基于光扳机型的光控药物释放体系的设计与合成
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摘要
随着生物医药材料科学的不断发展,新型药物释放系统,特别是可控药物释放系统(controlled drug delivery system)已成为药学领域的重要研究方向。可控药物传输系统有利于提高药效,降低药物的毒副作用,在疾病治疗和医疗保健等方面具有诱人的应用潜力和广阔的应用前景。可控药物释放分为体内和体外刺激两种途径,与体内响应相比体外刺激往往更能精确控制药物的释放。其中由于光能提供高度精准的非物理性接触的外部刺激,可以达到时间和空间同时可控,光控药物释放体系的设计与制备引起了科学家们的极大兴趣。目前,对光控药物释放体系的研究仍集中在基础研究阶段并存在诸多问题,主要表现在如下两方面：
(1)如何使光控释放的激发波长长波长化及降低对光源要求的问题。这是当前化学型光控药物释放体系遇到的核心瓶颈问题。目前为止,化学型光控药物释放体系大部分仍然被迫使用有毒的紫外光来激发药物的释放。为了避免紫外光的使用,人们尝试着合成新的长波长吸收的光响应基团或者用近红外的双光子激发来设计光控药物释放体系,这两种方法前者在合成上比较困难,后者对使用的光源要求比较高,存在着价格昂贵、便携性差等问题。针对以上这些问题,本论文的第一部分工作就是利用光诱导电子转移机理,设计合成了一个以QD为光敏剂、N-甲基-4-吡啶酯盐为电子受体、以及半胱氨酸、二硫苏糖醇等为电子给体的新的可见光激发的光控药物释放体系。在这个体系中,QDs(光敏剂)吸收光子后,其激发态将电子转移至连接抗癌药物五氟脲嘧啶乙酸的N-甲基-4-吡啶酯盐(电子受体),导致其发生分子内还原剪切,从而释放出五氟脲嘧啶乙酸,同时被氧化的QDs从电子给体处获取电子后回复到基态。这种方法使光吸收部分与光响应释放部分分开,可以分别对两部分进行优化,避免繁琐的有机合成的同时实现了可见光控制抗癌药物的释放。最后通过HPLC和荧光等分析手段的检测,证实了该体系可以有效地释放抗癌药物并在癌症治疗领域有潜在的应用价值。
(2)大部分药物分子难与光扳机直接化学键连接的问题。在光扳机类光控药物释放体系中,大部分药物是通过化学键直接与光扳机相连的,但是,很多药物的活性基团活性不够或不存在活性基团,导致无法与光扳机键连,使得在这个体系中可选用的药物分子很有限。针对该问题,本论文的第二部分工作提出了将环糊精与含有香豆素光扳机的聚合物键连,通过环糊精的超分子组装,将药物络合到其疏水性空腔中,最后通过光照切断环糊精,从而释放络合有药物的环糊精,环糊精被淀粉酶酶解之后最终释放出药物。在这个体系中,药物通过环糊精与光扳机间接相连,而非化学键直接相连,这样就解决了药物分子与光扳机连接难的问题,大大增加了可用于光控药物释放的药物种类。但是,由于在该体系中我们所选用的香豆素光扳机的光断裂效率比较低,没有得到预期的效果,我们期望将来可以通过改变香豆素光扳机的类型来得到良好的实验效果,该体系的研究将为今后的光控载药体系提供一种全新的思路和尝试。
Recently, with the continuous development of biomedical material science, new drug release system, especially for controlled drug release system, has become one of the most important tasks in the studies of pharmaceutical area. These "smart" drug release systems can realize the targeted drug release, which helps to improve drug efficacy, reduce side effects of drugs, and has attractive applications in disease treatment and health care. Generally, controlled drug release can be achieved in two strategies:internal and external stimulations. Comparing with the internal stimulations, the external stimulations often control the drug release more accurately. Among these, the design and synthesis of photocontrolled drug release system has attracted great interest, since light can provide the highly accurate external stimulation with non-physical contact at any desired times and sites. At present, the study for the photo-controlled drug delivery systems is still concentrated on the fundamental reaearch area, and there are many problems including the following two aspects:
(1) How to extend the irritation wavelength of photorelease and reduce the requirement for the light source. These are the main problem for the presented chemical photo-controlled drug release system. By far, one significant limitation of the aforementioned photo-controllable drug release system is the use of cytotoxic UV light. To avoid using UV light, one effort is to design new phototriggers that can absorb at longer wavelengths, however this approach encounters difficulty of synthesizing; another approach is to utilize two-photon excitation, however it is expensive due to the need of an fs-mode laser. For aforementioned problems, the first part of our work is to demonstrate a new anticancer drug release system under the irradiation of visible light based on photo-induced electron transfer. In this system, water soluble QDs and L-cysteine were used as the photosensitizer and electron donor, NAP ester linked with an anticancer drug 5-fluorouracil acid (5-FUA) as an electron acceptor to generate photo-controlled release. Upon the irradiation of light, the photosensitizer QDs adsorbed the light, and then the sensitized QDs transferred an electron to NAP ester which induced the cleavage of the 5-FUA. The donor in the system then supplied an electron to QDs which promoted the progress of cleavage. The allowance of the light absorption step decoupling from the drug release provided the opportunity to tune the properties of QDs to optimize the release, thus permitting more control over the wavelengths of light used in the release process. Finally, the HPLC and fluorescent analysis for the photolysis process proved that the drug can be released effectively. We envision that this novel method has the potential to fulfill an increasing need for versatile and controllable drug delivery systems.
(2) How to solve the problem for the difficulty of drug conjugated with the phototriggers. To our knowledge, the drug is always chemical conjugated to the phototriggers in most phototrigger-contained photo-controlled drug release systems. While, for most drug molecules, it is hard to achieve since there are no enough active groups, which induced the difficulty for conjugation and limitation of selected drugs. In order to solve this problem, in the second part of our paper, we put forward to use coumarin phototrigger to link cyclodextrins (CD) in a polymer system, in which hydrophobic drugs are enwrapped in the cavity of CD by supramolecular assembly. Upon the irradiation of light, the cyclodextrins (CD) containing drug molecules are released, and the drug molecules are released afterward when CD is enzymatic hydrolyzed by amylase. In this system, the drug is linked to the phototrigger through cyclodextrins indirectly, not the chemical bond directly. This strategy can avoid the difficulty of organic synthesis and highly enrich the drug types in the photocontrolled drug release system. In our work, we have not gotten the ideal result, because the photolysis efficiency of the 7-hydroxy-coumarin we used in this system is very lower. In our future work, we will try to further modify coumarin phototrigger to improve this system. After all, this new system also supplies a newly method and trial for the future research of photo-controlled drug release system.
(1)如何使光控释放的激发波长长波长化及降低对光源要求的问题。这是当前化学型光控药物释放体系遇到的核心瓶颈问题。目前为止,化学型光控药物释放体系大部分仍然被迫使用有毒的紫外光来激发药物的释放。为了避免紫外光的使用,人们尝试着合成新的长波长吸收的光响应基团或者用近红外的双光子激发来设计光控药物释放体系,这两种方法前者在合成上比较困难,后者对使用的光源要求比较高,存在着价格昂贵、便携性差等问题。针对以上这些问题,本论文的第一部分工作就是利用光诱导电子转移机理,设计合成了一个以QD为光敏剂、N-甲基-4-吡啶酯盐为电子受体、以及半胱氨酸、二硫苏糖醇等为电子给体的新的可见光激发的光控药物释放体系。在这个体系中,QDs(光敏剂)吸收光子后,其激发态将电子转移至连接抗癌药物五氟脲嘧啶乙酸的N-甲基-4-吡啶酯盐(电子受体),导致其发生分子内还原剪切,从而释放出五氟脲嘧啶乙酸,同时被氧化的QDs从电子给体处获取电子后回复到基态。这种方法使光吸收部分与光响应释放部分分开,可以分别对两部分进行优化,避免繁琐的有机合成的同时实现了可见光控制抗癌药物的释放。最后通过HPLC和荧光等分析手段的检测,证实了该体系可以有效地释放抗癌药物并在癌症治疗领域有潜在的应用价值。
(2)大部分药物分子难与光扳机直接化学键连接的问题。在光扳机类光控药物释放体系中,大部分药物是通过化学键直接与光扳机相连的,但是,很多药物的活性基团活性不够或不存在活性基团,导致无法与光扳机键连,使得在这个体系中可选用的药物分子很有限。针对该问题,本论文的第二部分工作提出了将环糊精与含有香豆素光扳机的聚合物键连,通过环糊精的超分子组装,将药物络合到其疏水性空腔中,最后通过光照切断环糊精,从而释放络合有药物的环糊精,环糊精被淀粉酶酶解之后最终释放出药物。在这个体系中,药物通过环糊精与光扳机间接相连,而非化学键直接相连,这样就解决了药物分子与光扳机连接难的问题,大大增加了可用于光控药物释放的药物种类。但是,由于在该体系中我们所选用的香豆素光扳机的光断裂效率比较低,没有得到预期的效果,我们期望将来可以通过改变香豆素光扳机的类型来得到良好的实验效果,该体系的研究将为今后的光控载药体系提供一种全新的思路和尝试。
Recently, with the continuous development of biomedical material science, new drug release system, especially for controlled drug release system, has become one of the most important tasks in the studies of pharmaceutical area. These "smart" drug release systems can realize the targeted drug release, which helps to improve drug efficacy, reduce side effects of drugs, and has attractive applications in disease treatment and health care. Generally, controlled drug release can be achieved in two strategies:internal and external stimulations. Comparing with the internal stimulations, the external stimulations often control the drug release more accurately. Among these, the design and synthesis of photocontrolled drug release system has attracted great interest, since light can provide the highly accurate external stimulation with non-physical contact at any desired times and sites. At present, the study for the photo-controlled drug delivery systems is still concentrated on the fundamental reaearch area, and there are many problems including the following two aspects:
(1) How to extend the irritation wavelength of photorelease and reduce the requirement for the light source. These are the main problem for the presented chemical photo-controlled drug release system. By far, one significant limitation of the aforementioned photo-controllable drug release system is the use of cytotoxic UV light. To avoid using UV light, one effort is to design new phototriggers that can absorb at longer wavelengths, however this approach encounters difficulty of synthesizing; another approach is to utilize two-photon excitation, however it is expensive due to the need of an fs-mode laser. For aforementioned problems, the first part of our work is to demonstrate a new anticancer drug release system under the irradiation of visible light based on photo-induced electron transfer. In this system, water soluble QDs and L-cysteine were used as the photosensitizer and electron donor, NAP ester linked with an anticancer drug 5-fluorouracil acid (5-FUA) as an electron acceptor to generate photo-controlled release. Upon the irradiation of light, the photosensitizer QDs adsorbed the light, and then the sensitized QDs transferred an electron to NAP ester which induced the cleavage of the 5-FUA. The donor in the system then supplied an electron to QDs which promoted the progress of cleavage. The allowance of the light absorption step decoupling from the drug release provided the opportunity to tune the properties of QDs to optimize the release, thus permitting more control over the wavelengths of light used in the release process. Finally, the HPLC and fluorescent analysis for the photolysis process proved that the drug can be released effectively. We envision that this novel method has the potential to fulfill an increasing need for versatile and controllable drug delivery systems.
(2) How to solve the problem for the difficulty of drug conjugated with the phototriggers. To our knowledge, the drug is always chemical conjugated to the phototriggers in most phototrigger-contained photo-controlled drug release systems. While, for most drug molecules, it is hard to achieve since there are no enough active groups, which induced the difficulty for conjugation and limitation of selected drugs. In order to solve this problem, in the second part of our paper, we put forward to use coumarin phototrigger to link cyclodextrins (CD) in a polymer system, in which hydrophobic drugs are enwrapped in the cavity of CD by supramolecular assembly. Upon the irradiation of light, the cyclodextrins (CD) containing drug molecules are released, and the drug molecules are released afterward when CD is enzymatic hydrolyzed by amylase. In this system, the drug is linked to the phototrigger through cyclodextrins indirectly, not the chemical bond directly. This strategy can avoid the difficulty of organic synthesis and highly enrich the drug types in the photocontrolled drug release system. In our work, we have not gotten the ideal result, because the photolysis efficiency of the 7-hydroxy-coumarin we used in this system is very lower. In our future work, we will try to further modify coumarin phototrigger to improve this system. After all, this new system also supplies a newly method and trial for the future research of photo-controlled drug release system.
引文
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