奈米載體釋放系統應用於階段性藥物控制及雙藥協同腫瘤療法之研究

Abstract

癌症，早已成為全球人類的頭號殺手。在傳統的癌症化學治療方法中，癌細胞容易產生抗藥性與藥物排斥性，造成治療效果有限，因此發展出有效率的多重藥物輸送系統抑制腫瘤的抗藥性與復發乃為現今藥物釋放系統所面臨重要的課題。因此，本計畫針對「癌症藥物協同治療」的需求，發展「階段性釋放藥物」功能之奈米殼核藥物載體，可以同時包覆不同油/水相藥物，可利用材料設計出階段性釋放不同藥物，達到有效率抑制癌細胞抗藥性之功能。在材料設計上，殼層的構成主要為有機物材料，如高分子衍生物與脂質，在細胞的溶脢體中可以迅速釋放「抑制抗藥性」藥物，先達到抑制細胞抗藥性目的；在「核」的部分，用「次奈米載體」（如微胞(micelles)或是自組裝高分子/脂質載體）進行包覆小分子抗癌藥物，將藥物分子進入細胞核中進行釋放。基於此創新的研究構想，在本計畫中利用生醫材料與藥物載體的製程結合，所開發出的智慧型多重藥物釋放的奈米載體，主要具有下列特性：(1)完美包覆藥物，在未輸送到目標細胞前，能達到低漏藥釋放功能；(2)能同時攜帶親水性藥物與疏水性藥物分子，並夾帶於載體不同部分；(3)自發性階段性釋藥功能，於殼層先釋放抑制抗藥性蛋白藥物或是抗血管新生藥物，接著再釋放「載體核內」小分子抗癌藥物，達到藥物療效最佳化；(4)可藉由分子及降解特性來調控不同釋放速率。此外，於本載體中，還可以加入奈米氧化鐵，可以藉由磁場強度的改變，來「操控」內外核殼的藥物釋放的模式，以強化自發性階段性釋藥功能的效果。也可以藉由藥物載體的表面經由化學表面改質，可帶有標靶癌細胞的分子，在體內中大幅提升奈米藥物載體進入癌細胞的效率。在研究計畫後期，也將進行細胞與動物的相關評估研究。此載體具有階段性控制多重藥物釋放的功能，並且可以達到快速釋放與腫瘤標靶的功能，期望在未來能夠成為更新一代的藥物釋放系統。

In the conventional cancer chemotherapy, cancer cells are easy to produce drug resistance and drug exclusion, resulting in the therapeutic effect is limited, and therefore inhibition of tumor drug resistance and recurrence develop the efficiency of multi-drug delivery system is faced by today's drug delivery system important topic. Here, the project is focused on the development of cancer synergistic drug therapy system with the functional core-shell nanocapsules capable of multiple-drugs delivery and controlled release to achieve the efficient inhibition of cancer drug resistance and cancer therapy. The nanocapsules can encapsulate the hydrophobic and hydrophilic drugs at the same time and release the entrapped drugs by stage-controlled release. On the material design, the composition of the shell is mainly organic materials, such as the polymer derivative with a lipid, the lysosomes of cells can dissolve them to reach rapidly released "inhibitors of drug resistance" carried in shells, reached first inhibit cell resistance purposes; in the core, the sub-nanometer vector (e.g. micelles (micelles) or self-assembled polymer / lipid carrier) encapsulated small molecule anticancer drugs can be delivered to the nucleus to release. Based on this innovative idea, process combined use of biomaterials and drug carriers in this project, the development of intelligent multi-drug release nano carrier, has the following characteristics: (i) carried drugs before conveying to the target cells to achieve low leakage drug release. (ii) Nanocapsules can carry both hydrophilic and hydrophobic drug molecules, and entrained them in carrier different parts. (iii) Spontaneously stage-releases in the shell the release of to suppress resistance protein drugs or anti-angiogenesis drugs, then release the "nuclear carrier" small molecule anticancer drugs to optimize drug efficacy. (iv) Controlling degradation characteristics exhibits different release rate. On the other hand, via a chemical surface modification, the capsules have the molecular targeting ligands to significantly enhance the accumulation carrier to the efficiency in vivo. The latter part of the project will also be relevant assessment studies of cells and animals. The new insights and capabilities represent a major step to nanovector engineering for stage-controlled release multiple-drugs, potentially in treating tough cancer with multi-drug resistance in the next generation of drug delivery systems.