摘要:本研究計畫將開發癌症篩查測試的創新技術 – 新技術可實施在任何生物材料,不需要昂貴的設備進行判數,且期望技術的開發未來能實現在小型化的手持設備使用已普及生醫材料)。眾多強有力的文獻證據均顯示,有潛在癌症可能的患者在其呼吸道或尿液的代謝物中存在著可以標定癌症的物質,也被證明可以成為檢測潛在癌症的指標。在我們過去的研究中,已經開發具備可以重複切換表面化學/生物特性的改質材料,實現可重複調控的表面親疏水性,可重複或是連續改變的表面化學或生物操控特性,這些技術也被成功實施在各種不同的生物材料基材之上;基於這些核心技術,我們更進一步認為,透過分子設計產生疏水側鍊可用於檢測脂質化蛋白質,並結合親水的終端分子設計,實現疏水/親水開關的表面特性。這種方法具有潛在的兩個主要優點:增強的專一性 - 目前是脂質檢測的一個主要挑戰 - 可以通過定制的結合分子實現如鑷子般的結合狀態(分子鑷子),(ii) 結合狀態的可切換特性可造成一個動態的檢測範圍,可以精確提升判讀臨界線以及基線的波動範圍,此一波動範圍也可藉由主動的操控(例如電性,磁性,溫度,化學親和性等等)來進行額外調控。特別是(ii)的性質,將解決代謝感知的一個非常重要的基本特性 – “代謝物濃度波動範圍 (the widely fluctuating range of metabolite concentrations)”, 是許多國家衛生研究機構在此一性質重要的研究方向。另外一方面,與傳統的檢測方法相比,本計畫下利用“智能表面”為機構的檢測方法可以在復雜環境下(例如,尿液或呼吸)具備更佳的篩選能力以及可操控的能力,也非常適合用來實現更廣泛以及更大量的篩檢活動,再者,此一可重複調控的“智能表面”機構技術可以確保連續採樣以及調節動態篩選範圍,此特性在面對代謝物等等感知物質時,是至關重要的課題。本計畫的具體目標如下:
1.設計和合成用於檢測標記物的功能性分子(具備分子開關能力)。
2.癌症專一性標記分子的基本篩選平台的驗證: 化學以及生物驗證。
3.開發此一篩選平台之動態模型: 確認生物標記物質與平台間的動態相互作用機制以及範圍。
研究計畫的成功,將能帶來新的癌症感測技術並更能將複雜的癌症感測技術普及在材料的選擇上以及使用者的層級: 使用價格經濟的材料或裝置即可搭配本技術,可以卻效實現利用尿液或呼吸中的代謝物來檢測潛在癌症指標。
Abstract: The proposed research aims to develop innovative technology that could ultimately lead to new cancer screening tests — ones, which will not require expensive equipment for read-out, but rather will be compatible with miniaturized systems integrated in cheap handheld devices. Strong evidencs revealed that adequate indicators include volatile cancer markers (VCMs) and/or metabolites (e.g. N1,N12-diacetylspermine, DiAcSpm) in the breath or urine have been shown to establish potentially powerful indicators for cancer. With our preliminary studies on switchable surfaces [Chen et al., ACS Applied Materials & Interfaces, 2015], [Chen et al., ACS Biomaterials Science & Engineering, 2017], [Chen et al., Journal of Materials Chemistry B, 2018] to realize switchable surface wettibility, step-wised conjugation, and programmable biological activities, we therefore hypothesize, that surfaces with molecularly designed hydrophobic binding sides could be useful in detection of lipidated proteins. This approach has potential two major advantages: Enhanced specificity – currently a major challenge in lipid detection – could be achieved by custom-tailored binding pockets (i.e. molecular tweezers), (ii) the switchability of the binding events will result in defined and stable baselines for sensing, tunability of dynamic ranges, and rechargability of the sensor chip. Especially the later aspect will address a very important aspect of metabolic sensing, the need for addressing “the widely fluctuating range of metabolite concentrations” (most recent NIH, USA and NHRI, Taiwan roadmap). In contrast to conventional screening approaches, a screening platform that relies on “smart surfaces” for signal transduction will have improved ability to be operated in a complicated environment, such as urine or breath, and thus will be amenable to widespread screening of large population groups. Moreover, the proposed “smart surfaces” can be replenished to ensure continuous sampling or to modulate dynamic screening ranges. This feature may prove to be critical when sensing metabolites, The specific objectives are as follows:
1. Design and synthesis of new molecules (molecular switches) for sensing of biomarkers.
2. Preparation and characterization of basic screening platforms for cancer-specific biomarkers.
3. Elucidating the interactions with model biomarkers.
If successful, the technology will allow for screening of hydrophobic markers, such as postranslationally modified proteins in human blood or cancer-indicative metabolites in the urine or the breath.