開發具免疫原性的氧化矽奈米粒子作為抗癌治療的酵素傳遞載體

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題名:	開發具免疫原性的氧化矽奈米粒子作為抗癌治療的酵素傳遞載體 Exploitation of Silica Nanoparticles with Immunogenicity as Enzyme Delivery Carriers for Cancer Therapies
作者:	張維元 ZHANG, WEI-YUAN
貢獻者:	奈米醫學工程研究所碩士班陳奕平吳忠哲
關鍵詞:	生物材料;二氧化矽奈米粒子 Biomaterials;Silica Nanoparticles
日期:	2022-01-13
上傳時間:	2022-08-05 10:02:24 (UTC+8)
摘要:	儘管生物製劑(蛋白質和酶)藥物在治愈許多無法治癒的人類疾病方面具有明顯的優勢，但在開發生物製劑治療方面仍有一些挑戰需要克服。癌症免疫療法現在是一種治療癌症的有效方法，可以使免疫系統增強抗腫瘤免疫力。因此，癌症免疫療法和生物製劑療法的結合為癌症治療提供了一種有前景的方法。為了實現這一目標，在本研究中，我們試圖證明中空二氧化矽奈米球(HSN-PEG) 作為誘導免疫的佐劑和作為載體遞送天冬酰胺酶的潛力，透過自佐劑性和生物製劑協同導致增強抗腫瘤功效。約為 50 nm 的聚乙二醇化中空二氧化矽奈米球(HSN-PEG)和對照奈米球的實心二氧化矽奈米球(SSN-PEG)被合成與鑑定，從 TEM 和 DLS 結果分別顯示出規則有序的結構以及在水和 PBS 溶液中的分散。HSN-PEG 處理的 4T1 乳腺癌細胞中未觀察到顯著的細胞毒性。血液與血清生化分析表明 HSN-PEG 具有生物相容性和生物安全性。為了進一步研究治療性抗腫瘤作用，接種 4T1 乳腺癌腫瘤的小鼠被以靜脈注射注入矽奈米球。與對照 PBS 和 SSN-PEG 相比， HSN-PEG 處理的小鼠可以顯著抑制 4T1 腫瘤生長，伴隨著腫瘤重量和腫瘤體積減小，這與腫瘤影像圖結果一致。流式細胞儀顯示具有自佐劑的 HSN-PEG 的免疫原性，表明 T 細胞介導的抗腫瘤免疫可以通過激活 T 細胞(IFNγ+CD8+ 和 IFNγ+CD4+)以及抑制巨噬細胞和 MDSCs。此外，L-天冬酰胺酶(ASNase) 被裝載在自佐劑性 HSN-PEG 並呈現出 ASNase@HSN-PEG。ASNase@HSN-PEG 的性質，包括大小、酶活性和裝載能力被評估。治療潛力研究顯示，在 KPC 小鼠胰臟癌細胞可以觀察到生長抑制，表示使用 ASNase@HSN-PEG 消耗 L-天冬酰胺酶可能是一種有效的治療胰腺癌的方法。 Despite apparent benefits of biologics（protein and enzyme）drugs to cure many untreatable human diseases, several challenges remain to be overcome in developing biologics therapeutics. Cancer immunotherapy is now a powerful approach to treat cancer that enables the immune system to enhance antitumor immunity. Hence, the combination of cancer immunotherapy and biologics therapy offers a promising approach for cancer treatment. Toward the goal, in this study we attempt to demonstrate the potential of hollow silica nanospheres（HSN-PEG）acting as adjuvants to induce immunity and as carriers to deliver asparaginase, resulting in enhanced antitumor efficacy via self-adjuvanticity and biologics synergistically. PEGylated hollow silica nanospheres（HSN-PEG）and control nanoparticles of solid silica nanospheres（SSN-PEG）with around 50 nm were synthesized and characterized, showing the well-ordered structure and dispersion in water and PBS solution from the TEM and DLS results, respectively. No significant cytotoxicity were observed in 4T1 breast cancer cells treated with HSN-PEG. Analysis of blood and serum biochemistry assays showed the biocompatibility and biosafety of HSN-PEG. To further investigate the therapeutic antitumor effect, 4T1 tumor bearing mice were intravenously injected with nanoparticles. As compared to control PBS and SSN-PEG, mice treated with HSN-PEG could significantly inhibit 4T1 tumor growth, followed by the decreased tumor weight and tumor volume which is consistent with tumor images results. Flow cytometry revealed the immunogenicity of HSN-PEG with self-adjuvanticity, indicating that T cells-mediated antitumor immunity could obviously be enhanced through the activation of T cells（IFNγ+CD8+ and IFNγ+CD4+）, as well as the suppression of macrophages and MDSCs. In addition, L-asparaginase (ASNase) was loaded with self-adjuvant HSN-PEG and presented ASNase@HSN-PEG. The properties of ASNase@HSN-PEG, including size, enzyme activity, and loading capacity were evaluated. Therapeutic potential studies have shown that growth inhibition can be observed in KPC cells, suggesting that asparagine deprivation via ASNases@HSN-PEG may be a useful approach for the treatment of pancreatic cancer.
描述:	碩士指導教授:陳奕平共同指導教授:吳忠哲委員:吳思翰委員:陳盈汝委員:黃姿雯委員:陳奕平委員:吳忠哲
資料類型:	thesis
顯示於類別:	[奈米醫學工程研究所] 博碩士論文

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