產熱之奈米材料於藥物傳輸上之應用

Development of Heat-Generating Nanomaterials and their Applications for Drug Delivery

蔣維倫(Wei-Lun Chiang)

指導教授 ： 宋信文

國立清華大學/工學院/化學工程學系/博士(2014年)

摘要

理想的藥物傳輸系統的條件之一，必須要能夠不影響到健康細胞，並且將藥物投遞於患部之中，透過這個目的，藥物載體可以改變藥物在人體內的分佈與分佈，以達到治療的目的。第1個研究主要在於開發出一個能夠透過外界磁場，進行多次且重複的藥物釋放系統，以利於將藥物控制在合理濃度範圍。本藥物載體系統由PLGA所構成，並在殼層中包覆氧化鐵奈米粒子，並於核心中承載化療藥物 (doxorubicin，DOX)，並利用環境溫度高於高分子的Tg點時，高分子間的自由體積會大幅度的增加，進而促進藥物的釋放。而從實驗的結果能了解到，本載體系統確實能夠回應磁場的重複開啟與刺激，使其核心內的藥物多次且重複性的釋放，以達到多次釋放的調控目的。
第2個研究則是結合熱敏感性的微脂體，同時搭配前一個研究的PLGA微球，以結合兩種釋放速率各異的載體系統，首先施加磁場提高溫度，促使釋放微脂體內部的維他命D3，以抑制細胞內部的抗氧化酵素，在24小時後，細胞內部的抗氧化能力降低，此時再施加磁場，釋放出PLGA微球內的DOX，使其產生高濃度的活性氧，進而殺死細胞。
第3部分的研究結合了一種高分子類型的光熱奈米材料，polypyrrole (PPy)。此一材料能夠轉換紅外光的光能變成熱能，同時在局部細菌感染的部位給予熱治療以及高濃度的抗生素治療，並以此合併性的療法，達到抑制細菌的效果。

關鍵字

藥物傳輸 ； 奈米材料 ； 控制釋放

並列摘要

Ideal drug delivery systems deliver high doses of a therapeutic agent to diseased cells or bacteria without considerably interfering with healthy cells, inducing the desired pharmacokinetics and biodistribution, maximizing the higher therapeutic while minimizing side effects. Study I describes a novel time-controllable drug delivery system that exploits hollow microspheres (HMs) that repeatably release the drug at a concentration that is tightly managed within a therapeutic range. The HMs were fabricated from poly(D,L-lactic-co-glycolic acid) (PLGA) using a double-emulsion method; the polymer shell contained iron oxide nanoparticles (IONPs) and the aqueous core contained doxorubicin (DOX). Simtulation by a high-frequency magnetic field (HFMF), the encapsulated IONPs transformed magnetic energy into heat to increase rapidly the local temperature. As the temperature approached the Tg of PLGA, the polymeric chains became much more mobile, significantly increasing the number of local voids and thereby promoting the diffusion of DOX. Exploiting the repeated ON/OFF HFMF operation, the HMs served as a stimuli-responsive carrier with pulsatile drug release.
Recent studies have suggested that chemopreventive agents can be used in cancer treatment to improve the antitumor activity of conventional chemotherapeutic drugs through synergistic actions. Study Ⅱ develops a co-delivery system that is based on the adsorption of cationic liposomes on an anionic hollow microsphere (Lipo-HM) by electrostatic interaction, allowing sequential drug release to be thermally driven in a time-controllable manner using an external magnetic stimulus. The sequential delivery of 1,25-dihydroxyvitamin D3 (VD3) and DOX remarkably promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing of antioxidant enzyme activity, which may contribute to VD3-potentiated DOX-induced cytotoxicity. Experimental results reveal that treatment with Lipo-HMs significantly worsened the damage that was caused to tumor cells by DOX, exhibiting a synergistic cytotoxic effect. The in vivo results demonstrate that Lipo-HMs exhibited stronger therapeutic action and significantly lower systemic toxicity than free-form drugs. Therefore, Lipo-HMs can be an effective delivery vehicle for chemopreventive agents and chemotherapy drugs, and therefore effective in the combined delivery of therapeutic agents. This sequential carrier system not only improves patient compliance by reducing the frequency of injections, but can also provide a synergistic therapeutic effect.
Eradicating subcutaneous bacterial infections remains a significant challenge. Study Ⅲ describes an injectable system of HMs that can rapidly and locally generate heat when activated by near-infrared (NIR) light and control the release of an antibiotic using a “molecular switch” in their polymer shells. This functionality supports a combined strategy for treating subcutaneous abscesses. The HMs have a shell of PLGA and an aqueous core that is composed of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results indicate that the micro-HMs ensure the efficient spatial stabilization of their encapsulated Van and PPy NPs at injection sites in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible concentration of the drug, but release markedly more when exposed to NIR light, suggesting that this system is effective as a photothermally-responsive drug delivery system. The combination of photothermally-induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity toward the bacteria in abscesses, to an extent that exceeds the sum of the cytotoxicities that are achieved by the two treatments alone, revealing a synergistic effect. This treatment platform may have other clinical applications, especially in localized hyperthermia-based cancer therapy.

參考文獻

Chapter 1

[3] C. J. Ke, T. Y. Su, H. L. Chen, H. L. Liu, W. L. Chiang, P. C. Chu, Y. Xia, H. W. Sung, Smart multifunctional hollow microspheres for the quick release of drugs in intracellular lysosomal compartments. Angew. Chem. Int. Ed. 50 (2011) 8086–8089.

[4] K. Na, S. Kim, K. Park, K. Kim, D. G. Woo, I. C. Kwon, H. M. Chung, K. H. Park, Heparin/poly(l-lysine) nanoparticle-coated polymeric microspheres for stem-cell therapy. J. Am. Chem. Soc. 129 (2007) 5788–5789.

[5] N. Kunou, Y. Ogura, T. Yasukawa, H. Kimura, H. Miyamoto, Y. Honda, Y. Ikada, Long-term sustained release of ganciclovir from biodegradable scleral implant for the treatment of cytomegalovirus retinitis. J. Control. Release 68 (2000) 263–271.

[6] K. C. Hribar, M. H. Lee, D. Lee, J. A. Burdick, Enhanced release of small molecules from near-infrared light responsive polymer-nanorod composites. ACS Nano 5 (2011) 2948–2956.