刺激响应介孔氧化硅纳米载药系统的可控组装及控制释放性能

Controlled assemblies of stimuli-responsive mesoporous silica drug delivery systems for controlled release of drugs

刺激响应介孔氧化硅纳米载药系统能够有效提高药物的治疗效果和尽量降低药物的毒副作用,相关研究领域近年来引起人们的极大关注.本文主要介绍作者课题组在阀控和门控的介孔氧化硅纳米载药系统的研究工作.以生物相容性的介孔氧化硅纳米粒子(MSN)作为药物载体,将端基为活性基团的硅烷自组装修饰在MSN表面,并进一步功能化,通过多重弱键相互作用、动态共价键甚至和强共价键,将大环主体化合物、蛋白、DNA和量子点等结合到MSN表面,将药物封装在MSN孔道内,构成纳米阀和纳米门.可控组装的阀控和门控的MSN纳米载药系统,在p H、氧化还原、竞争结合、生物酶和近红外光等条件刺激下,多重弱键相互作用消除、动态共价键断裂以及纳米门控元件降解等,实现药物控制释放.可控组装的刺激响应MSN纳米载药系统在肿瘤等疾病靶向药物治疗方面具有应用前景.最后对刺激响应纳米载药系统的未来发展前景作进一步展望.

There has been an ever increasing interest in developing stimuli-responsive mesoporous silica drug delivery systems to improve therapeutic efficacy and minimize the adverse effects of drugs. This paper reports the works of our research group on valved and gated mesoporous silica drug delivery systems. Biocompatible mesoporous silica nanoparticles（MSNs）, as drug carriers, were modified with active group-terminated silanes via self-assembly followed by diverse functionalization, a variety of macrocyclic hosts, proteins, DNA, and quantum dots were bound to the MSN surfaces to develop nanovalves and nanogates, through multiple noncovalent interactions, dynamic covalent bonds, and even strong covalent bonds, for the encapsulation of drugs within MSN pores, thus smart valved and gated MSN drug delivery systems were constructed. Under the stimuli of pH, redox, competitive binding, enzymes, and near infrared lights, controlled release of the encapsulated drugs was realized, because of the destruction of multiple noncovalent interactions, the cleavage of dynamic covalent bonds, and the disassociation of gatekeeping scaffolds. The carboxylate-substituted pillar[6]arene（CPA[6]）-valved dimethylbenzimidazolium or bipyridinium-functionalized MSN drug delivery systems were constructed for acidic pH, competitive binding, and metal chelating-responsive controlled release. The ？-CD-gated MSN delivery system functionalized with disulfide-linked carbamoylphenylboronic acid moieties and amines via dual dynamic covalent bonds with dual drug loading was constructed for simultaneous and cascade release of two drugs. It is a smart strategy to take advantage of the specific structures and properties of cyclodextrins（CDs） for use in the MSN drug delivery systems not only as gatekeepers but also as drug carriers. The ？-CD-gated MSN delivery system provided a smart platform for combination drug therapy, in addition to resistance to serum and normal blood glucose levels. The concanavalin A（Con A）-gated mannose-functionalized MSN drug delivery system via multivalent carbohydrate-protein interactions was constructed for the controlled release of drugs either by acidic pH or by competitive binding of glucose at high concentrations. The long and flexible spacers linked with the mannose ligands played an important role in adjusting the local spatial arrangement of the ligands to favor multivalent protein binding, as did the surface density of the ligands. The MSN drug delivery systems functionalized with N-（3-trimethoxysilylpropyl）ethylenediamine triacetate ligands, in the presence of metal ions with and without myoglobin containing surface-accessible histidine residues, were constructed for pH-responsive controlled release. Both the metal-latching ligands and the metal-chelating proteins played a synergetic role in gating MSNs for high-loading drug delivery and stimuli-responsive controlled release. The DNA-gated MSN drug delivery system functionalized with disulfide-linked acridinamine intercalators was constructed for multi-responsive controlled release under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I. The DNA-gated MSN drug delivery system integrated multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs in combination of dual stimuli. The DNA-gated gold nanorod-embedded MSN delivery system functionalized with titanium（IV）-chelating phosphonates with dual drug loading was constructed for simultaneous and cascade release of two drugs. Coordination chemistry is the first strategy for DNA cappings through multivalent chelating interactions in drug delivery systems not only as gatekeepers but also as drug carriers. The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating. The combination of NIR light-based thermotherapy and triggered chemotherapy（thermo-chemotherapy） could maximize therapeutic efficacy. In addition, the ZnO quantum dot（QD）-gated hollow mesoporous silica drug delivery system was constructed for pH and redoxresponsive controlled release, and the Zn O QD-gated mesoporous carbon nanoparticle（MCN） drug delivery system was for pH-responsive controlled release. These constructed stimuli-responsive MSN drug delivery systems have promising applications in targeted tumor therapy.