可標靶integrin的鐵蛋白奈米載體於癌症治療之研究

Abstract

近數十年來各式各樣的化學治療藥物已蓬勃被開發。其中，Doxorubicin (DOX) ，俗稱小紅莓，臨床上被應用在許多惡性腫瘤之治療。儘管其具有良好的治療功效，但DOX仍引起許多劑量限制性的副作用，而心臟毒性是主要的副作用，為了減緩副作用，可以透過奈米粒子將化學藥物包裹並專一性傳遞至腫瘤細胞。至今已有多種材料組成的奈米粒子被陸續開發出來。然而，這些奈米粒子的生物相容性和代謝機制限制了它們的臨床應用。最近，因ferritin (鐵蛋白) 的特性而被提出其為奈米粒子的可能性，ferritin是鐵轉運蛋白，由24個單體組成，可以自組裝成球體。由於鐵蛋白具有精確的奈米形狀，高生物安全性，高生物相容性，並且可以包覆多種類型的藥物，因此鐵蛋白具有應用於分子影像和治療的潛力。在本篇研究中，具標靶integrin α2β1的鐵蛋白被生產出來，用於增強其和高表現integrin α2β1的癌細胞的結合能力，而integrin α2β1主要是collagen I (膠原) 的受體，在各種腫瘤細胞中高度表達出來。與未修飾的鐵蛋白相比，具標靶integrin α2β1的鐵蛋白作為奈米載體更有潛力用於腫瘤治療。具標靶integrin 的鐵蛋白顯示出比鐵蛋白有更好的DOX包覆效率和產量。透過共軛焦顯微鏡觀察，具標靶integrin的鐵蛋白在兩株具高integrin α2β1表現量的細胞株－U-87 MG和PC3細胞上顯示出較好的細胞結合力，另外，在U-87 MG和PC3細胞中，具標靶integrin的鐵蛋白包覆DOX比鐵蛋白包覆DOX和DOX相比，具有較高的細胞毒性。在小鼠腫瘤模式實驗中，包覆著DOX的標靶integrin的鐵蛋白明顯地能抑制腫瘤生長以及具有標的腫瘤的能力。根據我們的研究結果，顯現具標靶integrin的鐵蛋白具有成為新型的抗癌奈米載體的潛力。

Various potent chemotherapeutic drugs have been developed over decades. Doxorubicin (DOX) has clinically usage in a wide range of malignancies. Despite its profound therapeutic efficacy, DOX causes numerous dose-limiting side effects and cardiotoxicity is the main one. To eliminate side effects, targeted delivery of chemo-drugs to tumor cells can be achieved via nanoparticles. Many promising nanoparticles consisted of various materials have been developed. However, biocompatibility and metabolism issues related to these nanoparticles have limited their clinical applications. Recently, ferritin which is iron-transport protein consisting of 24 subunits that could self-assemble into a shell-like sphere, have been investigated. Because ferritin have the precisely nanoscale shape, high biosafety, high biocompatibility, and could encapsulate many types of drugs, ferritin has the potential for in vivo imaging and therapeutic agent. In this study, integrin-targeted ferritin with the integrin α2β1-targeting peptide on the ferritin surface was produced to enhance and specifically target cancer cells with high expression of integrin α2β1, a major collagen receptor that highly expresses on various tumor cells. In comparison with unmodified ferritin, integrin-targeted ferritin has enhanced potential as nanoveichle for tumor therapy. Integrin-targeted ferritin showed higher DOX loading efficiency and yield than ferritin. Integrin-targeted ferritin showed strong cellular binding on U-87 MG and PC3 cells by confocal microscopy. Moreover, DOX-encapsulated integrin-targeted ferritin showed higher cytotoxicity effects than DOX-encapsulated ferritin and free DOX in U-87 MG and PC3 cells. Furthermore, DOX-encapsulated integrin-targeted ferritin showed significant inhibition of tumor growth and accumulation in tumors in vivo. All of our findings supported that integrin α2β1-targeted ferritin has the potential to be a novel anticancer nanomedicine.