一種具雙性之有機-奈米金混成分子之設計, 分析及其生醫應用

Abstract

近年來Theranostic nanomedicine醫療技術受到極大的重視，因為此醫療技術在進行 藥物治療的過程中，具有多功能性並同時進行多種的醫療行為，可大幅的改善醫療的成 效，對於病患來說將是莫大的利益。但是，具多功能的nanomedicine在製作過程中需要 多步驟的合成，這將導致無法準確的預期投藥劑量及治療效果。此外，多功能性添加物(例： 標靶官能基或顯影劑)在載體中的分布不均將會使nanomedicine的行為無法預測。因此， 一種由bottom-up design 的製程方法所製作出來的theranostic nanomedicine ， 例如 nanoparticle，可達到事先預期的目標，在未來應用上的重要關鍵。 在此研究計劃中，採用本實驗室多年前所研發出來的可自組裝成奈米膠囊的兩性幾 丁聚醣(Carboxymethyl-Hexanoly Chitosan, CHC)做為開發新型混成分子的主體，經由 amidation法將特定的胜肽(peptide)接枝到CHC上，並且利用胜肽鍵末端所露出的硫醇基， 做為一種可吸引Au吸附上之有利條件，形成類似Au”ligands”的結構，藉此合成新的混成 分子，peptide-modified amphiphilic CHC-Au hybrid (termed as P-Au-CHC)。預估此新型分 子就如同CHC分子一樣，具有自組裝的功能(self-assembled capability)，可在溶液中形成 奈米粒子。此外，這些修飾在P-Au-CHC上的Au”ligands”及peptide，在P-Au-CHC自組裝 成奈米粒子的同時，會傾向暴露在奈米粒子的外層，與外在環境做接觸，因此而同時展 現出標靶、顯影及熱治療的多功能性。 更進一步，此混成分子可用來乘載藥物，在水溶液的環境下將藥物包覆於其中，形 成奈米膠囊的特殊結構。此技術一旦發展成功，將可一個步驟合成具有治療診斷等多功 能的奈米載體，不需要繁複的步驟就可將這些多功能性的官能基修飾到最終奈米載體上， 促進未來應用於集藥物釋放、細胞內顯影技術、標靶藥物、及熱治療於一體之載體技術 上。 根據所調查到的最新資料，目前國內外僅有極少數的研究或報導與此項研究計劃有 些許相關性。因此，此計畫所開發出來的新型混成奈米載體系統將是具有新穎性並結合 了物理、化學與基礎生物醫學的技術優勢，再結合臨床用藥，在生物醫學的應用上將極 具有發展潛力。

Theranostic nanomedicine has recently been received greatest attention due to its wide versatility of being performing various functions simultaneously in medication, wherein a significantly improved therapeutic/medical purpose can be highly expected and brings enormous benefits to the patients. However, multifunctionalization of a given nanomedicine requires multiple steps of synthesis, which makes precise therapeutic dose and expected drug efficacy unpredictable, and uneven distribution of the functional dopants/modifications also make un-reliable of the resulting nanomedicine, included targeting and imaging capability. Therefore, a bottom-up design of expected theranostic nanomedicine, i.e., nanoparticles, to fulfill pre-determined functionalities is critical for its final utilization. In this work, a new hybrid molecule based on an amphiphilic chitosan (namely CHC) developed from this lab years ago, followed with a peptide modification via amidation and ends up with a further in-situ Au “ligands” anchorage toward the thiol groups of the peptide moieties. The new hybrid molecule, i.e., peptide-modified amphiphilic CHC-Au hybrid (termed as P-Au-CHC), is expected to possess self-assembled capability as original CHC molecule. The presence of residual peptide and Au “ligands” (which exhibit as nanoparticles anchored along the surface of the self-assembled nanoparticles) exposed toward the environment should provide targeting , imaging and photothermal capability simultaneously. More critically, such a hybrid molecule allows to be self assembled upon encapsulation of drug(s) in aqueous solution. Once being formed, a theranostic nanocarrier can be prepared at a one-step synthesis, i.e., without further steps to multifunctionalize the nanocarrier, facilitating a further evaluation included controlled drug release, intracellular imaging, targeting (to cancerous cell), cytocompatibility, hyperthermia effect, etc. This research work, to our best knowledge, has barely been reported yet and should pave a new avenue to provide both scientific and technical advantages based on an in-depth understanding the chemical, physical, and biomedical fundamentals of this new hybrid systems toward clinically important drug molecules, associated with its potential biomedical applications.