吲哚菁綠與PD-L1抑製劑共載全氟化碳雙納米乳用於結直腸癌光免疫治療的研製;Development of Indocyanine Green and PD-L1 Inhibitor Co-Loaded Perfluorocarbon Double Nanoemulsions for Photoimmunotherapy of Colorectal Cancer

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Title:	吲哚菁綠與PD-L1抑製劑共載全氟化碳雙納米乳用於結直腸癌光免疫治療的研製;Development of Indocyanine Green and PD-L1 Inhibitor Co-Loaded Perfluorocarbon Double Nanoemulsions for Photoimmunotherapy of Colorectal Cancer
Authors:	范舒媛;Uyen, Pham Nu Thu
Contributors:	生醫科學與工程學系
Keywords:	大肠癌;光免疫療法;吲哚菁綠;抗 PD-L1 抗體;全氟化碳;雙倍納米乳液;Colorectal cancer;photoimmunotherapy;indocyanine green;anti PD-L1 antibody;perfluorocarbon;doubles nanoemulsions
Date:	2022-01-20
Issue Date:	2022-07-13 18:16:33 (UTC+8)
Publisher:	國立中央大學
Abstract:	根據世界衛生組織 2020 年的統計報告，估計有超過 190 萬新病例和超過 900,000 例死亡病例，使結直腸癌 (CRC) 成為全球最常見的癌症之一。目前，放療和化療作為輔助治療，手術切除腫瘤組織是CRC患者的主要治療方法。儘管如此，該治療不會導致完全去除癌細胞，並且假設那些剩餘的癌細胞將從正常的身體免疫監視中去除。然而，癌細胞有不同的方式逃離人體免疫系統。近年來，免疫檢查點阻斷 (ICB) 療法已成為一種潛在的癌症治療選擇。由於癌細胞（包括 CRC 細胞）過表達 PD-L1，程序性死亡蛋白 1 和程序性死亡配體 1 (PD-1/PD-L1) 作為最重要的免疫檢查點配對之一已被深入研究。光療已獲得越來越多的認可，並被認為是一種前景光明的策略。不僅可以去除原發性腫瘤並最大限度地減少正常組織的損傷，而且光療還可以通過產生腫瘤相關劑來增加免疫原性。從這些知識來看，ICB 和光療的結合已成為一種前瞻性的治療方法，可提供強大的抗腫瘤免疫反應。本研究製備了抗 PD-L1 抗體 (PD-L1)-吲哚菁綠 (ICG)-共載全氟化碳 (PFC) 雙納米乳 (PIPDNEs) ，可為光療和免疫療法的結合提供CRC。 PIPDNES 不僅可以特異性阻斷 PD-1/PD-L1 級聯反應，還可以通過用近紅外 (NIR) 激光照射 ICG 來進行光療。通過TEM圖像，PIPDNEs首先被鑑定為球形雙層納米顆粒。使用 DLS 和 PALS，PIPDNE 具有負表面電荷 (-18.27  0.72 mV) ，尺寸為 241.90  3.04 nm。儘管與自由溶解的 ICG 相比，PIPDNEs 可以產生相對的熱療效果，但 PIPDNEs 可以在 NIR 照射下提供高單線態氧產生，從而對癌細胞產生相對較高的細胞毒性。此外，PIPDNEs 被證明可以在體外阻斷 CRC 細胞的 PD-L1 表達。因此，PIPDNEs 為提供光療和抗 PD-L1 功效帶來了潛在的希望。;Based on the statistics report 2020 of the World Health Organization, over 1.9 million new cases and more than 900,000 death cases were estimated giving colorectal cancer (CRC) became one of the most common cancers globally. Currently, radiotherapy and chemotherapy work as adjuvants followed by surgery to eliminate the tumor tissues is the major treatment for CRC patients. Nonetheless, the treatment does not result in complete removal of cancer cells and those remaining cancer cells is assumed that they will be removed from the normal body immunosurveillance. Yet, cancer cells have different ways to run away from the human immune system. Immune checkpoint blockade (ICB) therapy has come up as a potential cancer treatment option in recent years. Programmed death protein 1 and programmed death-ligand 1 (PD-1/PD-L1) have been intensively investigated as one of the most essential immunological check-point pairings since cancer cells overexpress PD-L1, including CRC cells. Besides that, phototherapy also has been gained increasing acceptance and considered a bright prospects strategy. Not only does removing the primary tumor with minimizing the normal tissues damage, but phototherapy can also increase the immunogenicity by producing tumor-associated agents. From that knowledge, the combination of ICB and phototherapy has become a prospective treatment to offer a strong antitumor immune response. In this study, anti-PD-L1 antibody (PD-L1) - indocyanine green (ICG) - co - loaded perfluorocarbon (PFC) double nanoemulsions (PIPDNEs), were fabricated, which may offer the combination of photo- and immunotherapy for CRC. PIPDNES can not only specifically block the PD-1/PD-L1 cascade but also perform phototherapy by irradiating ICG with near infrared (NIR) laser. Through TEM image, PIPDNEs were first identified as spherical double layers nanoparticles. Using DLS and PALS, PIPDNEs have negative surface charge (-18.27  0.72 mV) and size of 241.90  3.04 nm. Even though PIPDNEs could give a relative hyperthermia effect when compared with freely dissolved ICG, PIPDNEs could provide high singlet oxygen production under NIR illumination, giving a comparatively high cytotoxicity for cancer cells. Moreover, PIPDNEs were demonstrated to block PD-L1 expression of CRC cells in vitro. Thus, PIPDNEs bring potentially promising for providing both phototherapy and anti PD-L1 efficacy.
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