Department of Chemistry, New York University , New York, New York 10003, United States.
Department of Chemical and Biological Engineering, Program in Applied and Computational Mathematics, Princeton University , A319 Engineering Quad, Princeton, New Jersey 08544, United States.
Langmuir. 2016 Aug 23;32(33):8329-38. doi: 10.1021/acs.langmuir.6b01464. Epub 2016 Aug 8.
Effective targeting by uniformly functionalized nanoparticles is limited to cancer cells expressing at least two copies of targeted receptors per nanoparticle footprint (approximately ≥2 × 10(5) receptor copies per cell); such a receptor density supports the required multivalent interaction between the neighboring receptors and the ligands from a single nanoparticle. To enable selective targeting below this receptor density, ligands on the surface of lipid vesicles were displayed in clusters that were designed to form at the acidic pH of the tumor interstitium. Vesicles with clustered HER2-targeting peptides within such sticky patches (sticky vesicles) were compared to uniformly functionalized vesicles. On HER2-negative breast cancer cells MDA-MB-231 and MCF7 {expressing (8.3 ± 0.8) × 10(4) and (5.4 ± 0.9) × 10(4) HER2 copies per cell, respectively}, only the sticky vesicles exhibited detectable specific targeting (KD ≈ 49-69 nM); dissociation (0.005-0.009 min(-1)) and endocytosis rates (0.024-0.026 min(-1)) were independent of HER2 expression for these cells. MDA-MB-231 and MCF7 were killed only by sticky vesicles encapsulating doxorubicin (32-40% viability) or α-particle emitter (225)Ac (39-58% viability) and were not affected by uniformly functionalized vesicles (>80% viability). Toxicities on cardiomyocytes and normal breast cells (expressing HER2 at considerably lower but not insignificant levels) were not observed, suggesting the potential of tunable clustered ligand display for the selective killing of cancer cells with low receptor densities.
有效靶向需要每个纳米颗粒足迹处至少表达两个靶向受体的均匀功能化纳米颗粒（每个细胞大约≥2×10(5)受体拷贝）；这种受体密度支持相邻受体和来自单个纳米颗粒的配体之间所需的多价相互作用。为了在这种受体密度以下实现选择性靶向，脂质囊泡表面的配体被展示在簇中，这些簇被设计在肿瘤间质的酸性 pH 下形成。具有簇状 HER2 靶向肽的囊泡在这种粘性斑块内（粘性囊泡）与均匀功能化的囊泡进行比较。在 HER2 阴性乳腺癌细胞 MDA-MB-231 和 MCF7 上（分别表达 8.3±0.8×10(4)和 5.4±0.9×10(4)个 HER2 拷贝/细胞），只有粘性囊泡显示出可检测的特异性靶向（KD≈49-69 nM）；对于这些细胞，解离（0.005-0.009 min(-1))和内吞作用速率（0.024-0.026 min(-1))与 HER2 表达无关。只有封装阿霉素（32-40%活力）或α-粒子发射器（225)Ac（39-58%活力）的粘性囊泡才能杀死 MDA-MB-231 和 MCF7，而均匀功能化的囊泡对其没有影响（>80%活力）。在心肌细胞和正常乳腺细胞（HER2 表达水平低但并非微不足道）上未观察到毒性，这表明可调谐的簇状配体显示对于具有低受体密度的癌细胞的选择性杀伤具有潜在应用价值。
