| 摘要: | 中孔洞二氧化矽奈米粒子在傳遞抗癌藥物中是非常有潛力的奈米載體， Polyethylene glycol (PEG)已經與許多奈米載體連結，並增加分散性、生物利用性以及循環時間。在我們的研究中，有三個循序漸進的目標，首先提高材料對腫瘤的標靶能力，接著控制奈米粒子的藥物釋放，並將PEGylated造成的免疫相關問題之影響降到最低。
在第一部分，我們想要找到能夠提升腫瘤標靶效率以及延長在體內循環的MSNs，在之前的研究，我們開發了幾種MSNs，其中最特別的是，同時使用polyethylene glycol (PEG)和trimethoxysilylpropyl-N,N,N-trimethylammonium Chloride (TA) 修飾的奈米粒子展現了很好的抗汙能力，因此，我們透過改變PEG和TA的比例，開發了一系列的奈米粒子，並研究PEG和TA在腫瘤標靶能力及血液循環中的重要作用。根據體外的細胞攝取，以及體內生物分布的研究，RMSN-PEG/TA (7:1) 是表現最佳的。
在第二部分中，我們結合了有機和無機材料的優點，故引入了二硫化物及pH-responsive矽烷到MSN，一般來說，無機材料在化學和機械穩定性方面被認為比有機奈米粒子好；有機納米粒子則具有比無機納米粒子更好的生物相容性和生物降解性。利用在MSN中引入環境響應分子的優點，透過腫瘤微酸環境下水解苯甲酸 - 亞胺鍵(benzoic-imine bond)並在腫瘤細胞中由GSH觸發的二硫鍵的裂解而發生。此外，我們進一步的合成具有生物降解能力且裝載Epirubicin (EPI, 抗腫瘤藥物)，在動物實驗中，我們也研究了EPI@BD-RMSN-PEG/TA (7:1)的高滲透長滯留效應 (EPR effect)、腫瘤抑制效果和毒性，並且也與 free EPI 及Lipodox® (generic version of Doxil®) 做比較。
在第三部分，我們想要證明我們發展的藥物載體，在生物體內能夠躲過預先存在的anti-PEG antibodies的辨識，然而，大多數的人因為經常接觸到PEG相關的物品(例如藥物及化妝品)，因此可能會誘導預先存在的anti-PEG antibodies，人體中，anti-PEG antibodies的存在已經造成相當大的阻礙，其可能導致使用PEGylated藥物時，降低治療功效以及產生anti-PEG免疫反應。值得注意的是，當攜帶腫瘤的小鼠中存在anti-PEG antibodies時，修飾長鏈PEG的Lipodox®會失去治療能力。在我們的研究中，開發裝載了Doxorubicin且修飾短鏈PEG的MSN，並證明其可以抑制腫瘤並避免被anti-PEG antibodies辨識。雖然Lipodox®在原生的且帶腫瘤的小鼠中顯示出顯著的治療效果，但卻在含有anti-PEG antibodies的小鼠中引起嚴重的cytokine syndrome，臨床上在anti-PEG antibodies的辨識方面，Lipodox®的安全性可能具有很高的風險，而我們的奈米藥物載體在anti-PEG antibodies產生的嚴重問題中，提供了解決方法且可以彌合癌症納米醫學的轉化差距。
Mesoporous silica nanoparticles (MSNs) is a promising nanocarrier for delivering anti-tumor drugs to cancer. Polyethylene glycol (PEG) has been linked to many nanocarriers to increase the dispersity, bioavailability and circulation time of nanoparticles. In this study, we developed three progressive strategies for improving tumor-targeting efficiency, controlling drug release from nanoparticles, and minimizing the immune-related adverse events of PEGylated nanomedicine.
In the first part, we focused on enhancing the tumor-targeting efficiency and prolonging the blood-circulation of MSNs. In our previous study, several kinds of MSNs have been developed. Especially interesting is that the nanoparticles modified with polyethylene glycol (PEG) and N-trimethoxysilylpropyl-N,N,N-trimethylammonium Chloride (TA) simultaneously show the excellent anti-fouling property. Here, we developed a series of nanoparticles by switching the ratio of PEG/TA components to investigate the critical roles of PEG/TA on tumor-targeting and blood-circulation. According to the in vitro cellular uptake and in vivo biodistribution study, RMSN-PEG/TA (7:1) shows the best performance.
In the second part, we were dedicated to developing hybrid nanoparticles combine the advantages of organic and inorganic materials by introducing the disulfide and pH-responsive silanes into the MSNs. Generally, inorganic materials were considered better than organic nanoparticles (NPs) in turns of chemical and mechanical stability; organic NPs have better biocompatibility and biodegradability than inorganic ones. Taking advantages of the introduction of environment-responsive molecules in MSN, the degradation of the obtained nanohybrids can occur by hydrolysis of benzoic-imine bond under the acidic tumor microenvironment and cleavage of disulfide bond triggered by GSH in tumor cells. In addition, we further synthesized biodegradable (BD) and Epirubicin (EPI, anti-tumor drug)-loaded RMSN-PEG/TA (7:1). In vivo experiments have been performed to investigate the enhanced permeability and retention effect (EPR effect), tumor suppression effect and toxicity of EPI@nanohybrids. Free EPI group and Lipodox® (generic version of Doxil®) group also have been investigated for comparison.
In the third part, we would like to demonstrate that the developed drug@nanohybrid can avoid the recognition of the pre-existing anti-PEG antibodies in the animal model. In most people, casual exposure to PEG-related compounds, such as pharmaceutical and cosmetic products, may induce pre-existing anti-PEG antibodies. The existence of anti-PEG antibodies in human, which could result in reducing the therapeutic efficacy as well as severe anti-PEG immune responses while employing PEGylated therapeutics, has become a considerable obstacle. It is highlighted that the long-chain PEG-containing Lipodox® loss its therapeutic efficacy when anti-PEG antibodies existed in the tumor-bearing mice. Here, we developed and demonstrated that the doxorubicin-loaded, short-chain PEG-modified MSNs can suppress tumor and prevent the anti-PEG antibody recognition. Although Lipodox® displayed a significant therapeutic efficacy in naïve tumor-bearing mice, it caused severe cytokine syndrome in mice containing anti-PEG antibodies. The safety of Lipodox® could be at high risk by the anti-PEG antibody recognition in clinical applications. Our nano-platform provide a solution to this challenge and could bridge the translational gap in cancer nanomedicine. |
