以耗散粒子動力學法研究樹枝狀高分子之藥物攜帶及釋放功能

Studies of Drug Delivery and Drug Release of Dendrimer By Dissipative Particle Dynamics

吳翊帆(Yi-Fan Wu)

指導教授 ： 諶玉真

國立臺灣大學/工學院/化學工程學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.00391

摘要

本文是利用秏散粒子動力學法探討不同世代數的樹枝狀高分子攜帶及釋放藥物之行為，其中樹枝狀高分子之核心組成為疏水性，外殼組成為親水性，因此在水溶液中，樹枝狀高分子會形成單一分子的微胞，而藥物分子為疏水性，會聚集於微胞的中心部位，所以樹枝狀高分子所形成之單一分子的微胞，可以作為攜帶藥物的載體。在固定藥物及樹枝狀高分子體積分率之下，代數高的樹枝狀高分子，其攜帶藥物所需之平衡時間略久，而對於相同樹枝狀高分子，若親水外殼與藥物之斥力(aphilic-drug)越大，平衡的時間也會越久。但當aphilic-drug太大時，平衡時間過久，藥物容易在微胞外之溶液中形成團塊(aggregation)，又若此時微胞球殼(philic-shell)夠厚實，藥物的團聚物將無法進到微胞裡面。平衡後的微胞，其密度分佈與aphilic-drug的值有很大的關連，在中心點附近，aphilic-drug值越大，藥物的密度分佈越高，疏水鏈段的密度分佈則越小，造成微胞與微胞核心的尺寸隨著aphilic-drug值的增加而變大。但是代數較小的樹枝狀高分子，藥物粒子趨向保護核心，因此其尺寸均會略小於代數高的。一般來說，代數越多的樹枝狀高分子攜帶藥物達到平衡後，其藥物濃度在微胞內外之比值越大，而對相同的樹枝狀高分子，aphilic-drug越大藥物濃度比就越小。
而在釋放藥物的部份，我們將攜帶藥物的樹枝狀高分子置於純水中，並在藥物釋放的過程中，每隔特定的時間，移除排出的藥物之30%或70%，以模擬藥物為人體吸收的程序。模擬結果顯示，正如預期，藥物釋放的速率隨移除藥物的比例增加而加大。而在固定藥物移除比例時，代數低的樹枝狀高分子，由於親水殼層結構鬆散，不管aphilic-drug為何值，藥物釋放都一樣快速，但代數高的樹枝狀高分子，親水殼層結構密實，其藥物釋放的速率則是隨aphilic-drug值的增大而明顯降低。藥物載體在人體中，可能經歷不同的溶液環境，如電解值濃度及酸鹼度的改變，而影響微胞的型態。若當微胞核心組成與溶劑之斥力變小，微胞核心澎潤展開，藥物釋放的速率便會加快。模擬結果並顯示，代數低的樹枝狀高分子，由於親水殼層結構鬆散，藥物釋放速率無明顯變化。但代數高的樹枝狀高分子，親水殼層結構密實，其藥物釋放的速率則是隨微胞核心組成與溶劑之斥力變小而明顯增快。

關鍵字

樹枝狀高分子 ； 耗散粒子動力學法 ； 藥物傳遞

並列摘要

Controlled drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is carried and released from the material in a predesigned manner. Using controlled-delivery systems can maintain the drug levels within a desired range, and provide optimal use of the drug in question. Dendrimers are ideal candidates among model hyperbranched polymers because of their well-defined structure and high density of functional groups.
In this work, the behavior of dendrimers in drug carrying and delivery is explored by using Dissipative Particle Dynamics (DPD). The dendrimer is modeled with three generations of inner hydrophobic core (Gcore) and two to three generations of outer hydrophilic shell (Gshell). The total generation (G) of the dendrimer is the sum of Gcore and Gshell. In aqueous solution, the dendrimer can form uni-micelle and can serve as drug carrier. The characteristic times for the drug carrying processes are significantly affected by the Gshell and the repulsive interaction between hydrophilic shell and drug (aphilic-drug). Under the same volume fraction of dendrimer and drug,the characteristic times increases as aphilic-drug increases for dendrimer with fixed Gcore and Gshell. For systems with rather compatible interaction between hydrophilic shell and drug, equilibrium processes proceed at similar speeds irrespective of the dendrimer generation. However,the characteristic times grows as the thickness of the hydrophilic shell (i.e. Gshell) increases for large enough aphilic-drug. Generally speaking, the partition (P = drug concentration within the dendrimer/ drug concentration in the bulk) increases as G increases and P decreases as aphilic-drug increases.
In the study of drug release process, the drug-carried dendrimer is originally placed in the water free of drug. The drug is then released to the bulk phase through diffusion. To simulate the procedure of drug being absorbed by the human body, we remove part of the released drug (30% and 70%) for every 5000 timesteps in our simulation. The results show that the characteristic times remain the same for various aphilic-drug as long as the hydrophilic shells consist of loose structures. For example, Gshell is small enough or the hydrophilic shell is linear instead of dendritic formation. For dendrimers with thick and tight shells, the drug diffuses out much slower as aphilic-drug increases.

並列關鍵字

dendrimer ； DPD ； drug delivery

參考文獻

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