奈米藥物載體同時包覆Sunitinib 及Doxorubicin 結合光動力治療與化療於抗藥性癌症的應用

Abstract

癌症長年為全國十大死因之首，許多在初期有效的抗癌藥物會隨著治療時間越久，癌細胞產生突變產生抗藥性而失效，為了有效治療癌症，聯合療法為目前研究致力的方向。在此實驗，我們想藉由藥物載體同時包覆藥物Doxorubicin及Sunitinib(sutent)，透過藥物Doxorubicin達到藥物化學治療效果，以及藥物Sutent照射特殊波段光源產生ROS來達到光動力治療效果。Doxorubicin為現今常見的化療藥物，其作用機制為抑制DNA合成，常用於治療血癌、乳癌等其他各種癌症。Sutent為一種能抑制多種與腫瘤生長及血管生成相關的酪胺酸激酶受體的小分子化合物，會累積在細胞中溶酶體內，近期被發現此藥物同時也具有光感藥物性質，在照射特定波長光源後可以產生ROS以治療腫瘤細胞。然而此藥物的最佳吸收波長為430nm，此波段光源能夠抵達照射的範圍較短，在進行光動力治療上會造成很大的限制，為了改善其缺點，我們使用了雙光子雷射光源，讓原子或分子同時吸收兩個光子而躍遷到高能階，進而激發光動力藥物，達到腫瘤治療的效果。

Combination therapy has become a new trend in oncology since its potential to improve treatment response, minimize development of resistance or adverse events. Herein, we report a nanoparticle encapsulate two anti-cancer drugs to achieve synergic therapeutic efficiency of photodynamic therapy and chemotherapy through two-photon laser. Due to its high bio-compatibility and excellent bio-degeadability, mPEG-PCL was utilized as drug delivery vehicle material. Doxorubicin (DOX) and sunitinib (sutent) were both encapsulated in empty mPEG-PCL micelles as sutent/DOX NPs and achieve Enhanced Permeability and Retention (EPR) effect to accumulate in tumor. As to the results, the sutent/DOX NPs were with an average diameter around 110nm and the encapsulated efficiency were more than 60%. Morphology was further confirmed by TEM image. In addition, sutent/DOX NPs showed a great ability to generate ROS after exposed to a specific region of laser. However, obstacles for the region of laser to activate sutent is with low permeability and not ease to achieve the tumor. Two-photon laser was utilized in the experiment according to its high permeability compare to the normal 430nm laser. MCF-7 cells and MCF-7/ADR cells were utilized in the in vitro experiments. Experiments about DOX IC50 was measured to ensure the drug resistance of MCF-7/ADR cells. Regarding to the cell viability test, sutent/DOX NPs triggerd by laser were quite efficient to kill the MCF-7/ADR cells. As a result, the co-loaded nanoparticles would simultaneously achieve PDT treatment and chemotherapy effect to kill drug-resistant cancer cells.