基于近红外光的纳米药物输送系统研究进展

Advances in Near-infrared Light Responsive Nanoscale Drug Delivery Systems

纳米药物输送系统(NDDS)可以将治疗剂量的药物以可控的方式输送至病变部位,在时间和空间上实现药物的精准释放,具有药物利用率高、毒副作用低等诸多优点,为各种重大疾病如肿瘤的精准治疗提供了新思路。理想的NDDS应具备载药量高、运输过程药物泄漏量低、有效靶向病灶部位以及药物可控释放等特点。目前,能对外界环境中的微小刺激(如光、pH、氧化还原、酶、温度等)产生快速响应,从而实现药物可控释放的NDDS引起了国内外研究者的广泛关注。相比其他刺激响应,光是一种理想的外部刺激,不需要任何体内环境的变化,仅仅通过调节光的波长、强度、照射时间等就可以实现药物在病灶部位的快速释放,具有较高的时空分辨率,是一种无创、高效、洁净的刺激类型。因此光刺激响应NDDS在生物医学领域有着巨大的应用价值和广阔的发展前景。高能量的UV-vis光常用于触发药物释放,然而由于体内血红蛋白和水的强烈散射和吸收,UV-vis的组织穿透能力较差,同时UV光还容易引起细胞光损伤,从而限制了其临床应用。相比之下,近红外光(NIR)能够穿透10 cm厚的生物组织,对组织和细胞的损伤也很小,已成为NDDS刺激响应释放的研究焦点。此外,NDDS的光敏载体和光敏基团是实现药物输送和可控释放的基础,各类光敏载体及其光响应机理成为研究NIR刺激响应NDDS的另一焦点。NIR作为理想的光源,具有良好的生物相容性和组织穿透能力,但是单个NIR光的光子能量低。大量研究报道:双光子激发技术利用脉冲NIR作为激发光源,在获得局部即时有效的能量的同时具有较强的组织穿透能力和较小的光毒性,可以有效克服传统方式(利用紫外或者可见光)触发药物释放时组织穿透能力差的问题。此外,近年来研究者采用能量转移的思路报道了一系列基于上转换发光的NIR刺激响应NDDS体系,该技术以NIR激发上转换发光载体,在体内产生光敏分子所需要的紫外或可见光,可有效避免光危害问题,同时精确控制药物释放。光控NDDS的药物释放机制源于NDDSs中含有光敏基团,在NIR作用下,体系的结构将发生异构形变或者降解,从而实现光控药物释放。目前国内外学者在基于NIR的光热响应NDDS、光动力学NDDS、光异构化NDDS、光致重排NDDS和光降解NDDS方面进行了大量研究,取得了较为显著的成果。本文根据引入的光敏基团对光响应机制的不同,从五个方面综述了基于NIR响应的纳米药物输送系统的新研究与新进展,并对各自的机理进行了简单介绍,同时指出其存在的问题及未来研究方向,以期为今后相关方面的深入研究提供参考和借鉴。

The nanoscale drug delivery systems(NDDS)are able to transport drug of the therapeutic dose to the lesions in a controllable manner,and realize the precise release of the drug in spatiotemporal level,which feature high utilization ratio of drug,less side-effects to normal tissues and so forth.Hence,NDDS has provided a novel strategy for the precise treatment of diverse serious diseases,especially tumors.The ideal NDDS should be equipped with high drug-loading,low drug leakage,strong targetability and controllable drug release.In recent years,NDDS capable of generating rapid response to small stimuli(such as light,pH,redox,enzyme,temperature,etc.)in the external environment and realizing the controllable release of drugs have attracted tremendous interests at home and abroad.Compared with internal stimuli,light is an ideal external stimulus,which does not require any changes in the internal environment.Photo stimulus can achieve rapid release of drugs in the lesion by adjusting the light wavelength,intensity,irradiation time and so forth,realizing the precise control of treatment timing and location in a non-invasive,highly efficient and clean manner.Consequently,the photo stimulus responsive NDDS shows great application value and broad development prospect in biomedical field.A large amount of light-responsive NDDS release their entrapped drugs under excitation by UV or visible light.However,suffered from intense scattering and absorption by hemoglobin and water,the UV-vis light presents poor tissue penetration ability,and a certain light damage to the cell,which blocks its in vivo applications.In contrast,near-infrared(NIR)light exhibits great tissue penetration depth and less damage to the cells and tissues,hence it has become a focus in the field of stimulus responsive NDDS.Besides,satisfactory photosensitive carriers and groups are the premise of achieving effective drug delivery and controlled release,thus the different responsive mechanisms of photo stimulus responsive NDDS have become another research focus.As an ideal light source,NIR light possesses favorable biocompatibility and tissue penetration.Nevertheless,the energy of single NIR light is not strong enough to induce photo-responsive reaction.Recently,considerable studies have reported that the two-photon excitation technology with pulsed NIR as the excitation light source,exhibit strong tissue penetration ability and less phototoxicity while obtaining local immediate and effective energy.It can effectively overcome the problem of poor tissue penetration when drug release is triggered by conventional methods(ultra-violet or visible light is used).Besides,a series of reports show that upconversion nanoparticles(UCNPs)are able to absorb NIR light and convert it into UV-vis emission by fluorescence resonance energy transfer(FRET).Such promising optical property of UCNPs has been widely explored for bioimaging owing to its greatly improved tissue penetration depth,excellent photo stability,and minimal autofluorescence background.The drug release mechanism of photo stimulus response NDDS is derived from photosensitive groups.Before and after the response to the specific stimulus,the composition or conformational of photosensitive groups will be changed,damaging the original balance of the delivery systems and releasing the drug from the delivery systems.In recent years,photo stimulus responsive NDDS based on different photo-responsive mechanisms including photothermal,photodynamic therapy,photoisomerization,photo-induced rearrangement and photodegradation,have been designed and developed for precise photo-controlled release of drugs,and fruitful results have been achieved.In this article,we review five NIR light response stimulus responsive NDDS and their different photo-responsive mechanisms.The research progress of photo-controlled drug delivery systems based on different photo-responsive mechanisms are introduced in detail.Additionally,the existing problems and the future research perspectives of photo-controlled drug delivery systems are proposed.