With recent development of nanoscience and nanotechnology, a great amount of efforts have been devoted to nanomedicine development. Among various nanomaterials, silica nanoparticle (NP) is generally accepted as non-toxic, and can provide a versatile platform for drug loading. In addition, the surface of the silica NP is hydrophilic, being favorable for cellular uptake. Therefore, it is considered as one of the most promising candidates to serve as carriers for drugs. / The present thesis mainly focuses on the design of silica based nanocarrier-drug systems, aiming at achieving safe nanocarrier excretion from the biological system and enhanced drug efficacy, which two are considered as most important issues in nanomedicine development. / To address the safe carrier excretion issue, we have developed a special type of self-decomposable SiO₂-drug composite NPs. By creating a radial concentration gradient of drug in the NP, the drug release occurred simultaneously with the silica carrier decomposition. Such unique characteristic was different from the conventional dense SiO₂-drug NP, in which drug was uniformly distributed and can hardly escape the carrier. We found that the controllable release of the drug was primarily determined by diffusion, which was caused by the radial drug concentration gradient in the NP. Escape of the drug molecules then triggered the silica carrier decomposition, which started from the center of the NP and eventually led to its complete fragmentation. The small size of the final carrier fragments enabled their easy excretion via renal systems. / Apart from the feature of safe carrier excretion, we also found the controlled release of drugs contribute significantly to the drug efficacy enhancement. By loading an anticancer drug doxorubicin (Dox) to the decomposable SiO₂-methylene blue (MB) NPs, we achieved a self-decomposable SiO₂(MB)-Dox nanomedicine. The gradual escape of drug molecules from NPs and their enabled cytosolic release by optical switch, led to not only high but also stable drug concentration in cytosol within a sustained period. This resulted in enhanced drug efficacy, which is especially manifested in multidrug resistant (MDR) cancer cells, due to the fact that the NP-carrier drug can efficiently bypass the efflux mechanisms and increase drug availability. Together with its feature of spontaneous carrier decomposition and safe excretion, this type of nanomedicine’s high drug efficacy highlights its potential for low dose anticancer drug treatment and reduced adverse effect to biological system, holding great promise for clinical translation. / The enhanced drug efficacy by employing the self-decomposable silica nanocarrier is also demonstrated in photodynamic therapy (PDT). The loose and fragmentable features of the self-decomposable SiO₂-photosensitizer (PS) NPs promoted the out-diffusion of the generated ROS, which resulted in a higher efficacy than that of dense SiO₂-PS NPs. On the other hand, we also explored another nanocarrier configuration of Au nanorods decorated SiO₂ NP, with PS drug embedded into dense SiO₂ matrix. A different mechanism of drug efficacy enhancement was presented as the Au’s surface plasmon resonance enhanced the ROS production. Although the drug efficacy of such SiO₂(PS)-Au NPs was similar to that of self-decomposable SiO₂-PS NPs, their potential for clinical applications was limited without the feature of safe carrier excretion. / In summary, the self-decomposable SiO₂ based NP developed is a most promising system to serve as safe and effective carriers for drugs. Together with the known biocompatibility of silica, the feature of controllable drug release and simultaneous carrier decomposition achieved in the self-decomposable SiO₂-drug NPs make it ideal for a wide range of therapeutic applications. / 隨著近年來納米科學技術的快速發展，致力於納米藥物的研发也越來越多。在眾多納米材料體系中，二氧化硅納米顆粒因其無毒、易載藥、且易於細胞攝入等特性，被認為是最具前景的藥物載體之一。 / 本文主要致力於設計以二氧化硅納米顆粒為載體的納米藥物體系，使之同時具備能夠被生物體安全排泄以降低潛在不良影響，并且能夠加強藥效的特性，而這兩方面被認為正是納米藥物發展中最重要的議題。 / 爲了實現藥物載體安全排泄，我們設計了一種特殊類型可自降解的二氧化硅-藥物複合納米顆粒。通過在納米顆粒中控制形成徑向藥物濃度梯度分佈，我們達到了藥物釋放的同時伴隨二氧化硅載體解體的效果。這一特徵不同於傳統二氧化硅-藥物複合納米顆粒中藥物均勻分佈而難以擴散出載體的情況。我們發現在這種可自降解的二氧化硅-藥物複合納米顆粒中，首先徑向藥物濃度梯度分佈所引起的擴散控制著藥物釋放，而後藥物分子的流失促發二氧化硅載體由內而外的逐步分解，最終全面解體分裂成碎片。這些碎片的小尺度使得它們易於經泌尿系統安全排泄出體外。 / 除此之外，我們發現這種納米載體的可控藥物釋放特性可以大大提高藥效。通過將抗癌藥阿黴素載入自降解二氧化硅-亞甲藍納米顆粒中，我們得到一種可自降解二氧化硅/亞甲藍-阿黴素(SiO₂(MB)-Dox)複合納米顆粒。藥物分子可以逐漸擴散出納米顆粒，並且在光控開關作用下釋放到細胞胞漿中，使之在胞漿中持續保持穩定高濃度。這樣使得藥效得以加強，尤其是在多藥抗藥性腫瘤細胞中作用尤為明顯，這得益於納米載體藥物可以有效避開藥泵機制并提高藥物利用率。除了它的自發載體分解和安全排泄特性，這種納米藥物的高藥效使得它在低藥量治療和減少不良副作用方面的潛力突出，臨床應用前景廣大。 / 可自降解二氧化硅納米載體所帶來的的藥效增強亦顯示在光動力學治療法中。可自降解二氧化硅-光敏劑藥物(SiO₂-PS)複合納米顆粒鬆散易分解的結構特性促使其內部產生的活性氧物質易於擴散出藥物載體，這使得它的藥效高於傳統二氧化硅-光敏劑複合納米顆粒。另一方便，我們設計了一種金修飾的二氧化硅納米顆粒載體。它具有另一種不同的藥效增強機制，即利用金納米顆粒表面等離子體共振效應來增強活性氧物質的產生。雖然藥效與可自降解二氧化硅-光敏劑複合納米顆粒相似，但是它無法安全排泄，限制了其在臨床上的應用。 / 綜上所述，我們發展的可自降解二氧化硅納米顆粒作為一種安全高效的藥物載體顯示出其非常大的應用前景。二氧化硅以其衆所周知的生物相容性，和我們發展的可控藥物釋放及同步載體分解特性，已成為理想的藥物載體并有希望廣泛適用於治療應用。 / Zhang, Silu = 基於無定二氧化硅納米顆粒的安全高效納米藥物的研究 / 張思鷺. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references. / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Zhang, Silu = Ji yu wu ding er yang hua gui na mi ke li de an quan gao xiao na mi yao wu de yan jiu / Zhang Silu. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_1290657 |
| Date | January 2014 |
| Contributors | Zhang, Silu (author.), Li, Quan , 1975- (thesis advisor.), Chinese University of Hong Kong Graduate School. Division of Physics. (degree granting institution.) |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography, text |
| Format | microform, electronic resource, remote, 1 online resource (xvi, 122 leaves) : illustrations (some color), computer, online resource |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons "Attribution-NonCommercial-NoDerivatives 4.0 International" License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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