智慧型生物訊號誘導藥物釋放系統前瞻研究---以癲癇症為模式---應用於訊號誘導藥物釋放系統之智慧型生醫複合材料結構製程與性質研究---總計畫及子計畫二(I)

Abstract

傳統的藥物釋放僅利用藥物載體的特性與所在的環境變化來運作，在人體中並未真正達到 完善地控制釋放的目標，因此更完善的藥物輸送系統應當利用生物性刺激來達到更精準釋放的 效果，換句話說，當病人需要藥物時，藥物載體可以自我「偵測」出此訊號，並且立即的釋放 所需的藥物。此類的生物刺激型的藥物載體可使用於慢性疾病，例如本計畫之重點疾病研究- 癲癇，如此處理之後相信可減少釋放時不必要的副作用產生與不當的釋放藥物劑量。 本研究計畫主要是要發展一種具有智慧型快速反應型的藥物結構釋放系統，因此本跨領域 研究團隊提出一創新的構想，利用藥物載體的製程控制，來發展具有電/磁敏感性的奈米或次 微米的核殼膠囊結構，進而利用自組裝及表面偶合，來建構智慧型奈米複合生醫材料厚膜 (membrane)元件結構，此智慧型載體因本身奈米複合結構具有高度的電/磁敏感性，可感應來 自當人體內部由於疾病發作時所產生的病理訊號或病徵，例如癲癇症的瞬間放電，經由訊號的 判讀、偵測及轉換成為電場或磁場誘導之訊號，來刺激或啟動此智慧型奈米複合材料結構及形 態的改變，進而釋放出適當藥物劑量，以達到有效疾病預防或治療的效果。而且藥物的釋放量 大小及模式，是可以經由生物體所產生的電場訊號大小與此智慧型載體內部的電感應分子或奈 米粒子的濃度與大小來操控及設計。此外這種智慧型的奈米複合載體，因奈米結構的存在，可 以增加其ON/OFF 抗疲勞的特性。 由於癲癇症是一種具有危險性的慢性疾病，在發作時會突然產生局部或全面的大腦異常放 電的訊號，因此本研究計畫將開發即時偵測此異常癲癇波之系統(subproject 1)並且觸發藥物輸 送系統(subproject 2)以便在癲癇大鼠大腦局部釋放抗癲癇藥物(subproject 3)，期望能夠即時抑 制此突發性之異常癲癇波，以降低傳統藥物控制下突發性癲癇發作時可能造成的個人與社會之 損失。本計劃整合奈米材料科學與生物領域，設計與發展出新穎的藥物輸送系統，透過生物反 應或刺激訊號來，達到控制釋放藥物。因此整個研發團隊至少需要有材料、電機資訊及生物醫 學等相關人力來參與。包括(1)交通大學/材料科學與工程學系 陳三元教授 (2)成功大學/資訊 工程系及醫學資訊所 梁勝富助理教授 (3)成功大學/認知科學所 蕭富仁副教授。來研發此種 利用奈米複合材料及結構，使其具有自我診斷與釋藥，以達到疾病預防與治療。

Controlled drug release has been received greatest attention worldwide since the past few decades because it revolutionizes the use of a given active drug with a therapeutically smarter, more effective, and more patient-wide compliant manner to treat diseases. However, up-to-date, almost all of those existing drug delivery systems required an external control system to trigger the release of drug and in some cases, can hardly meet immediate urgent physiological needs and with dosing compatibly match chronological changes. Therefore, it is more technically desirable and therapeutically effective if the fast-acting drug delivery system can be triggered by a biologically-induced mechanism and releases drug effectively and locally into patient』s body instead of dosing via an externally-controlled system. In other words, drug can be released in a highly controllable manner if the drug delivery system is able to 「sense」 or 「detect」 the need of patient according to the disease state of patients, in particular for chronic diseases such as dysrhythmic complications, i.e., epilepsy. To fulfill such a novel drug delivery system, this research proposal designs 3 subprojects, included signaling (smart embedded) system, a smart-gel-based nanocomposite and its biocompatibility evaluation, and in-vivo disease model. The signaling system is focusing on detection and translation of a specific biological response, i.e, spike-wave discharges for epileptic syndrome, from disease host (rat or rabbit), and a suitable signal is further triggering a magnetic or electrical field to cause a bursting of drug from the smartgel composites into the disease host. The layer-by-layer deposition and nanocapsule assembly process will be used to develop the smartgel composite with core-shell structure where the drugs were entrapped within core. The dosing of this anti-epileptic drug has to be designed according to the intensity of the signal and the controlled deformation of the field-stimuli smartgel, where a therapeutically effective dosing can be properly administered. The research objectives of this proposal are then aimed to (1) integrate field-sensitive nanomaterials technology to life science (2) build a novel drug delivery system that has yet to be developed, (3) fulfill the practical and clinical needs for patients suffering from chronic diseases (epilepsy), (4) build physical and biological models in relation to both in-vitro and in-vivo evaluation for such a 「biosignal」-「field intensity」-「dosing」 correlation, and (5) establish a medical device system to eliminate or minimize in advance the occurrence of a disease before it is fatally activated. Therefore, an intimate collaboration of different expertises from the fields including (1) computer science, (2) biomaterial science, drug delivery technology, and (3) biomedical science will be systematically integrate in order to build up a smart and useful biologically-triggered drug delivery system for epilepsy treatment.