Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Drive, Cleveland, OH 44106, USA.
Biomacromolecules. 2013 Mar 11;14(3):910-9. doi: 10.1021/bm301996p. Epub 2013 Feb 14.
There is compelling evidence that, beyond their traditional role in hemostasis and thrombosis, platelets play a significant role in mediating hematologic mechanisms of tumor metastasis by directly and indirectly interacting with pro-metastatic cancer cells. With this rationale, we hypothesized that platelets can be an effective paradigm to develop nanomedicine platforms that utilize platelet-mimetic interaction mechanisms for targeted diagnosis and therapy of metastatic cancer cells. Here we report on our investigation of the development of nanoconstructs that interact with metastatic cancer cells via platelet-mimetic heteromultivalent ligand-receptor pathways. For our studies, pro-metastatic human breast cancer cell line MDA-MB-231 was studied for its surface expression of platelet-interactive receptors, in comparison to another low-metastatic human breast cancer cell line, MCF-7. Certain platelet-interactive receptors were found to be significantly overexpressed on the MDA-MB-231 cells, and these cells showed significantly enhanced binding interactions with active platelets compared to MCF-7 cells. Based upon these observations, two specific receptor interactions were selected, and corresponding ligands were engineered onto the surface of liposomes as model nanoconstructs, to enable platelet-mimetic binding to the cancer cells. Our model platelet-mimetic liposomal constructs showed enhanced targeting and attachment of MDA-MB-231 cells compared to the MCF-7 cells. These results demonstrate the promise of utilizing platelet-mimetic constructs in modifying nanovehicle constructs for metastasis-targeted drug as well as modifying surfaces for ex-vivo cell enrichment diagnostic technologies.
有确凿的证据表明，血小板除了在止血和血栓形成方面发挥传统作用外，还通过直接和间接与促转移癌细胞相互作用，在介导肿瘤转移的血液学机制方面发挥重要作用。基于这一原理，我们假设血小板可以成为开发纳米医学平台的有效范例，该平台利用血小板模拟相互作用机制，用于转移性癌细胞的靶向诊断和治疗。在这里，我们报告了我们对开发通过血小板模拟异多价配体-受体途径与转移性癌细胞相互作用的纳米结构的研究。在我们的研究中，研究了促转移的人乳腺癌细胞系 MDA-MB-231 表面表达的血小板相互作用受体，与另一种低转移性人乳腺癌细胞系 MCF-7 进行了比较。发现某些血小板相互作用受体在 MDA-MB-231 细胞上明显过表达，与 MCF-7 细胞相比，这些细胞与活性血小板表现出明显增强的结合相互作用。基于这些观察结果，选择了两种特定的受体相互作用，并将相应的配体工程设计到脂质体的表面作为模型纳米结构，以实现与癌细胞的血小板模拟结合。与 MCF-7 细胞相比，我们的模型血小板模拟脂质体构建体显示出对 MDA-MB-231 细胞的增强靶向性和附着性。这些结果证明了利用血小板模拟构建体来修饰用于转移靶向药物的纳米载体构建体以及修饰用于体外细胞富集诊断技术的表面的前景。
