We previously proved the superiority of the ligand reversible shielding strategy based on the pH-responsive self-assembly/disassembly of gold nanoparticles through computed tomography imaging in vivo. Herein, the practicality of this strategy in tumor therapy was investigated by a ligand reversible shielding system based on a temperature-responsive polymer. The ligand biotin, cisplatin-loaded chain poly(acrylic acid)-Pt, and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm)) were co-modified onto the surface of gold nanostars. In the blood circulation (37 °C), the ligand was shielded by the extension of P(NIPAAm-co-AAm), whose lower critical solution temperature (LCST) is approximately 39 °C. After the nanoparticles accumulate at the tumor site by the enhanced permeability and retention (EPR) effect, the heat generated from gold nanostars upon near-infrared light irradiation would trigger the contraction of P(NIPAAm-co-AAm), thus deshielding the ligand for enhanced tumor cellular uptake. Owing to the reversible extension-contraction transformation change of P(NIPAAm-co-AAm), the reversible shielding effect on the ligand could be accomplished even if the nanoparticles return to the blood circulation. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower), and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. This strategy showed significantly superior tumor inhibition (11% higher) than the irreversible system. All these results make clear that the ligand reversible shielding strategy is effective and offers important references for the design of nanomaterials for improving tumor accumulation. STATEMENT OF SIGNIFICANCE: Herein, the practicality of the ligand reversible shielding strategy in tumor therapy was investigated. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm) which LCST is about 39 °C) were co-modified onto the surface of gold nanostars. This well-designed NPs could shield target ligand in blood circulation (37 °C) and deshield it at tumor site (40-41 °C) reversibly. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower) and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. Significantly, the strategy showed superior tumor inhibition than the irreversible system (11% higher).

中文翻译：

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靶向递送和肿瘤治疗中配体可逆屏蔽策略有效性的研究。

我们先前通过体内计算机层析成像技术，基于金纳米颗粒的pH响应自组装/分解，证明了配体可逆屏蔽策略的优越性。在此，通过基于温度响应性聚合物的配体可逆屏蔽系统研究了该策略在肿瘤治疗中的实用性。将配体生物素，负载顺铂的链聚（丙烯酸）-Pt和屏蔽链段热敏性聚（N-异丙基丙烯酰胺-共-丙烯酰胺）（P（NIPAAm-co-AAm））共修饰到表面上金纳米星。在血液循环（37°C）中，配体被P（NIPAAm-co-AAm）的延伸所屏蔽，P（NIPAAm-co-AAm）的下临界溶液温度（LCST）约为39°C。通过增强的渗透性和保留（EPR）效应，纳米颗粒积聚在肿瘤部位后，金纳米星在近红外光照射下产生的热量将触发P（NIPAAm-co-AAm）的收缩，从而屏蔽配体以增强肿瘤细胞的摄取。由于P（NIPAAm-co-AAm）可逆的伸缩转变变化，即使纳米粒子返回血液循环，也可以实现对配体的可逆屏蔽作用。结果表明，与不可逆配体屏蔽系统相比，该系统可有效延长血液循环（24 h时为1.6倍），降低免疫系统清除率（降低28％）和增强肿瘤蓄积（提高37％）。 。该策略显示出比不可逆系统明显更好的肿瘤抑制作用（高11％）。所有这些结果清楚地表明，配体可逆屏蔽策略是有效的，并且为改善肿瘤积累的纳米材料的设计提供了重要的参考。意义声明：本文研究了配体可逆性屏蔽策略在肿瘤治疗中的实用性。将配体生物素，顺铂负载链聚（丙烯酸）-Pt和屏蔽链段热敏性聚（N-异丙基丙烯酰胺-共-丙烯酰胺）（LCST约为39°C的P（NIPAAm-co-AAm）） -修饰到金纳米星的表面上。这种经过精心设计的NP可以屏蔽血液循环（37°C）中的目标配体，并在肿瘤部位（40-41°C）可逆地对其进行屏蔽。结果表明，该系统可以延长血液循环（24小时时为1.6倍），通过分析铂，与不可逆配体屏蔽系统相比，可有效降低免疫系统清除率（降低28％）并有效地增强肿瘤蓄积（提高37％）。值得注意的是，该策略显示出比不可逆系统更好的肿瘤抑制作用（高11％）。