新型標靶性奈米/微米藥物傳輸系統在癌症治療之應用

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研究生：	呂宜霖 Lu, I-Lin
論文名稱：	新型標靶性奈米/微米藥物傳輸系統在癌症治療之應用 Development of Novel Targetable Nano/Micro-Scaled Therapeutic Delivery Systems for Cancer Treatments
指導教授：	邱信程 Chiu, Hsin-Cheng
口試委員:	張建文 Chang, Chien-Wen 糜福龍 Mi, Fwu-Long 姜文軒 Chiang, Wen-Hsuan 沈名吟 Shen, Ming-Yin
學位類別：	博士 Doctor
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2023
畢業學年度：	111
語文別：	英文
論文頁數：	89
中文關鍵詞：	兩性離子共聚物、酸引發團聚、結腸癌、口服給藥、微凝膠/奈米顆粒
外文關鍵詞：	zwitterionic copolymer, acid triggered agglomeration, colon cancer, oral administration, microgel/nanoparticles
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奈米技術有望通過提供更有效的藥物傳遞系統來徹底改變癌症治療。使用奈米載體封裝多種化療藥物有若干好處，如降低毒性、改善吸收和生物利用度以及延長藥物半衰期。刺激回應型奈米載體已被設計用於在腫瘤微環境中實現精確的藥物釋放，而定制的奈米載體已被證明可以改善治療藥劑的生物分佈和藥物動力學，同時增加對癌細胞的靶向作用。奈米載體還可以裝載成像顯影劑、抗腫瘤藥物、光敏劑、抗體和其他貨物，以增強診斷和治療的效果。這篇文章強調了奈米技術的潛力，為改善癌症檢測和治療提供了新的機會。
第一部分討論用於改善在腫瘤周圍聚集和近紅外光（NIR）觸發的光熱療法，使用帶有兩性電離子聚合物的奈米粒子來改善治療效果。開發一個由PLGA為核心，並在表面修飾mPEG-b-P(MAA-co-HMA)共聚物組成的奈米粒子，此粒子表面兩種嵌入物可切換表面電荷，並作為IR780的載體。當抵達腫瘤周圍由微酸環境引起的表面電荷相互吸引近而造成奈米顆粒的聚集，進一步增強在腫瘤中的停留時間和被TRAMP-C1細胞吸收的能力。同時搭配近紅外光（NIR）啟動IR780升溫的光熱療法，這種奈米粒子也有治療其他癌症的潛力。
第二部分介紹了一種新的方法，利用微流道控制生成方式，形成葡聚糖微凝膠內含有順鉑/ SPIONs脂質奈米粒子，通過口服使用治療局部結腸癌。開發出多功能的連續標靶傳遞系統，以有效地讓藥物靶向惡性腫瘤，同時盡可能減少藥物在其他腸道系統內的吸收。此藥物系統經由微流道形成葡聚糖微凝膠，凝膠內部包裹Trilaurin製成的奈米粒子（LNPs）。LNPs中裝載有順鉑和SPIONs，通過乳化技術將trilaurin, oleate-CDDP adduct, oleate-SPIONs, and FA-TPGS共同組裝而成。當葡聚醣微凝膠被大腸內葡聚醣水解酶降解時，釋放出的LNPs更容易被葉酸受體過度表現的結腸癌細胞所發現和吞噬。微凝膠中的雙重靶向LNPs內含脂質化的順鉑和交替磁場處理過的SPIONs，產生合併的化療/磁熱治療效應，可以顯著抑制腫瘤生長並抑制轉移。本研究展示了奈米科技可以通過特定的pH、消化時間或酶降解實現控制腸道內藥物釋放，從而改善腫瘤局部藥物吸收和減少不良反應。

Nanotechnology has the potential to revolutionize cancer treatment by providing more effective systems for drug delivery. The use of nanocarriers to encapsulate multiple chemotherapeutic agents offers several benefits, such as reduced toxicity, improved absorption and bioavailability, and longer drug half-lives. Stimuli-responsive nanocarriers have been designed to achieve precise drug release in the tumor microenvironment. To achieve this, two nanocarrier systems were developed.
The first part describes the development of zwitterionic polymer nanoparticles for enhanced tumor retention and NIR-guided photothermal therapy. Nanoparticles consisting of PLGA cores coated with switchable surface charge zwitterionic deblock copolymers, the mPEG-b-P(MAA-co-HMA), have been designed as carriers for IR780. The agglomeration of nanoparticles induced by acidity further enhances their ability to be retained in tumors and taken up by TRAMP-C1 cells. While the focus is on near-infrared (NIR) activated photothermal therapy, these nanoparticles may also have potential for other forms of cancer treatment. In the second part, a microfluidic method is presented for preparing dextran microgels that contain lipid-based nanotherapeutics loaded with cisplatin/SPION. This innovative approach offers a new method for the oral treatment of colon cancer that is localized. The dual-targeted delivery system has been developed to efficiently target malignant tumors while minimizing systemic drug uptake. The system consists of microfluidized dextran microgels that encapsulate trilaurin-based lipid nanoparticles (LNPs) loaded with cisplatin/superparamagnetic iron oxide nanoparticles (SPIONs).
LNPs are loaded with cisplatin and SPIONs using a co-assembly method that involves trilaurine, an OA-CDDP adduct, OA-SPIONs modified with oleate, and FA-TPGS. This is achieved through an emulsion technique. When the dextran microgels are degraded by dextranase, which is unique to the large intestine, the released LNPs are more easily detected and taken up by FA-receptor overexpressing colorectal cancer cells. This dual-targeted lipid nanoparticle-loaded microgel provides a combined chemo/magnetothermal therapeutic effect by entrapping lipid-coated cisplatin and magnetically treated SPIONs. This treatment significantly inhibits tumor growth and suppresses metastasis. This text highlights the potential benefits of nanomedicines in improving specific site drug absorption and reducing side effects. Nanomedicines achieve this through controlled drug release based on specific factors such as change of pH value, ingestion time, and enzymatic breakdown.

摘要    I
Abstract    III
Chapter 1-Introduction    1
Chapter 2-IR780-loaded zwitterionic polymeric nanoparticles with acidity-induced agglomeration for enhanced tumor retention    6
1. Introduction    6
2 Experimental Section    9
2.1 Materials.    9
2.2 Synthesis of mPEG-carbamate imidazole (mPEG-CI).    9
2.3 Synthesis of aminated semitelechelic poly(methacrylic acid) (PMAA-NH2).    10
2.4 Synthesis of diblock copolymer mPEG-b-PMAA.    11
2.5 Synthesis of mPEG-b-P(MAA-co-HMA).    12
2.6 Preparation of IR780-loaded PMHPNs.    13
2.7 Nanoparticles Characterization.    14
2.8 Temperature Measurement under NIR Laser Irradiation.    15
2.9 In Vitro Cellular Uptake.    15
2.10 Temperature Change of Treated TRAMP-C1 Cells under NIR Laser Irradiation.    16
2.11 In Vitro Photothermal Effects.    16
2.12 In Vivo Imaging.    17
3. Results and discussion    18
4. Conclusion    29
References    30
Chapter 3-Microfluidized Dextran Microgels Loaded with Cisplatin/SPION Lipid Nanotherapeutics for Local Colon Cancer Treatment via Oral Administration    32
1. Introduction    32
2. Experimental Section    36
2.1 Materials:    36
2.2 Synthesis of C18-Dex and MA-Dex:    37
2.3 Synthesis of FA-TPGS:    38
2.4 Preparation of LNPs:    38
2.5 Preparation of LNPs@MGs:    39
2.6 Structural Characterization:    40
2.7 Colloidal Stability of LNPs in Simulated GI Environment:    40
2.8 In Vitro Drug Leakage:    41
2.9 Magnetothermal Evaluation:    41
2.10 Cellular Uptake:    41
2.11 Cytotoxicity Evaluation:    42
2.12 Distribution in GI Tract and Tumor Growth Inhibition:    44
2.13 Systemic Side Effect Evaluation:    45
2.14 Tissue Staining Examination:    45
2.15 Statistical Analysis:    46
3. Results and Discussion    47
3.1. Preparation and Characterization of Lipid Nanoparticle-Loaded Microgels (LNPs@MGs)    47
3.2. Colloid Stability and Enzymatic Degradation of NPs@MGs    57
3.3. In Vitro Cellular Uptake of DFCNPs    60
3.4. In Vitro Therapeutic Effects of Chemo/Thermo combination Therapy    63
3.5. Distribution of LNPs@MGs in GI Tract    70
3.6. In Vivo Therapeutic Effects and Tumor Metastasis Inhibition    75
4. Conclusion    83
References    84
Chapter 4-Summary    88

                                

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