設計與合成磁酸鹼敏感型含鈣磷酸鹽包覆雙性明膠奈米藥物載體於癌症治療之研究

Abstract

本研究為設計與合成一種多功能且能包覆不同藥性之奈米藥物載體，其載體的主體為一種由親/疏水雙性改質之明膠經自我組裝的方式，形成奈米粒子來作為藥物載體之核心結構。並可藉由不同實驗參數的調控如疏水性分子的種類及不同親水性之官能基，進而改變其不同接枝率和微胞濃度。雙性明膠分子，可在溶於水溶液後，自我組裝形成奈米級尺寸的奈米球結構。此結構能夠使其擁有更多的空間來裝載藥物，大量提升疏水性藥物包覆率。並可藉由不同親疏水性的變化來做為不同速度的釋放之載體。雙性明膠利用自組裝的特性使其得以在不破壞藥物本身的活性下完成藥物的包覆工作，得以保存最佳藥物活性。雙性明膠奈米球結構擁有能夠有效包覆各種藥物分子、如抗癌藥物等。此外，雙性明膠本身具備的負電荷可與正電荷之離子有電荷吸引的作用，因此可利用此方式與一些生物礦物結合，設計與製備出一種具酸鹼敏感及磁性之新型核-殼奈米藥物載體，利用乳化步驟包覆疏水性藥物及磁性奈米粒子，製備出磁性雙性明膠奈米球體之藥物載體，再者，將氧化鐵@雙性明膠奈米球體作為核心，並利用共沉法的方式，同時在形成氫氧基磷灰石殼層的過程中，同時加入親水性藥物分子，將親水性藥物分子完美的包覆於殼層當中，此包覆藥物的方式可以氧化鐵/雙性明膠@氫氧基磷灰石載體同時包覆兩種不同性質之藥物分子，形成雙藥載體。此時由於藥物包覆在不同位置，而核心與殼層之藥物釋放機制不同，因此可以造成不同階段藥物釋放行為。此外，可以利用特殊的磷酸根分子鍵結在氫氧基磷灰石的表面提供官能基，進一步再載體表面修飾上抗體，使載體本身具有標靶辨別，並提高癌症的治癒療效。而且藥物的釋放行為，則因為氫氧基磷灰石殼層會在酸性溶液下溶解，而且若外在環境酸性程度越高則藥物釋放越快速，因此達到有效控制藥物分佈。 此藥物奈米載體之材料特性與藥物的結合特性，除了具有控制釋放藥物可利用磁性氧化鐵粒子來當作磁場引導，並同步監測藥物載體的位置情形，磁振顯影(MRI)的顯影劑用於偵測腫瘤細胞位置，可將大量的抗癌藥物累積及控制藥物的釋放，以達到腫瘤治療的效果。

The investigation discloses that amphiphilic gelatin derivatives modified by hydrophobic functional groups can be formed nanoparticles in aqueous solutions by self-assembly. Control of synthetic parameters included the type of hydrophilic and hydrophobic functional groups, the ratio of the degree of hydrophobic substitutions and critical aggregation concentration (CAC). This amphiphilic gelatin nanoparticle can be used as a drug carrier for various therapeutic purposes. The positively-charged ions attract toward carboxyl group of amphiphilic gelatin by electrostatic interactions to permit the deposition of biomineral on the surface of nanoparticles. Therefore, An amphiphilic gelatin-assembled iron oxide/calcium phosphate core-shell (AGIO@CaP) nanoparticle were developed for co-delivery of anti-cancer drug Camptothecin (CPT) and doxorubicin(DOX) where the hydrophobic agent (CPT) was encapsulated via emulsion with an amphiphilic gelatin core, and the hydrophilic drug (DOX) was encapsulated through precipitation on a CaP shell. Release studies from core/shell carriers showed the possibility of achieving sequential release of more than one type of drug. In addition, we proposed the surfactant-free method to link targeting ligand (Herceptin) on AGIO@CaP nanoparticles based on the affinity of Amifostine binding calcium phosphate. This strategy with the simultaneous formation of CaP-DOX nanostructure provided high biocompatibility and a highly pH-sensitive control when the AGIO@CaP nanoparticles were subjected to acidic environment such as cancer tissue or subcellular endosome. Furthermore, the AGIO@CaP nanoparticles combining advantages of magnetic nanoparticles and calcium phosphate can be optimally tuned to realize a multifunctional nanodevice with integrated modalities including drug delivery, environmentally-responsive intracellular release and MR imaging.