiting LN metastases and tumor lymphatics.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yan
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhan
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Wen
authors.forename: Linglin
authors.initials: L
authors.lastname: Feng
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiangkun
authors.initials: X
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000648:ultrastructure; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; C533969:LyP-1 peptide; D010456:Peptides, Cyclic; D004317:Doxorubicin