Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.
Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.
复制标题
DOI：
10.1371/journal.pone.0061359
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zamboni WC
中科院分区：
文献类型：
--
作者：
Anders CK;Adamo B;Karginova O;Deal AM;Rawal S;Darr D;Schorzman A;Santos C;Bash R;Kafri T;Carey L;Miller CR;Perou CM;Sharpless N;Zamboni WC
乳腺癌脑转移（BCBM）是晚期乳腺癌的一个具有挑战性的后果。纳米颗粒制剂，包括脂质体，已经显示出对实体肿瘤和大脑的增强输送。我们比较了聚乙二醇化脂质体阿霉素（PLD）和非脂质体阿霉素（NonL-doxo）在BC颅内模型中的药代动力学（PK）和疗效。将表达mda - mb -231- br -荧光素酶的细胞接种于胸腺小鼠脑内。荷瘤小鼠分别以6mg/kg IV×1剂量给予PLD或NonL-doxo，分别于治疗前、治疗后0.083、1、3、6、24、72和96 h实施安乐死。样品处理后用高效液相色谱法测定阿霉素总量。PLD和NonL-doxo每周静脉单药（6 mg/kg）或与PARP抑制剂ABT-888、PO 25 mg/kg/天联合（4.5 mg/kg）给药。通过生存期和生物发光来评估疗效。与非l -doxo相比，PLD治疗导致血浆高约1500倍，颅内肿瘤总阿霉素AUC高20倍。96 h检测PLD；24 h后，血浆和肿瘤中均检测不到NonL-doxo。pld治疗动物的中位生存期为32天（d, [CI] 31-38），显著长于对照组（26d [CI 25-28], p = 0.0012）或NonL-doxo治疗（23.5d [CI 18-28], p = 0.0002）。与NonL-doxo/ABT-888相比，PLD/ABT-888联合治疗可提高生存期（35天[CI 31-38]对29.5天[CI 25-34]； p = 0.006）。在治疗BCBM的体内模型中，PLD比NonL-doxo具有PK和疗效优势。该结果为BCBM患者将发现转化为PLD的早期试验提供了临床前理论依据，无论是否使用ABT-888。
Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC. Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6mg/kg IV×1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg) or in combination (4.5 mg/kg) with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence. Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31–38), which was significantly longer than controls (26d [CI 25–28]; p = 0.0012) or NonL-doxo treatment (23.5d [CI 18–28], p = 0.0002). Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31–38] versus 29.5d [CI 25–34]; p = 0.006). PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.
登录
查看更多内容
影响因子：
5.7
作者：
Ali M;Kamjoo M;Thomas HD;Kyle S;Pavlovska I;Babur M;Telfer BA;Curtin NJ;Williams KJ
通讯作者：
Williams KJ
影响因子：
50.5
作者：
O'Brien, MER;Wigler, N;Tendler, C
通讯作者：
Tendler, C
影响因子：
3.4
作者：
Mason, Kathryn A.;Valdecanas, David;Milas, Luka
通讯作者：
Milas, Luka
影响因子：
3.8
作者：
Harrell, J. Chuck;Prat, Aleix;Perou, Charles M.
通讯作者：
Perou, Charles M.
影响因子：
11.5
作者：
Donawho, Cherrie K.;Luo, Yan;Frost, David J.
通讯作者：
Frost, David J.