title: Polymeric micelles for enhanced lymphatic drug delivery to treat metastatic tumors.
abstract: Polymeric micelles have been proven to be a promising nano-sized system for drug delivery. Understanding its in vivo behaviors at the whole body, tissue and cellular levels is critical for translating this drug delivery system into clinical practice. In this study, the 14.5 nm micelles made of polyethylene glycol-phosphatidylethanolamine (PEG-PE) for delivery of doxorubicin and vinorelbine were investigated. Using confocal and two-photon microscopy imaging of live mice or tissue sections, we observed that after systemic administration, the fluorescently labeled PEG-PE micelles encapsulating doxorubicin migrated through blood vessels in entirety into the interstitial tissue, collected by lymphatic vessels, and accumulated in lymph nodes. Importantly, encapsulated drugs such as vinorelbine (Nanovin), preferentially accumulate in lymph nodes when compared to the free drugs. Moreover, the in vivo bioluminescent imaging showed that Nanovin significantly reduced lymph node metastasis rate (P<0.05) in 4 T1-luc2 murine breast tumor bearing mice. Finally, we observed that Nanovin enhanced antitumor activity against primary tumors and lung metastases while having low toxicity in various 4 T1 tumor models. This study suggests that PEG-PE micelle is a promising drug delivery system for the treatment of lymphatic metastases, and may also have important applications in other lymphatic system-related diseases.
authors.affiliation: Protein & Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qin
authors.forename: Fayun
authors.initials: F
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wei
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Fang
authors.forename: Duanyun
authors.initials: D
authors.lastname: Si
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008198:Lymph Nodes / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D010714:Phosphatidylethanolamines; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; D011092:Polyethylene Glycols; D014747:Vinblastine; D000077235:Vinorelbine
keywords: Axi; Biodistribution; Dox; Extravasation; ICG; Ing; LN; Lymphatic drug delivery; Mes; Metastatic tumor; PEG-PE; Polymeric micelles; Vin; axillary; distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000]; doxorubicin; i.v; indocyanine green; inguinal; intravenous; lymph node; mesentery; vinorelbine