Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland.
Mol Cancer Ther. 2023 May 4;22(5):646-658. doi: 10.1158/1535-7163.MCT-22-0815.
Advances in drug treatments for brain metastases of breast cancer have improved progression-free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: transferrin receptor (TfR) peptide, low-density lipoprotein receptor 1 (LRP1) peptide, albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P < 0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor, galectin-3, and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other central nervous system (CNS) cancers.In conclusion, drug therapy for brain metastasis needs improvement. We surveyed three transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel endocytic mechanism.
乳腺癌脑转移的药物治疗进展提高了无进展生存期，但需要新的、更有效的策略。大多数化疗药物通过在脑毛细血管内皮细胞之间移动，即细胞旁分布，渗透到脑转移灶，导致分布不均匀，低于全身转移灶。在此，我们测试了三种已知的穿过脑毛细血管内皮细胞的转胞吞途径，作为药物进入的潜在途径：转铁蛋白受体（TfR）肽、低密度脂蛋白受体 1（LRP1）肽、白蛋白。每个都用远红标记，注射到两种血源性脑转移模型中，循环不同的时间，并在转移灶和未受累（非转移性）脑中定量摄取。令人惊讶的是，这三种途径在体内都表现出不同的分布模式。两种途径不理想：TfR 分布到未受累的脑中，但在转移灶中分布较差，而 LRP1 分布较差。白蛋白在两种模型系统中几乎都分布到所有转移灶，明显高于未受累的脑（P < 0.0001）。进一步的实验表明，白蛋白进入大转移灶和微转移灶，这是治疗和预防转移策略的靶点。白蛋白进入脑转移灶的摄取与细胞旁探针（生物胞素）的摄取无关。我们发现了一种白蛋白通过脑转移内皮细胞内吞的新机制，与网格蛋白非依赖内吞（CIE）一致，涉及新生 Fc 受体、半乳糖凝集素-3 和糖脂。CIE 过程的成分在人类开颅术中的转移性内皮细胞上被发现。数据表明，需要重新考虑白蛋白作为改善脑转移药物递送的转化机制，可能还有其他中枢神经系统（CNS）癌症。总之，脑转移的药物治疗需要改进。我们在脑趋向性模型中调查了三种转胞吞途径作为潜在的输送系统，发现白蛋白具有最佳的性质。白蛋白使用了一种新的内吞机制。
