title: DOPA-based paclitaxel-loaded liposomes with modifications of transferrin and alendronate for bone and myeloma targeting.
abstract: Treatment for multiple myeloma (MM) with a combined strategy of bone and tumor targeting remains a crucial technical challenge due to the incorporation of various functional components into one single system. Here, we developed dioleoyl phosphatidic acid (DOPA)-based paclitaxel (PTX)-loaded liposomes with modifications of alendronate and transferrin (Ald-/Tf-modified PTX-L), which were capable of bone affinity mediated by phosphate groups in DOPA and alendronate, and tumor targeting offered by transferrin. Ald-/Tf-modified PTX-L had clear and well-defined spherical shape with an intermediated size of 118.8 ± 4.8 nm, a highly negative surface charge of -46.9 ± 6.8 mV and a drug entrapment efficiency (DEE) of approximately 80%. When the pH was changed from pH 7.4 to pH 6.5, the accumulative release of PTX from Ald-/Tf-modified PTX-L significantly increased from 26.7 ± 3.7% to 41.7 ± 4.9%. Importantly, liposomes based on DOPA displayed an obviously stronger affinity with hydroxyapatite (HAp) than 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-based liposomes. Compared to PTX-L, Ald-/Tf-modified PTX-L exhibited obvious improvement of cytotoxicity (IC50=1.25 ± 0.09 μg/mL), significant enhancement on PTX intracellular accumulation (16.58 ± 0.62 μg/mg) and notable promotion to apoptosis induction (45.21 ± 3.10%) toward myeloma (MM1s) cells. In this study of antitumor efficacy, Ald-/Tf-modified PTX-L with bone-specific targeting showed a significant effect on extending the median survival time (48 days) and terminal survival time (> 58 days) against the MM1S-injected nude mice among all formulations. The results suggested that Ald-/Tf-modified PTX-L had potential as an efficient anticancer drug delivery system for MM therapy.
authors.affiliation: a Department of Orthopaedics , School of Medicine, Zhongda Hospital, Southeast University , Nanjing , P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: a Department of Orthopaedics , School of Medicine, Zhongda Hospital, Southeast University , Nanjing , P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Geng
authors.affiliation: a Department of Orthopaedics , School of Medicine, Zhongda Hospital, Southeast University , Nanjing , P.R. China.
authors.forename: Shanzheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: b Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing , P.R. China , and.
authors.forename: Ding
authors.initials: D
authors.lastname: Qu
authors.affiliation: a Department of Orthopaedics , School of Medicine, Zhongda Hospital, Southeast University , Nanjing , P.R. China.|c Surgical Research Center, School of Medicine, Southeast University , Nanjing , P.R. China.
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Kong
mesh_terms: D019386:Alendronate / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry*; D010712:Phosphatidic Acids / Q000008:administration & dosage / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D014168:Transferrin / Q000008:administration & dosage / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D010712:Phosphatidic Acids; D010714:Phosphatidylethanolamines; D014168:Transferrin; D017239:Paclitaxel; D019386:Alendronate
keywords: Bone targeting; DOPA; alendronate; liposomes; multiple myeloma; transferrin