Fluolab【Adv.Mater.】天津大学李振、武文博联手南方医科大学胡方|性能飙升14倍！消除同耦合缺陷，开启光疗新纪元
通讯作者： Fang Hu, Wenbo Wu, Zhen Li
文章概要
引言
在材料的合成与制备过程中，缺陷往往是难以避免的，而这些极少量的缺陷有时会对材料性能产生巨大影响。共轭聚合物（CPs） 因其卓越的光物理性质，被广泛应用于生物传感、成像和疾病治疗。特别是供体-受体（D-A）交替型共轭聚合物，因其吸收波长易调控至近红外区而备受关注。然而，传统的Suzuki或Stille偶联反应在制备这些聚合物时，不可避免地会引入D-D或A-A同耦合缺陷。这种结构缺陷如何影响生物医用共轭聚合物的性能，一直是该领域被忽视的关键科学问题。理论上，同耦合结构会形成电荷“陷阱”，阻碍激子在共轭主链上的扩散，从而削弱聚合物的性能优势。
The effects of structural defects on material performance. (a) Some previous work on how defects significantly affect the final performances of materials or devices. MA, Cz, and BD are short for methylammonium, 1H-benzo[f]indole, and carbazole, respectively. (b) The idea of this work: differences between alternating CPs with or without homocoupling defects for biomedical applications.
主要实验及结论
研究团队通过直接芳基化缩聚（DArP） 和传统的Suzuki偶联法，制备了三系列具有不同D-A结构的共轭聚合物。实验发现，所有通过DArP法制备的无缺陷聚合物在活性氧（ROS）产生效率和荧光强度方面，均显著优于对应的Suzuki法产物。最令人振奋的数据显示，PTB-DArP的羟基自由基生成效率比PTB-Suzuki高出整整14.6倍，而PDB-DArP的近红外二区荧光强度也实现了翻倍。通过在DArP体系中人工引入1%的缺陷单体进行对比验证，研究者证实了即使是极微量的同耦合缺陷，也会通过缩短激子寿命来剧烈降低材料的光疗效能。
The differences between CPs prepared by DArP and Suzuki polymerization. (a) The synthesis of PTD through both DArP and Suzuki polymerization. (b) UV-vis absorption (solid line) and photoluminescence (PL) spectra (dash line) of different CPs after forming NPs in aqueous solutions. (c) The relative ROS generation efficiencies of different CPs upon suitable laser (100 mW cm−2 530 nm laser for PTB, 100 mW cm−2 660 nm laser for PTD, and 300 mW cm−2 808 nm laser for PDB) excitation by using ABDA, DHR123, and HPF as indicators, respectively. [CPs] = 1 × 10−5 g mL−1, [ABDA] = 5 × 10−5 m. [DHR123 or HPF] = 5 × 10−6 m. 530 nm or 660 nm laser: 100 mW cm−2; 808 nm laser: 300 mW cm−2.
Mechanism investigation of the influence of homocoupling defects in properties of CPs. (a) The syntheses of PTD-DArP, PTD-1%TT, PTD-1%DD and PTD-1%TT+1%DD. (b and c) UV–vis absorption (b) and PL spectra (c) of different CPs NPs in aqueous solutions. (d) The relative ROS generation efficiencies of different CPs upon 660 nm laser excitation by using ABDA and DHR123 as indicators, respectively. (e) The relative ROS generation efficiencies of PTD-DArP NPs with physical doped with 1% of different defects in them upon 660 nm laser excitation by using ABDA and DHR123 as indicators, respectively. (f) The PL and phosphorescence (P) spectra, as well as their lifetimes of PTD-DArP and PTD-1%TT+1%DD films at 100 K. (g) fs-TAS spectra of PTD-DArP in THF at indicated delay time. (h) Decay dynamics and lifetimes of PTD-DArP in THF upon excitation; (i) Schematic diagram of the influence of homocoupling defects in CPs. [PSs] = 1 × 10−5 g mL−1, [ABDA] = 5 × 10−5 m. [DHR123] = 5 × 10−6 m. 660 nm laser: 100 mW cm−2.
在深入的机制研究中，瞬态吸收光谱（TAS）和低温磷光分析揭示了无缺陷聚合物拥有更长的激子寿命和更强的能量传递能力。无缺陷的PTD-DArP不仅在660 nm临床常用激光下表现出卓越的光动力与光热协同治疗效果，还展现出了优异的生物降解能力。在小鼠肿瘤模型实验中，PTD-DArP实现了一次治疗即可达到99.0%的肿瘤抑制率。此外，在糖尿病伤口感染模型中，该材料也表现出极强的杀菌能力，帮助受损组织在13天内完全愈合。研究团队还将这一策略推广至其他已报道的高性能聚合物，同样实现了性能的跨越式提升，验证了消除缺陷策略的普适性。
Anti-tumor applications of PTD-DArP. (a) Viabilities of 4T1 cells treated with different NPs upon laser irradiation (660 nm, 500 mW cm−2, 6 min). (b) Viabilities of 4T1 cells treated with various amounts of PTD-DArP or PTD-Suzuki NPs under different conditions. Single PDT or PTT was realized by adding excess ice or Vitamin C to the system, respectively. (c) The ROS generation efficiencies of PTD-DArP and PTD-Suzuki NPs in 4T1 cells, which was also the quantification of fluorescence intensities in Figure S30. (d) Schematic diagram of in vivo image-guided antitumor phototherapy. (e, f) Fluorescence imaging (e) and quantification fluorescence intensities (f) of living mice after intravenous injection of PTD-DArP NPs (0.2 mL, 5 × 10−4 g mL−1) for different times, and ex vivo tissue and tumor imaging of PTD-DArP NPs after 48 h post injection. (g) Tumor volume changes of mice after different treatments for different times. (h) The tumor photographs of tumors after different treatments. (i) Mean tumor weight of anatomic mice tumors in different groups. (j) The body weight changes of mice after different treatments for different times. (k) H&E staining of the tumors of mice after different treatments for 17 days. (l) The serum analysis of mice in different groups. In this figure, L indicates laser irradiation, error bars indicate SEM (standard error of the mean, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 5 per group).
Anti-infection applications of PTD-DArP. (a) Viabilities of S. aureus treated with different NPs upon laser irradiation (660 nm, 500 mW cm−2, 6 min). (b) Viabilities of S. aureus treated with various amounts of PTD-DArP or PTD-Suzuki NPs under different conditions. Single PDT or PTT was realized by adding excess ice or vitamin C to the system, respectively. (c) CLSM images of S. aureus upon incubation with PTD-DArP or PTD-Suzuki NPs with or without laser irradiation (660 nm, 500 mW cm−2, 2 min), followed incubated with DCFH-DA (15 µm) for 15 min. (d) Schematic diagram of in vivo image-guided anti-infection phototherapy. (e, f) Fluorescence imaging (e) and quantification fluorescence intensities (f) of living mice after intravenous injection of PTD-DArP NPs (0.2 mL, 5 × 10−4 g mL−1) for different times, and ex vivo tissue and wounds imaging of PTD-DArP NPs after 48 h post injection. (g) Photographs of infected wounds and bacterial colonies from wound tissues after different treatments for different times. (h and i) Wound sizes (h) and body weight changes (i) of mice after different treatments for different times. (j) H&E and Masson staining of the wounds of mice after different treatments for 13 d. In this figure, L indicates laser irradiation, error bars indicate SEM (standard error of the mean, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, n = 5 per group).
总结及展望
本研究通过系统对比证实了同耦合缺陷是限制共轭聚合物光疗性能的核心瓶颈。通过采用直接芳基化缩聚法消除这些结构缺陷，不仅能显著增强材料的荧光成像亮度和活性氧产生能力，还能提升材料的生物安全性。这一发现填补了学术界关于结构缺陷影响光疗效果的研究空白，为开发下一代高效率、高生物相容性的光疗药剂提供了清晰的指导思路。未来，这种精准控制聚合结构的方法有望在生物医学成像和复杂疾病的精准治疗领域发挥更大的商业化潜力与临床价值。