Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: Pharmacokinetics and biodistribution in tumor-bearing mice
Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: Pharmacokinetics and biodistribution in tumor-bearing mice
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DOI：
10.1023/a:1016096910822
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发表时间：
1996-06-01
影响因子：
3.7
通讯作者：
Barenholz, Y
中科院分区：
文献类型：
--
作者：
Emanuel, N;Kedar, E;Barenholz, Y
目的，为了评估通过小型（小于或等于 120 nm）空间稳定免疫脂质体递送的阿霉素 (DOX) 在肿瘤定位、可用性和非癌性器官分布方面的益处，该免疫脂质体针对纤维肉瘤小鼠中的肿瘤相关抗原。方法，用 (i) 特异性单克隆 IgG 制备载有 DOX 的脂质体 (3) 抗体（32/2，D-SSIL-32/2）； (ii) 非特异性 IgG(3) (D-SSIL-IgG)； (iii) 其表面没有 IgG (D-SSL)。通过每种类型的脂质体将等量的 DOX 静脉注射到 BALB/c 小鼠中，该小鼠携带多瘤病毒诱导的纤维肉瘤（A9 等 220）的实验性肺转移，其表面表达多瘤病毒诱导的肿瘤相关抗原（PAA）。转移主要发生在肺部。小鼠在肿瘤发展的3个阶段（微小转移、中等大小转移和大坏死转移）接受治疗。性能评估基于肺肿瘤、非癌性器官和血浆中 DOX 和 DOX 代谢物 (DOX-M) 的时间依赖性定量。结果，(i) 通过两个 SSIL 递送的 DOX 保留了通过 D-SSL 递送的 DOX 典型的延长循环时间。 (ii) 所有制剂的非癌性器官中 DOX 积累相似。除肝脏外，所有三种制剂在所有器官中均获得低水平的 DOX-M，表明处理过程类似。 (iii) 根据肿瘤大小和显微解剖结构，制剂在肺肿瘤中的行为有所不同。仅在微转移阶段，特异性靶向的 D-SSIL-32/2 才优于 D-SSL 和 D-SSIL-IgG，向肿瘤输送的药物量是其 2-4 倍。 (iv)所有三个肿瘤阶段中的DOX-M水平按以下顺序排列：D-SSIL-32/2>>D-SSL>>D-SSIL-IgG，这表明作为D-SSIL-32/2递送的DOX最容易被肿瘤细胞利用。结论。空间稳定脂质体特异性靶向的优势主要体现在以依赖于肿瘤显微解剖结构的方式增加DOX对肿瘤细胞的可用性。这一优势对治疗效果的影响仍有待确定。
Purpose, To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (less than or equal to 120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice.Methods, DOX-loaded liposomes were prepared with (i) specific monoclonal IgG(3) antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG(3) (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 etc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma.Results, (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing. (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2-4 times more drug into the tumor. (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 >> D-SSL >> D-SSIL-IgG, suggesting that DOX delivered as D-SSlL-32/2 is most available to tumor cells.Conclusions. The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.