Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
The University of Alabama at Birmingham, Birmingham, AL, United States.
Biomaterials. 2019 Jun;206:146-159. doi: 10.1016/j.biomaterials.2019.03.029. Epub 2019 Mar 23.
Maximal surgical resection of glioma remains the single most effective treatment. Tools to guide the resection while avoiding removal of normal brain tissues can aid surgeons in achieving optimal results. One strategy to achieve this goal is to rely upon interoperative fluorescence staining of tumor cells in vivo, that can be visualized by the surgeon during resection. Towards this goal we have designed a biodegradable fluorescent mini nano imaging agent (NIA) with high specificity for U87MG glioma cells and previously unmet high light emission. The NIA is the conjugate of polymalic acid (PMLA) with chlorotoxin for tumor targeting, indocyanine green (ICG) for NIR fluorescence and the tri-leucin peptide as fluorescence enhancer. PMLA as a multivalent platform carries several molecules of ICG and the other ligands. The NIA recognizes multiple sites on glioma cell surface, demonstrated by the effects of single and combined competitors. Systemic IV injection into xenogeneic mouse model carrying human U87MG glioblastoma indicated vivid tumor cell binding and internalization of NIA resulting in intensive and long-lasting tumor fluorescence. The NIA is shown to greatly improve tumor removal supporting its utility in clinical applications.
最大限度地切除脑胶质瘤仍然是最有效的单一治疗方法。有一些工具可以在避免切除正常脑组织的情况下指导切除，帮助外科医生获得最佳效果。实现这一目标的策略之一是依靠术中对肿瘤细胞进行荧光染色，以便外科医生在切除过程中进行观察。为此，我们设计了一种具有高特异性的可生物降解的荧光迷你纳米成像剂（NIA），该成像剂对 U87MG 神经胶质瘤细胞具有特异性，并且具有以前未达到的高光发射。NIA 是聚马来酸（PMLA）与氯毒素的缀合物，用于肿瘤靶向，吲哚菁绿（ICG）用于近红外荧光，三亮氨酸肽用作荧光增强剂。PMLA 作为多价平台携带几个 ICG 分子和其他配体。NIA 识别神经胶质瘤细胞表面的多个位点，这一点可通过单一和组合竞争物的作用得到证明。将其静脉注射到携带人 U87MG 胶质母细胞瘤的异种移植小鼠模型中，表明 NIA 与肿瘤细胞结合并内化，导致肿瘤荧光强烈且持久。NIA 被证明可以大大提高肿瘤切除率，支持其在临床应用中的效用。
