Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.
Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.
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DOI：
10.1007/s11095-016-1872-x
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发表时间：
2016-05
影响因子：
3.7
通讯作者：
Uchegbu IF
中科院分区：
文献类型：
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作者：
Fisusi FA;Siew A;Chooi KW;Okubanjo O;Garrett N;Lalatsa K;Serrano D;Summers I;Moger J;Stapleton P;Satchi-Fainaro R;Schätzlein AG;Uchegbu IF
血脑屏障影响了胶质母细胞瘤的化疗。然而，血液中高浓度的亲脂性、烷基化药物会导致大脑摄取，但会导致骨髓抑制。我们假设纳米颗粒可以在没有剂量限制的骨髓抑制的情况下达到治疗性的脑浓度。给小鼠静脉注射洛莫司汀分子包膜技术(MET)纳米粒(13 mg/kg−1)或乙醇洛莫司汀(6.5 mg/kg−1)，并进行组织分析。在原位U-87 MG胶质母细胞瘤模型中，在静脉注射美洛莫司汀(每天13 mg/kg−1)或乙醇洛莫司汀(每天1.2 mg/kg−1-可能的最高重复剂量)后，对疗效进行评估。骨髓抑制和MET颗粒巨噬细胞摄取也进行了研究。MET制剂具有适度的脑靶向性(MET和乙醇洛莫司汀 = 的脑/骨AUC0-4h比值分别为0.90和0.53，脑/肝AUC0-4h比值分别为0.24和0.15)。Met制剂显著延长了小鼠(U-87 MG肿瘤)的生存时间；Met、乙醇Lomustine和未治疗的平均生存时间分别为33.2、22.5和21.3d，血细胞和股骨细胞计数没有与物质治疗相关的差异。MET纳米颗粒的巨噬细胞摄取速度慢于脂质体。微粒药物制剂改善了脑肿瘤的治疗，而不会产生重大的骨髓毒性。
The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg−1) or ethanolic lomustine (6.5 mg kg−1) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg−1) or ethanolic lomustine (daily 1.2 mg kg−1 - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.