光熱治療是一種藉由光敏劑吸收光產生熱而進一步殺死腫瘤細胞之引人注目的治療技術。因為生物組織在近紅外光範圍無明顯的吸收，故通常使用近紅外光以避免對健康細胞造成非特異性加熱，並可穿透至較深的組織。此外，由於電漿奈米材料可令此技術具有空間選擇性，故常做為其光敏劑。在過去十年，以奈米材料為基礎的近紅外光光熱治療受到明顯增加的重視。光熱治療用材料主要包括金奈米材料、奈米碳管、及還原氧化石墨烯等。其中，金奈米材料最受關注。最近，六硼化鑭奈米粒子已被證實具有優異的近紅外光光熱轉換特性，相較於金奈米材料，由於價格相對較低、易於製備以及具有優異的近紅外光熱轉換性質，因此可作為一種新穎的近紅外光光熱治療材料。另一方面，在過去十年，碳摻雜二氧化矽奈米材料和近紅外光上轉換材料在生物螢光顯影上也頗受到重視。它們與近紅外光光熱轉換材料的結合可形成兼具近紅外光驅動光熱治療與螢光顯影的新穎性多功能複合奈米粒子。
此外 感染性細菌引發的疾病持續造成人類死亡和殘疾，特別是從革蘭氏陽性菌所引起的感染仍然是造成人類發病和死亡的主要原因。萬古黴素是一種常用的聚肽醣抗生素，可透過與細菌終端的胜肽(D-alanyl-D-alanine)形成氫鍵，進而抑制細菌細胞壁生成，因此萬古黴素修飾的磁性奈米粒子已被開發作為有效選擇性抓取抗萬古黴素的格蘭氏陽性菌與陰性菌的親和性探針。如此，這些萬古黴素修飾的磁性奈米粒子與近紅外光光熱轉換材料的結合，可得到兼具細菌選擇性磁性分離與光熱消融雙功能的新穎多功能複合奈米粒子。
本論文係有關近紅外光光感性複合奈米粒子之製備與應用，根據上述，以近紅外光光熱轉換材料為主體，結合具螢光顯影、磁性分離或選擇性抓取等功能的材料或分子，發展功能性複合奈米粒子，應用於癌細胞的光熱治療與螢光顯影以及細菌的選擇性磁性分離與光熱消融。本論文內容共包括三個主題: (1)製備表面被覆摻碳二氧化矽之六硼化鑭奈米粒子，並探討其在癌細胞螢光顯影與近紅外光光熱治療上的應用；(2)製備表面被覆二氧化矽之六硼化鑭與摻雜Yb,Er之NaYF4所共同構成的LaB6@SiO2/NaYF4:Yb,Er@SiO2複合奈米粒子，並探討其在癌細胞近紅外光螢光顯影與光熱治療上的應用；(3)製備表面被覆二氧化矽且修飾萬古黴素之六硼化鑭與氧化鐵所構成之複合奈米粒子，並探討其在細菌磁性分離與近紅外光光熱消融的應用。
第一部分研究係製備表面被覆摻碳二氧化矽之六硼化鑭(LaB6@C-SiO2)奈米粒子，並探討其在癌細胞螢光顯影與近紅外光光熱治療上的應用。藉由改良式Stöber法以TEOS和APTES做為前驅物和碳源與進一步熱處理成功製備出六硼化鑭被覆碳摻雜二氧化矽奈米粒子。在6％的APTES/TEOS的莫耳比和350℃的熱處理溫度可得到最佳量子產率。六硼化鑭奈米粒子具備優異的光熱轉換效率，在近紅外光照射15個循環後仍保有優異的光熱轉換特性。在碳摻雜二氧化矽修飾後，所產生的LaB6@C-SiO2奈米粒子具有優異的近紅外光熱轉換性能和分別在紫外線照射或可見光照射下，可產生藍色與綠色螢光。以HeLa癌細胞做測試，結果顯示LaB6@C-SiO2奈米粒子沒有顯著的細胞毒性。然而，在近紅外光照射下，含LaB6@C-SiO2奈米粒子的細胞，細胞存活率顯著的降低至小於10％。進一步透過共軛焦顯微鏡，可知LaB6@C-SiO2奈米粒子經過細胞吞噬後存在於細胞質而非細胞核，此結果證實LaB6@C-SiO2奈米粒子的螢光顯影的功能。此外，含有六硼化鑭被覆二氧化矽奈米粒子之腫瘤在近紅外光照射後可急速升溫且保持在50℃左右。在活體光熱治療研究方面，注射表面被覆二氧化矽之六硼化鑭奈米粒子與照射近紅外光雷射之NOD-SCID小鼠的腫瘤相對體積明顯較其它條件為低。這些結果證實LaB6@C-SiO2奈米粒子確實可有效用於癌細胞的螢光顯影與近紅外光熱治療。
第二部分研究係製備由表面被覆二氧化矽之六硼化鑭與掺雜Yb,Er之NaYF4所共同構成的LaB6@SiO2/NaYF4:Yb,Er@SiO2(LaB6@SiO2/UC@SiO2)複合奈米粒子，並探討其在癌細胞近紅外光螢光顯影與光熱治療上的應用。經由LaB6@SiO2和NaYF4:Yb,Er@SiO2的結合而成功製備出LaB6@SiO2/UC@SiO2複合奈米粒子。LaB6@SiO2/UC@SiO2複合奈米粒子具有優異的近紅外光熱轉換性能與在波長980nm雷射照射下產生綠色螢光。以HeLa癌細胞做測試，結果顯示即使LaB6@SiO2/UC@SiO2複合奈米粒子濃度高至400 μg/ml依然沒有顯著的細胞毒性。然而，含LaB6@SiO2/UC@SiO2複合奈米粒子濃度為250 μg/ml的細胞在近紅外光照射10分鐘下，細胞存活率降低至小於10％，但在不含LaB6@SiO2/UC@SiO2複合奈米粒子的細胞經過近紅外光照射十分鐘後並無顯著的細胞死亡。此外，透過共軛焦顯微鏡得知，LaB6@SiO2/UC@SiO2複合奈米粒子會被細胞吞噬至細胞質，且在近紅外光照射下發出螢光。這些結果證實LaB6@SiO2/UC@SiO2複合奈米粒子可利用近紅外光照射同時達到螢光顯影與癌細胞光熱治療的功能。
第三部分研究係製備由表面被覆二氧化矽且修飾萬古黴素之六硼化鑭與氧化鐵(Van-LaB6@SiO2/Fe3O4)所構成之複合奈米粒子，並探討其在細菌磁性分離與近紅外光光熱消融上的應用。經由被覆二氧化矽殼層與羧基修飾的六硼化鑭奈米粒子將其表面藉由碳二醯胺活化，可以讓萬古黴素和Fe3O4奈米粒子鍵結於其表面，成功製備出Van-LaB6@SiO2/Fe3O4複合奈米粒子。從特性分析結果證實Van-LaB6@SiO2/Fe3O4複合奈米粒子接近超順磁，且同時保有LaB6核心優良的近紅外光吸收與光熱轉換性能以及萬古黴素捕捉 S. aureus和E. coli的能力。在近紅外光照射下，Van-LaB6@SiO2/Fe3O4複合奈米粒子確實可有效用於S. aureus和E. coli的捕獲和光熱消融。藉由磁場協助，可將捕獲細菌磁性聚集而進一步提升光熱消融的效率。

Photothermal therapy is an attractive therapy technique using photosensitizers to generate heat from light absorption and then kill the cancer cells. To avoid the nonspecific heating of healthy cells, near-infrared (NIR) light is usually utilized because the tissues are transparent in this window and deep penetration could be achieved. Also, plasmonic nanomaterials are usually used as the photosensitizers because they make this technique possess spatial selectivity. In the past ten years, nanomaterials-based NIR photothermal therapy has received considerably increasing attention. The main materials developed for photothermal therapy include gold nanostructures, carbon nanotubes, and reduced graphene oxide. Among them, gold-based nanomaterials received most of attention. Recently, LaB6 nanoparticles have been demonstrated to be an excellent NIR photothermal conversion material and might be used as a novel nanomaterial for NIR photothermal therapy because of their relatively low price, easy-preparation, and excellent NIR photothermal conversion property as compared to gold-based nanomaterials. On the other hand, carbon-doped silica nanomaterial and NIR up-conversion nanoparticles also have received considerable attention in the bio-imaging in the past ten years. Their combination with NIR photothermal conversion materials may form the novel multifunctional nanocomposites for the NIR-triggered photothermal therapy and fluorescence imaging of cancer cells.
In addition, infectious bacterial diseases continue to be a leading cause of death and disability. In particular, infections resulting from Gram-positive bacteria remain a leading cause of morbidity and mortality in human. Since vancomycin is a commonly used glycopeptide antibiotic which can inhibit the cell wall synthesis by forming hydrogen bond with the terminal D-alanyl-D-alanine (D-Ala-D-Ala), the vancomycin-modified magnetic nanoparticles have been developed as an effective affinity probe to trap vancomycin-resistant Gram-positive or negative bacteria selectively. Thus, their combination with NIR photothermal conversion materials could yield a novel multifunctional nanocomposite with both functions of selective magnetic separation and NIR photothermal ablation of bacteria.
This dissertation concerns the fabrication and application of near infrared (NIR)-photoresponsible composite nanoparticles. According to the above, the functional composite nanoparticles combining the NIR photothermal conversion materials and the materials or molecules with the functions of fluorescence imaging, magnetic separation, or selective capture are developed for the photothermal therapy and fluorescence of cancer cells as well as the magnetic separation and photothermal ablation of bacteria. The contents include: (1) prepare the LaB6 nanopartilces with carbon-doped silica coating and study their application in the fluorescence imaging and NIR photothermal therapy of cancer cells; (2) prepare LaB6@SiO2/NaYF4:Yb,Er@SiO2 composite nanoparticles and study their application in the NIR fluorescence imaging and photothermal therapy of cancer cells; (3) prepare the vancomycin-modified LaB6@SiO2/Fe3O4 composite nanoparticles and study their application in the magnetic separation and NIR photothermal ablation of bacteria.
The first part concerns the preparation of LaB6 nanopartilces with carbon-doped silica coating (LaB6@C-SiO2) and their applications in the fluorescence imaging and NIR photothermal therapy of cancer cells. LaB6@C-SiO2 nanoparticles have been fabricated successfully via the modified Stöber method and the followed heat treatment with TEOS and APTES as the precursor and carbon source, respectively. The optimal quantum yield was obtained at an APTES/TEOS molar ratio of 6% and an annealing temperature of 350oC. The LaB6 nanoparticles have excellent photothermal conversion efficiency. After irradiated near infrared laser 15 cycles, they still retain excellent photohermal conversion characteristics. After the carbon-doped silica coating, the resulting LaB6@C-SiO2 nanoparticles exhibited an excellent NIR photothermal conversion property and a bright blue emission under UV irradiation or a green emission under visible irradiation. By using a HeLa cancer cell line, it was shown that LaB6@C-SiO2 nanoparticles had no significant cytotoxicity. However, under NIR irradiation, the presence of LaB6@C-SiO2 nanoparticles could result in the remarkable decrease of cell viability to less than 10%. Furthermore, by the confocal microscope, LaB6@C-SiO2 nanoparticles were found to be cellular uptaken in cytoplasm rather than nucleus, which also confirmed their function of fluorescence imaging. Moreover, the heating curve of the tumor incubated with the LaB6@SiO2 nanoparticles under NIR laser irradiation increases steeply and is kept at around 50°C. The relative tumor volume after in vivo photothermal therapy of NOD-SCID mice treated with the LaB6@SiO2 nanoparticles followed by NIR laser irradiation decreases significantly compares to other controls. These results demonstrated that LaB6@C-SiO2 nanoparticles were indeed efficient for the fluorescence imaging and NIR photothermal therapy of cancer cells.
The second part concerns the preparation of LaB6@SiO2/NaYF4:Yb,Er@SiO2 (LaB6@SiO2/UC@SiO2) composite nanoparticles and their applications in the NIR fluorescence imaging and and photothermal therapy of cencer cells. the LaB6@SiO2/UC@SiO2 composite nanoparticles have been fabricated successfully via the amino- functionalized LaB6@SiO2 and carboxylic-functionalized UC@SiO2 conjugated. The resulting LaB6@SiO2/UC@SiO2 composite nanoparticles exhibited an excellent NIR photothermal conversion property and a green emission under 980nm laser irradiation. By using a HeLa cancer cell line, it was shown that LaB6@SiO2/UC@SiO2 composite nanoparticles had no significant cytotoxicity even the concentration of LaB6@SiO2/UC@SiO2 composite nanoparticles was up to 400 μg/ml. However, under NIR irradiation for 10 min, the presence of LaB6@SiO2/UC@SiO2 composite nanoparticles at 250 μg/ml could decrease the cell viability to less than 10% but no significant cell death was observed under NIR irradiation for 10 min in the absence LaB6@SiO2/UC@SiO2 composite nanoparticles. Furthermore, by the confocal microscope, LaB6@SiO2/UC@SiO2 nanoparticles were found to be cellular uptaken in cytoplasm under NIR irradiation. These results demonstrated that LaB6@SiO2/UC@SiO2 nanoparticles were indeed efficient for the fluorescence imaging and photothermal therapy of cancer cells with NIR irradiation.
The third part concerns the preparation of vancomycin-modified LaB6@SiO2/Fe3O4 composite nanoparticles and their applications in the magnetic separation and NIR photothermal ablation of bacteria. Van-LaB6@SiO2/Fe3O4 composite nanoparticles have been fabricated successfully by the successive binding of vancomycin and Fe3O4 nanoparticles via carbodiimide activation onto the surface of LaB6 nanoparticles with silica coating and carboxyl functionalization. The characteristic analysis results confirm that the Van-LaB6@SiO2/Fe3O4 composite nanoparticles were nearly superparamagnetic and they retained the excellent NIR absorption and photothermal conversion properties of LaB6 cores and the capability of vancomycin for targeting S. aureus and E. coli. Under NIR irradiation, they were demonstrated to be quite efficient for the capture and photothermal ablation of S. aureus and E. coli. Furthermore, by the assistance of Van-LaB6@SiO2/Fe3O4 composite nanoparticles, the photothermal ablation efficiency could be further enhanced via the magnetic assembling of captured bacteria.

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