Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Program in Structural Biology and Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
ACS Nano. 2021 Jul 27;15(7):11789-11805. doi: 10.1021/acsnano.1c02864. Epub 2021 Jun 30.
Several diseases exhibit a high degree of heterogeneity and diverse reprogramming of cellular pathways. To address this complexity, additional strategies and technologies must be developed to define their scope and variability with the goal of improving current treatments. Nanomedicines derived from viruses are modular systems that can be easily adapted for combinatorial approaches, including imaging, biomarker targeting, and intracellular delivery of therapeutics. Here, we describe a "designer nanoparticle" system that can be rapidly engineered in a tunable and defined manner. Phage-like particles (PLPs) derived from bacteriophage lambda possess physiochemical properties compatible with pharmaceutical standards, and particle tracking and cell targeting are accomplished by simultaneous display of fluorescein-5-maleimide (F5M) and trastuzumab (Trz), respectively (Trz-PLPs). Trz-PLPs bind to the oncogenically active human epidermal growth factor receptor 2 (HER2) and are internalized by breast cancer cells of the HER2 overexpression subtype, but not by those lacking the amplification. Compared to treatment with Trz, robust internalization of Trz-PLPs results in higher intracellular concentrations of Trz, prolonged inhibition of cell growth, and modulated regulation of cellular programs associated with HER2 signaling, proliferation, metabolism, and protein synthesis. Given the implications to cancer pathogenesis and that dysregulated signaling and metabolism can lead to drug resistance and cancer cell survival, the present study identifies metabolic and proteomic liabilities that could be exploited by the PLP platform to enhance therapeutic efficacy. The lambda PLP system is robust and rapidly modifiable, which offers a platform that can be easily "tuned" for broad utility and tailored functionality.
几种疾病表现出高度的异质性和细胞途径的多样化重编程。为了解决这一复杂性，必须开发额外的策略和技术来定义它们的范围和可变性，以期改善当前的治疗方法。源自病毒的纳米药物是模块化系统，可以轻松适应组合方法，包括成像、生物标志物靶向和治疗剂的细胞内递药。在这里，我们描述了一种可以快速以可调且明确的方式设计的“设计纳米颗粒”系统。源自噬菌体 lambda 的噬菌体样颗粒 (PLP) 具有与药物标准兼容的物理化学性质，通过同时显示荧光素 5-马来酰亚胺 (F5M) 和曲妥珠单抗 (Trz) 分别实现颗粒跟踪和细胞靶向（Trz-PLP）。Trz-PLP 与致癌活性的人类表皮生长因子受体 2 (HER2) 结合，并被 HER2 过表达亚型的乳腺癌细胞内化，但不被缺乏扩增的细胞内化。与使用 Trz 治疗相比，Trz-PLP 的强烈内化导致 Trz 的细胞内浓度更高，细胞生长的抑制时间延长，并调节与 HER2 信号、增殖、代谢和蛋白质合成相关的细胞程序。鉴于对癌症发病机制的影响以及失调的信号和代谢可能导致耐药性和癌细胞存活，本研究确定了代谢和蛋白质组学的缺陷，这些缺陷可能被 PLP 平台利用来增强治疗效果。lambda PLP 系统强大且易于修改，为广泛应用和定制功能提供了一个易于“调整”的平台。
