新型標靶性奈米蛋白質載體搭載鉑類化療藥物應用於人類大腸直腸癌之應用

Abstract

目前臨床上對於大腸直腸癌的治療，除了手術以外輔助性的化學治療能顯著降低接受治療的病人大腸直腸癌的復發機率，鉑類藥物也是目前臨床上常用的化療藥，鉑類藥物的作用機制是阻斷DNA的合成，在第一代的cisplatin雖然有好的治療效果但因為其副作用造成病人的不適,因此研究者們發展出目前臨床在用的第三代鉑類化療藥物oxaliplatin，雖然oxaliplatin的副作用沒有cisplatin那麼高,但還是會產生腎毒性及神經毒性的副作用影響病人的生活品質，所以大家開始結合不同的藥物載體，希望透過搭配奈米載體可以有效提升其療效並且降低副作用，DACH-Pt為oxaliplatin的作用形式，因此在我的實驗中選擇DACH-Pt做為要搭載的藥物。 蛋白載體是一種新型藥物載體，在我的研究中我選擇脫鐵蛋白（Apo），它是由24個亞基組成的球狀鐵蛋白。脫鐵蛋白會在中性環境下自我形成中空納米載體，其具有12奈米的外徑和8奈米內徑，這能擁有更長的循環半衰期和更好的腫瘤累積率，它是原本就存在於動物體中的蛋白質，所以該載體具有高的生物相容性且是生物可降解的。最近的研究中發現，脫鐵蛋白通過與轉鐵蛋白受體一（TfR1,CD71）相互作用連結到人類細胞上，在一般情況下，為了維持細胞內的鐵濃度的平衡，細胞對於轉鐵蛋白受體一會有一程度的表現量。轉鐵蛋白受體一高度表達於人大腸癌細胞是眾所皆知的事情，長期以來轉鐵蛋白受體一一直被視為標靶指標作為腫瘤的診斷與治療。脫鐵蛋白在酸性（pH值= 2）的環境下會崩解，且此過程是可逆的。當pH值回到中性，脫鐵蛋白將重新回復成一個空心的載體形式，並且幾乎不會有任何的改變，因此，我們可以利用這種特性來有效率地將藥包覆。

Currently clinical treatment for colorectal cancer, in addition to surgical, adjuvant chemotherapy can significantly reduce the chances of recurrence of colorectal cancer patients. Platinum drugs mechanism of action is to block DNA synthesis, the first generation of cisplatin although have good treatment, but because of its side effects induce patient discomfort, so researchers have developed current clinical use of third generation platinum drugs oxaliplatin (Oxa). Although oxaliplatin side effects compared to cisplatin is not so high, but the side effects of nephrotoxicity and neurotoxicity affect the patient's quality of life, so we began to combine different pharmaceutical carriers, hope with nanocarrier can enhance the efficacy and reduce side effects. Dichloro(1,2-diamino-cyclohexane)platinum(II) (DACH - Pt) is oxaliplatin active form, so in this study, we use the DACH - Pt as carried drugs. Protein carrier is a novel drug carrier, in my study I choose apoferritin (Apo), is a spherical iron storage protein composed of 24 subunits. Apo protein self-assembles naturally into a hollow nanocage with an outer diameter of 12 nm and an interior cavity 8 nm in diameter, this may lead to a longer circulation half-life and a better tumor accumulation rate, and it is a protein present in animal body, so the carrier has a high biocompatibility and biodegradable. Recently, it was reported that apoferritin binds to human cells via interacting with the transferrin receptor 1 (TfR1, CD71), and under normal circumstances the cells in order to maintain the balance of intracellular iron concentration so regard to a certain degree of expression TFR1. It is well known that TfR1 is highly expressed on human colorectal cancer cells and has long been used as a targeting marker for tumor diagnosis and therapy. The Apo nanocages can be collapse in an acidic environment (pH = 2) into subunits, and the process is reversible. When the pH is turned back to neutral, the Apo subunits will be reconstituted into a hallow structure, and almost in an intact appearance, so we can use this characteristic to achieve effectively loading into the cavity, such as pH dependent disassembly and reassembly can be exercise of construct Apo.