Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.
Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.
复制标题
DOI：
10.1007/s11095-017-2278-0
复制
发表时间：
2018-01-09
影响因子：
3.7
通讯作者：
Lockman PR
中科院分区：
文献类型：
--
作者：
Mohammad AS;Griffith JI;Adkins CE;Shah N;Sechrest E;Dolan EL;Terrell-Hall TB;Hendriks BS;Lee H;Lockman PR
血肿瘤屏障（BTB）限制了伊立替康在中枢神经系统肿瘤中的分布。然而，鉴于BTB的被动渗透性增加，我们假设伊立替康脂质体由于增强渗透和保留（EPR）效应，相对于常规伊立替康，可改善伊立替康及其活性代谢产物SN-38在脑转移瘤中的局部暴露。雌性裸鼠心内或颅内植入人脑寻找乳腺癌细胞（乳腺癌脑转移模型）。从第21天开始，对小鼠静脉内给予溶媒、非脂质体伊立替康（50 mg/kg）、脂质体伊立替康（10 mg/kg和50 mg/kg）。评价药物蓄积、肿瘤负荷和存活率。伊立替康脂质体显示血浆药物暴露时间延长，SN-38的平均滞留时间（MRT）为17.7 ± 3.8小时，而伊立替康非脂质体的MRT为3.67 ± 1.2小时。此外，与非脂质体伊立替康相比，脂质体伊立替康在转移性病变中蓄积，并显示SN-38暴露时间延长。脂质体伊立替康对SN-38的AUC值为6883 ± 4149 ng-h/g，而非脂质体伊立替康对SN-38的AUC值显著较低，为982 ± 256 ng-h/g。脂质体伊立替康的中位生存期为50天，比赋形剂的37天（p<0.05）增加。伊立替康脂质体在脑转移瘤中积聚，充当伊立替康和SN-38缓释的储存库，从而延长乳腺癌脑转移临床前模型的生存期。
The blood-tumor barrier (BTB) limits irinotecan distribution in tumors of the central nervous system. However, given that the BTB has increased passive permeability we hypothesize that liposomal irinotecan would improve local exposure of irinotecan and its active metabolite SN-38 in brain metastases relative to conventional irinotecan due to enhanced-permeation and retention (EPR) effect. Female nude mice were intracardially or intracranially implanted with human brain seeking breast cancer cells (brain metastases of breast cancer model). Mice were administered vehicle, non-liposomal irinotecan (50 mg/kg), liposomal irinotecan (10 mg/kg and 50 mg/kg) intravenously starting on day 21. Drug accumulation, tumor burden, and survival were evaluated. Liposomal irinotecan showed prolonged plasma drug exposure with mean residence time (MRT) of 17.7 ± 3.8 h for SN-38, whereas MRT was 3.67 ± 1.2 for non-liposomal irinotecan. Further, liposomal irinotecan accumulated in metastatic lesions and demonstrated prolonged exposure of SN-38 compared to non-liposomal irinotecan. Liposomal irinotecan achieved AUC values of 6883 ± 4149 ng-h/g for SN-38, whereas non-liposomal irinotecan showed significantly lower AUC values of 982 ± 256 ng-h/g for SN-38. Median survival for liposomal irinotecan was 50 days, increased from 37 days (p<0.05) for vehicle. Liposomal irinotecan accumulates in brain metastases, acts as depot for sustained release of irinotecan and SN-38, which results in prolonged survival in preclinical model of breast cancer brain metastasis.
登录
查看更多内容
影响因子：
11.2
作者：
Espelin, Christopher W.;Leonard, Shannon C.;Hendriks, Bart S.
通讯作者：
Hendriks, Bart S.
影响因子：
51.1
作者：
Bachelot, Thomas;Romieu, Gilles;Labbe-Devilliers, Catherine
通讯作者：
Labbe-Devilliers, Catherine
影响因子：
3.8
作者：
Adkins, Chris E.;Nounou, Mohamed I.;Lockman, Paul R.
通讯作者：
Lockman, Paul R.
影响因子：
5.6
作者：
Adkins CE;Mittapalli RK;Manda VK;Nounou MI;Mohammad AS;Terrell TB;Bohn KA;Yasemin C;Grothe TR;Lockman JA;Lockman PR
通讯作者：
Lockman PR
影响因子：
1.3
作者：
El-Habashy SE;Nazief AM;Adkins CE;Wen MM;El-Kamel AH;Hamdan AM;Hanafy AS;Terrell TO;Mohammad AS;Lockman PR;Nounou MI
通讯作者：
Nounou MI