水溶性鑭系元素摻雜的能量上轉換奈米粒子: 合成、分析與作為近紅外光驅動光動力療法之光敏劑探討

本研究中，我們開發出一個可以吸收近紅外光而驅動光動力療法之複合材料，而在材料的合成上採用layer-by-layer (LBL)的策略，將不同化合物修飾在奈米粒子。首先我們利用具有能量上轉換之摻雜鑭系元素奈米粒子(upconversion nanoparticles; UCNP)作為複合材料的主體，接著使用檸檬酸鈉進行Ligand Exchange，將UCNP表面上的油酸分子置換成檸檬酸根，藉此將UCNP修飾為水溶性並且表面帶負電。接著利用靜電吸附力將表面帶有64個NH2的第四代G4 PAMAM 樹枝狀高分子固定在UCNP表面上。帶有負電荷的三重態光敏感劑Ce6，再藉由靜電作用力吸附在奈米粒子的最外圍，而得到具備光動力療法的複合材料。相較於一般化學修飾法，透過LBL靜電吸附法便能夠快速而方便地將材料製備出來。接著使用980nm近紅外雷射光照射UCNP複合材料，當產生能量上轉換而釋放出三種不同波長的螢光-紫外光(365nm)、藍光(460nm)、紅光(660nm)。這三種光就會激發吸附在材料表面的Ce6，當能量轉移給周邊的三重態氧分子產生單重態活性氧分子，進而達到光動力療法的目的。在細胞實驗中，發現複合材料沒有毒性而且當複合材料吸附在低濃度Ce6(0.25μM)並藉由紅光驅動光動力療法，其細胞毒殺效果可達62.4%而單一藥物-Ce6僅12%，所以透過複合材料能夠有效增強光動力療法療效。此外，當利用近紅外光雷射驅動光動力療法其細胞毒殺效果將近70%。在未來希望能夠將此複合材料進行動物實驗來測試實際抑制癌細胞的效果。

關鍵字

上轉換奈米粒子；能量上轉換；樹枝狀高分子；光動力療法；逐層吸附法

並列摘要

In the study, we successfully synthesized a hybrid material that can carry functional molecules through a layer-by-layer (LBL) absorption strategy to perform near-infrared light (NIR)-promoted photodynamic therapy (PDT). First, the NIR-triggered PDT system was based on the lanthanide-doped energy upconversion nanoparticles (UCNP); then, the hydrophobic UCNPs were turned into the carboxylate-functionalized UCNP by exchanging the oleic acid with citrate ligands. We then loaded the G4 PAMAM dendrimers onto UCNP surface by simple electrostatic interactions between those NH2 groups of dendrimers and the COOH groups of citrate ligands. Afterward, a photosensitizer of Chlorin e6 (Ce6) bearing negatively charged COOH groups was allowed to absorb onto the dendrimer-coated UCNP by electrostatic binding. The LBL strategy provides a convenient route to prepare the stable nanocomplexes. The lanthanide-doped UCNP can emit upconverted UV, blue and red light under NIR-light excitation, and the visible light will excite the Ce6 on the UCNPs surface, followed by the energy transfer between the triplet Ce6 and surrounding oxygen to produce toxic singlet-oxygen (1O2), thus achieving the NIR-triggered PDT. In vitro experiments show that the NIR promoted-PDT material is nontoxic in dark but kill approximate 62% of MCF-7 cells under 660-nm (red) laser excitation at low Ce6 concentrations (0.25μM). In sharp contrast, the pristine Ce6 only kills approximately 12% of cells under the same red-light exposure. Most importantly, approximate 70% of cells is killed under the same concentration upon 980-nm (NIR) laser excitation, suggesting that the NIR-triggered is more effective than conventional red-light triggered PDT using the hybrid UCNPs as the photosensitizers. We anticipate the hybrid materials will be promising toward in vivo PDT for cancer treatment.

並列關鍵字

UCNP ； Energy upconversion ； PAMAM dendrimer ； Photodynamic therapy ； Layer-by-Layer assembly

參考文獻

1. Dougherty, T. J., An Update on Photodynamic Therapy Applications. Journal of Clinical Laser Medicine & Surgery 2002, 20 (1), 3-7.

2. Stummer, W.; Hassan, A.; Kempski, O.; Goetz, C., Photodynamic therapy within edematous brain tissue: Considerations on sensitizer dose and time point of laser irradiation. J. Photochem. Photobiol. B: Biol. 1996, 36 (2), 179-181.

3. Figueroa, E. R.; Lin, A. Y.; Yan, J.; Luo, L.; Foster, A. E.; Drezek, R. A., Optimization of PAMAM-gold nanoparticle conjugation for gene therapy. Biomaterials 2014, 35 (5), 1725-1734.

4. Liu, H.; Shen, M.; Zhao, J.; Zhu, J.; Xiao, T.; Cao, X.; Zhang, G.; Shi, X., Facile formation of folic acid-modified dendrimer-stabilized gold-silver alloy nanoparticles for potential cellular computed tomography imaging applications. Analyst 2013, 138 (7), 1979-1987.

5. He, X.; Wu, X.; Cai, X.; Lin, S.; Xie, M.; Zhu, X.; Yan, D., Functionalization of Magnetic Nanoparticles with Dendritic–Linear–Brush-Like Triblock Copolymers and Their Drug Release Properties. Langmuir 2012, 28 (32), 11929-11938.

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水溶性鑭系元素摻雜的能量上轉換奈米粒子: 合成、分析與作為近紅外光驅動光動力療法之光敏劑探討

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