專題討論7:奈米醫學的基礎與臨床應用

程 序 表

S7-5
奈米科技之轉譯醫學應用
Nanotechnology in Translational Medicine
謝達斌
國立成功大學口腔醫學科/研究所

  奈米科技在轉譯醫學領域具有極大的發展潛力並涵蓋整個疾病處置的預防、診斷、治療與研發層面。成功的奈米醫學轉譯研發需要極佳的跨領域整合,其中包含化學、物理、化工、機電、分子生物學以臨床醫學等。過去由基因體國家型科技計劃與奈米國家型科技計劃累積了龐大的生物性及技術性平台與基礎建設資源,例如細胞與組織銀行、小動物疾病模式資料庫、奈微米核心設施等。都將成為奈米醫學發展的重要資源及推動力。

  我們已能人工合成奈米氧化鐵並進行統整分子磁振造影、射頻誘發局部熱化療於一體的癌症治療。此一整合性同步熱化療在動物活體實驗證實能有效控制腫瘤生長,並優於化療或熱療單一處理。而我們更進一步能合成可控制藥物釋放的多孔性奈米氧化鐵棒並已證實能進行環境控制藥物釋放。而模組化設計的的概念已應用於奈米探針的設計。我們透過分子鎖與分子鑰匙結構設計將氧化鐵奈米粒子與標靶結合子設計成功能性模組,並成功地展示其選擇性活體分子靶向磁振造影成像能力優於傳統的交聯技術。而此一平台更能針對不同疾病與臨床需求自由組裝標靶與奈米探針模組,使其臨床應用更具彈性。

  金奈米棒具有可調的表面電漿共振頻率,此一頻率取決於他們的高寬比。在接受等同其表面電漿共振頻率之電磁波照射下,金奈米粒子能產生超音波訊號,因此得以用超音波探頭檢測其位置與強度。而過高之電磁波強度則能造成高度的熱效應甚至使奈米粒子產生形變。運用此原理,我們成功的檢測局部的微體液流動,這類測量在檢測腫瘤微循環等有其價值。而由於奈米高寬比與激發波長相關,因此透過製造不同高寬比的金奈米棒能藉由結合不同的抗體或配體探針達到多分子目標的光聲測量,提供結合超音波之重要臨床分子醫學資訊。進一步,我們能在同一平台上立即透過提高雷射功率轉換光為熱而達到局部性高精準熱治療,藉由破壞細胞膜的完整性殺死癌細胞於原地,而大幅降低副作用。

  進一步透過金奈米粒子與特殊設計的寡合酸連結則能藉由三股核酸的特異性結合將整個復合體標示於標靶基因序列上,並透過光化學反應形成之活氧基對進行雙股目標DNA的專一性切割,達到永久性基因表現抑制。此一設計以在細胞中成功實現,能將報導基因及功能性抗藥基因切除。

  許多奈米科技新的生物醫學應用正在快速的發展中。奈米粒子與影響生命現象之健康與疾病的生物巨分子在同一個尺度範圍,因此整合奈米科技與分子醫學據有其基本面的利基。而探討生物系統與奈微環境的交互作用更是一個重要而代開發的領域。整合奈米工程與分子醫學已是一全球趨勢,而即將開啟一全新的微觀醫療時代。

Nanotechnology holds a great potential in the translational development of medicine. It covers the spectra of the entire advanced disease management including prevention, diagnosis, treatment, and research aspects. Successful translational nanomedicine development required excellent interdisciplinary integration, which contains the chemical, physical, chemical engineering, electromechanical, molecular biology and clinical medicine. A tremendous bases in the biomedical and nanotechnological platforms and infrastructure have been established by the National Science and Technology Program Projects in Genomics and Nano science and technology. Examples include cell and tissue banks, small animal disease model database, nanotechnology core facilities etc. These will become important resources and driving force for the development of Nanomedicine in Taiwan.
We have synthesized nano iron oxides and integrated the particles in molecular magnetic resonance imaging and the RF induced local hyperthermo-chemotherapy for cancer diagnosis and therapeutics in one platform. This integrated synchronized hyperthermo-chemotherapy showed promising disease control in the in vivo animal experiments, and outperform chemotherapy or hyperthermia alone. We were able to further synthesize porous iron oxide nanorods with porous structure to load drugs within. With the LbL technology, we developed such nanorods into a precision environment controlled drug release carrier and proved their therapeutic efficacy in cancer cells. In addition, we implemented the modular design concept at the nano scale for disease targeting nanoprobes. Through engineering molecular key and lock on the functional nanoparticle surface and the targeting molecular probes such as antibody or ligands, respectively, we could separate the functional module and the targeting modules into different compartments. We successfully demonstrated selective in vivo molecular targeted MRI imaging better than the traditional cross-linking technology could achieve. This platform improves flexibility of the nanoprobes in different clinical applications through selective re-assembly of the targeting and the functional nanoparticles.
Gold nanorods have tunable surface plasmon resonance frequency associated with their aspect ratio. The electromagnetic irradiation that matches their surface plasmon resonance frequency will induce the nanoparticles to produce ultrasonic signals to be detected by the transducer. Higher intensity electromagnetic waves could induce high heat and even to deform the nanoparticles. Using this principle, we successfully detect local micro fluid flow rate that applicable to the detection of tumor microcirculation. Multiplex photoacoustic imaging of multiple molecular targets were achieved by combining different antibodies or ligand probes with particles of different aspect ratio. Thus offers a combination of ultrasound imaging and localized high-precision hyperthermia therapy to significantly reduce side effects.
Further, gold nanoparticles combined designed oligonucleotides were able to form triple-strand DNA on the target gene sequence. Through a photochemical reaction, the oxygen radical pair would attack the double-stranded target DNA and induce double stand break at desired site to achieve permanent gene expression inhibition. This design has successfully demonstrated in the cell using reporter genes and functional genes associated with cancer drug resistance.
Nanomedicine is rapidly developing field. The nanoparticles and biological macromolecules fall in the same size range and their integration is an yet to be fully explored field. The integration of nano engineering and molecular medicine is a global trend that anticipated to transform our clinical disease management in the near future.