奈米標靶檢測與毒殺致病菌-致病奈米標靶探針之研發---總計畫暨子計畫一(I)

Abstract

抗生素雖然已被廣泛使用於治療細菌感染，但當病人感染到抗藥性菌株時，有可能因為無 法及時給予適當之抗生素治療而導致病人死亡。但最近十年來在新型抗生素的開發上並沒有太 大的進展，因此開發更有效可抑制抗藥性細菌生長的方法有其迫切性。本計劃的目標是以奈米 粒子為材料，研究發展一套可有效供快速檢測及治療細菌感染的方法。我們計劃利用具吸收近 紅外光特性的功能性奈米粒子為基材，因為近紅外光具有穿透較深組織的能力，因此很適合當 作在活體實驗中熱療法的光源。我們將在奈米粒子表面修飾上可辨認細菌細胞壁的分子如萬古 黴素及抗體等，使此功能性奈米粒子成為可專一辨認目標細菌的標靶探針，在標靶探針黏附上 目標細菌後再照以近紅外光，應可達到抑制細菌生長的目的。細菌生長會被抑制的原因是因為 標靶探針在吸收近紅外光後，可以即時以熱能傳遞的方式使已黏附標靶探針的細菌表面溫度瞬 間提高，當超過細菌可耐受的溫度時便可達到抑制細菌生長的目的。本計劃將利用院內常見感 染菌如革藍氏陽性菌、革藍氏陰性菌、及抗藥性細菌為實驗樣品，探討此奈米熱療法的可行性。 本研究團隊包含了在化學領域及生物醫學領域的研究人員，期望能在細菌檢測及抑制細菌的生 長研究能有所貢獻。此跨領域計劃主要是由二個互有關聯的子計劃所組成：第一個子計劃是由 交通大學應用化學系陳月枝博士所帶領的研究團隊，他們將進行具有功能性的奈米探針的設計 及製作，以便進行快速細菌檢測的方法發展及體外測試的實驗，以確定功能性奈米探針對致病 菌之標靶熱療效能，並提供子計劃二所需的功能性奈米粒子；而第二個子計劃則是由慈濟大學 醫技系蔡佩珍博士所領導的研究團隊所執行，研究目標為利用功能性奈米粒子進行活體中熱療 標靶的實驗，他們將利用三種動物細菌感染模式進行功性奈米探針在抑制細菌感染的測試。本 計劃希望製作合成出可辨識及抑制致病菌生長的功能性奈米探針，探討其成為奈米抗生素的可 能性，期望實驗結果可提供治療細菌感染的另一新途徑。

Bacterial infections without promptly treated by appropriate antibiotics may lead to death. The cases are generally observed from the patients suffering the infections of antibiotic resistant bacterial strains. The third-generation of antibiotics such as ceophalosporins may become ineffective in many patients with nosocomial infections because the emergence of new resistant strains is increasing at an alarming rate. Thus, it is urgent to develop new types of antibiotics against these tedious pathogens. Nevertheless, there is no much progress in the discovery of new antibiotics in the recent decade. We believe that employing the unique optical features of nanoparticles to the design of the new therapeutics for pathogens is an alternative option. We plan to fabricate nanoparticles to have two functions: (1) as nanodiagnostic probes and (2) as nanotherapeutic agents, for pathogenic bacteria. It has been demonstrated that near infrared (NIR) light is capable of penetrating deeper tissues. Thus, nanoparticles capable of absorbing NIR light are very suitable to be used as the photothermal agents in vivo. The surfaces of the nanoparticles will be immobilized with either vancomycin or antibodies to have the capability of attaching onto the cell walls of pathogenic bacteria. Once the functional nanoparticles attach onto the surfaces of target bacteria, the bacteria are destroyed under irradiation by NIR light as a result of suffering from high temperature. The heat transfer from the anchoring nanoparticles directly on their target bacteria is expected to be effective under light irradiation. We will use nosocomial pathogens including Gram-positive, Gram-negative, and antibiotic resistant bacteria as the samples to investigate the feasibility of our approach. To inhibit the bacterial growth in vitro and in vivo will be investigated. This interdisciplinary research project is composed of two mutually related sub-projects: (1) Design and Construction of Functional Nanoparticles as Nanodiagnostic Probes and Nanotherapeutic Agents for Pathogenic Bacteria, led by Dr. Y. -C. Chen from the Department of Applied Chemistry of National Chiao Tung University, will put efforts on the generation of functional nanoparticles and investigates the efficacy of the functional nanoparticles in inhibiting the bacterial growth in vitro, and (2) The Protection Roles of Functional Nanoparticles in Three Bacterial Infected Animal Models, led by Dr. P. -J. Tsai from the Department of Laboratory Medicine and Biotechnology of Tzu-Chi University focuses on the investigation of the capacity of the functional nanoparticles in inhibiting the bacterial growth in vivo on the basis of three bacterial infected animal models. We expect new types of nanoparticle-based antimicrobial agents for the use in medicine diagnostics and therapeutics can be explored through our studies.