開發以抗體作為載體搭載鉑類藥物並針對大腸直腸癌之標靶藥物

Abstract

設計開發一以抗體作為載體並搭載化療藥物之奈米標靶藥物，利用抗體專一性標靶，將搭載的藥物專一性的送往標的癌細胞，使化療藥物在腫瘤細胞有更多更快的藥物累積，進而達到提升治癒能力以及降低副作用兩效果。選用Panitumumab這一全人類單株抗體作為載體，其能專一性的鍵結上EGFR，EGFR為大腸直腸癌臨床治療常用標靶，Panitumumab除了專一性的鍵結能力外，更能抑制EGFR下游所調控的細胞生長、分裂、DNA修復(此為鉑類藥物在臨床上治療大腸直腸癌常有抗藥性之原因)等訊息傳遞路徑。另外我們所選用搭配的鉑類化療藥物為DACHPt，是oxaliplatin的轉化物，擁有更高的毒性，但因其水溶性較oxaliplatin為差，在臨床應用上有其限制性，因而尚未應用為臨床治療藥物。我們將DACHPt以配位共價鍵接枝在Panitumumab上，並由其自組裝成約120nm大小的奈米標靶藥物，命名為Pt-Pan(N)。Pt-Pan(N)有良好的穩定度及藥物動力學特性，在血液中能穩定運輸並較長時間循環，又其大小為奈米等級，會藉由EPR effect聚集於腫瘤組織附近，除此之外，Panitumumab此EGFR抗體會有效且專一的鍵結上腫瘤細胞，並被腫瘤細胞胞吞後，經酵素水解後釋出80 %以上的攜帶藥物，有效的提高鉑類藥物在細胞內的累積量，達到毒殺癌細胞的效果。在細胞實驗中證實，Pt-Pan(N)比起臨床用藥oxaliplatin更能短時大量的被細胞吞噬，也具有更好的毒殺癌細胞的效果。在動物實驗中，也已證實比起臨床上的合併治療(Panitumumab與oxaliplatin複合療法)，Pt-Pan(N)有著更好的腫瘤抑制效果，以及降低副作用能力，因此，Pt-Pan(N)具有發展成臨床用藥之潛能。

Using the combination of Panitumumab, a monoclonal antibody, and oxaliplatin, a Pt-based drug, to treat patient with colorectal cancers (CRC) is known to be effective in clinical. It is thought that Panitumumab can efficiently bind to EGFR, inhibiting cell growth. Pt-based drug can cause DNA damage, inducing cell death. Synergistic effect is found when Panitumuamb and Pt-based drug are combined. However, new strategy to cure patients with CRC is to be explored. Therefore, In this study, to cure patient with EGFR-overexpressed CRC, our research team designed and created a novel nanoparticle, named Pt-Pan(N). Pt-Pan(N) is self-aggregated from Panitumumab conjugated Dichloro(1,2-diaminocyclohexane) platinum(II) (DACHPt), named Pt-Pan. It is noted that panitumumab in Pt-Pan(N) can serve as tumor-targeted drug delivery vehicles, efficiently facilitating EGFR-overexpressed CRC cells to take up Pt-based drug. After evaluation of in vitro cytotoxicity, cellular uptake and cellular binding, it is proven that Pt-Pan(N) has good ability to bind to EGFR-overexpressed colorectal cancer cells , resulting in more cancer cell death. Pt-Pan(N) could kill colorectal cancer cells more efficiently when compared with the results achieved by combination of Panitumuamb and oxaliplatin. In addition, evaluating the in vivo tumor inhibition, it is found that Pt-Pan(N) could help achieve outstanding antitumor efficacy. In sum, our findings suggest that Pt-Pan(N) could replace the use of combination of Panitumuamb and oxaliplatin and help achieve optimal anticancer efficacy for colorectal cancer treatment in clinical.