利用多光子顯微術探討奈米藥物載體在小鼠組織內血管通透性與擴散係數以及累積量之時間與空間變化

在腫瘤的化學治療中，總希望藥物能傳輸到腫瘤部位，並且在腫瘤部位的累積量達到最大值，以達到殺死腫瘤細胞的最大效果。為避免有治療以外的副作用發生，藥物在正常組織的累積量則是越少越好。利用腫瘤血管通透性較大，以及腫瘤組織內缺乏完善的淋巴系統這兩種特性，可以使化療藥物在腫瘤組織內的累積量增加，並且拉長藥物停留在腫瘤組織內的時間。因此，藥物在血管循流的半衰期，腫瘤血管的通透性，腫瘤組織內的擴散係數等物理參數，皆會影響藥物在腫瘤組織的累積量。為了能夠在活體中觀察到藥物分子在(微)血管內濃度的變化，以及藥物分子從(微)血管內通過血管壁滲出至組織間隙的相互關係，需要微米等級解析度的影像系統，輔以光學對比劑，以得到較好的藥物擴散影像。本論文利用多光子非線性顯微術，搭配市售螢光葡聚醣模擬藥物載體，以葡聚醣所發散的螢光強度來分析葡聚醣在生物體內之濃度空間分布，在小鼠耳朵腫瘤模式，得到葡聚醣在距離腫瘤血管壁不同距離之濃度對時間之曲線以及累積量和血管通透性，同時也得到葡聚醣在組織內的擴散係數。在本論文的研究中發現，在腫瘤初期，因為免疫反應的關係，血管通透性會增加，而這也使得藥物分子在組織中的濃度以及累積量提升，此時的組織擴散係數與一般組織相似。在腫瘤中期，因為免疫反應告一段落，血管通透性也隨之降低，連帶藥物分子在組織中的濃度以及累積量也降低。在腫瘤晚期，腫瘤因為生長的需要而進行血管新生，而藥物分子也因為腫瘤血管的特性，使得在組織中的濃度以及累積量再度得到提升。

關鍵字

腫瘤；多光子非線性顯微術；累積量；血管通透性；擴散係數

並列摘要

The goal of drug delivery in cancer chemotherapy is to kill tumor cell by maximal drug accumulation in tumor tissues. In order to reduce side effect in normal tissue, drug accumulation in normal tissue is the less the better. Exploiting the properties of high vascular permeability and lack of well-defined lymphatic system around tumors, drug can effectively extravasate and accumulate for a period of time in tumor tissues. How long and how much will the drug accumulate in tumor tissues depends on physical parameters such as plasma circulation half-life, vascular permeability, and diffusion coefficients in tumor tissues. For in vivo measuring these parameters in a microscopic scale, in this thesis, we employed a nonlinear multi-photon microscopy and imaged the kinetics of drug carriers with fluorescent dextran. Vascular permeability, accumulation of dextran, and matrices diffusion constants are measured via melanoma mice ear tumor model. In early stage, we found vascular permeability increased due to the immune response. In mid-stage, vascular permeability decrease because of the end of immune response and the decreased vascular permeability makes lower concentration and accumulation in tumor tissue. In late stage, tumor induces more leaky vessels and the concentration and accumulation of drug accumulation in tumor tissues are increased.

並列關鍵字

tumor ； multiphoton nonlinear microscopy ； accumulation ； vascular permeability ； diffusion coefficient

參考文獻

[1] Theresa M. Allen and Pieter R. Cullis, ”Drug Delivery Systems: Entering the Mainstream” Science 2004;303:1818-1822

[2] Robert Langer, “New method of drug delivery” Science 1990;249:1527-1533

[3] James D. Byrne, Tania Betancourt , Lisa Brannon-Peppas ,” Active targeting schemes for nanoparticle systems in cancer therapeutics,” Advanced Drug Delivery Review 2008;60:1615-1626

[4] Barbara Haley and Eugene Frenkel, ” Nanoparticles for drug delivery in cancer treatment,” Urologic Oncology 2008;26:57-64

[5] Matthew R. Dreher, Wenge Liu, Charles R. Michelich, Mark W. Dewhirst, Fan Yuan and Ashutosh Chilkoti,”Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers” Journal of the National Cancer Institute 2006;98:335-344

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利用多光子顯微術探討奈米藥物載體在小鼠組織內血管通透性與擴散係數以及累積量之時間與空間變化

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