奈米顆粒在孤立及皮下腫瘤空間與時間分佈之研究

Abstract

腫瘤中的藥物載體濃度及其分佈是評估腫瘤治療效果的重要因子，而奈米藥物載體的傳輸受許多因素影響，如腫瘤的血管密度及分佈、腫瘤的大小、壞死區大小比例等。本研究利用流體流動方程式開發出腫瘤藥物運輸模型，模擬不同大小的奈米藥物在不均勻血管分佈的孤立腫瘤以及皮下腫瘤的傳輸情況和濃度分佈，並且分析不同的腫瘤生理條件對藥物濃度的影響。我們以阿黴素(doxorubicin)作為傳統藥物的代表並與奈米藥物比較其傳輸情況及治療效果。除此之外，我們從藥物濃度中推算出腫瘤細胞的單次和多次治療後存活率，藉此更客觀地評估腫瘤的治療效果。 研究結果顯示(1)大顆藥物載體在腫瘤血管附近有較高的累積劑量，而小顆載體雖累積劑量較低但較容易滲透至腫瘤壞死區及正常組織；(2)當腫瘤越小，藥物載體越容易滲透至壞死區及正常組織，但其最高累積劑量相對較低；(3)藥物載體在腫瘤中的累積劑量會隨著血管密度增加而提高，而血管密度對於大顆藥物載體的影響力較大；(4)奈米藥物的腫瘤細胞存活率較傳統藥物低，而正常組織的存活率較高且受影響的範圍較小。結果顯示出血管密度以及藥物的大小對於在腫瘤治療效果有較大的影響力，而細胞的存活率結果顯示使用奈米藥物載體有更好的治療效果並且對正常組織的傷害較少。

The distribution and accumulation of nanoparticle dosage in a tumor are important in evaluating the effectiveness of cancer treatment. The transportation of nanoparticles in a tumor is affected by many factors such as the sizes of the tumor and necrotic region, vascular density and its distribution in the tumor, and the characteristics of nanoparticles. We developed a mathematical tumor model based on the governing equations for the fluid flow to investigate the drug transportation in a tumor and computed the resulting accumulative concentration. Moreover, the cell survival rate, which was calculated with the help of the accumulative concentration, was evaluated to quantify the therapeutic effect. The survival rates after multiple treatments are helpful to evaluate the efficiency of the chemotherapy plan. The model was applied to both an isolated tumor and a subcutaneous tumor with heterogeneous vascular distribution, and various dextrans were chosen as the nanodrug carrier to study the impact of the sizes of tumor and necrotic region and vascular surface area per unit tumor volume ( ) on the average accumulative concentration. Furthermore, doxorubicin was chosen as the traditional chemotherapeutic agent and the treatment effect was compared with that of dextrans. The results showed that: 1) large nanoparticles produced a large accumulative concentration in the well-vascular region, but low dose in the necrotic region; 2) small nanoparticles can penetrate into the necrotic region; however, its accumulative concentration was low and was more toxic to normal tissues; 3) the influence of the tumor size on the average accumulative concentration was much more pronounced for small nanoparticles, while the effect of was relatively more significant when employing large nanoparticles; 4) the treatment effect of nanoparticles on tumor is better than traditional chemotherapeutic agent and the damage on normal tissue is much smaller as well. The results indicated that the effectiveness of the anti-tumor drug delivery was determined by the interplay of the vascular density and nanoparticle size, and using nanoparticles as anti-tumor drug is better because its high treatment efficiency on tumors and less damage to normal tissues.