title: Tertiary amine mediated targeted therapy against metastatic lung cancer.
abstract: In this work, two tertiary amine-derived 4'-demethylepipodophyllotoxin (DMEP) conjugates (DC and DP) have been designed and synthesized using N,N,N'-trimethyl-N'-(4-carboxyl benzyl)-1,3-propanediamine (CPDM) and 4-(4-methylpiperazinomethyl)benzoic acid (PBA) as the targeting ligands. Both DC and DP exhibited strong in vitro cytotoxicity against small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Cellular uptake efficiencies of DC and DP in human alveolar type II epithelial cells were significantly enhanced compared to DMEP and etoposide (VP-16), which were demonstrated to be concentration-, time- and energy-dependent. The active transport process of DC and DP might be mediated by organic cation transporters (OCTs). After systemic administration in mice, both DC and DP selectively accumulated in the lung, displaying the highest Cmaxand AUC0-tvalues of all tested tissues. Compared with DMEP and VP-16, DC and DP remarkably reduced the lung weight and the number of lung metastases of B16 melanoma in mice, and further prolonged the survival of tumor-bearing mice. Also, DC and DP exhibited comparable levels of cell cycle arrest and cell apoptosis. Furthermore, DC and DP demonstrated minimum toxicity towards vital organs and reduced gastrointestinal injury compared to DMEP and VP-16. Taken together, tertiary amine-derived moieties such as CPDM and PBA represent an efficient yet safe strategy to achieve lung-targeted drug delivery.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: yfu4@scu.edu.cn.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: zrzzl@vip.sina.com.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000737:chemistry; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011437:Propylamines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D010879:Piperazines; D011437:Propylamines; D011034:Podophyllotoxin; C072088:4'-demethylepipodophyllotoxin
keywords: 4-(4-Methylpiperazinomethyl)benzoic acid (PubChem CID: 736532); 4′-Demethylepipodophyllotoxin (PubChem CID: 122797); Etoposide; Etoposide (PubChem CID: 36462); Imipramine (PubChem CID: 3696); Lung cancer; Lung-targeting; Metastatic lung cancer; N,N,N′-trimethyl-1,3-propanediamine (PubChem CID: 78302); Podophyllotoxin; Podophyllotoxin (PubChem CID: 10607); Tert-butyl 4-(chloromethyl) benzoate (PubChem CID: 18959012); Tertiary amine; Tetraethylammonium chloride (PubChem CID: 5946)