Construction Of Mesoporous Silica-based Smart Drug Controlled Release System And Its Application In Nanomedicine

Materials science and chemical engineering are regarded as the two fundamental impetuses to bloom nanobiotechnology and nanomedicine.Owing to strong loading capacity,good biocompatibility,controllable particle size and pore size as well as morphology,easy surface modification and functionalization,water dispersion stability and other characteristics,the mesoporous silica nanoparticles(MSNs)are a key example of innovation in material science to develop nanotechnology-based delivery systems,which provided unprecedented opportunities for the development of next-generation cancer nanomedicine.In this dissertation,by controlling the transition of the surface wettability of MSNs nanochannels,a smart free-blockage drug controlled release system that responds to the tumor microenvironment was designed,which bypasses the use of nano"gatekeeper"(such as nanoparticles,organic molecules,etc.)and overcomes the limitations of traditional and commonly entity structure physical blockage drug controlled release system.Furthermore,the cell uptake performance and biological safety of MSNs-based drug delivery system were improved by synthesizing sub-50 nm urchin-like mesoporous organosilica nanoparticles(MONs).Finally,the tumor acidic microenvironment-induced sub-40 nm hollow-structure MONs(HMONs)system aggregation strategy makes the HMONs system have the ability for tumor accumulation and retention for a long time,thus realizing the effective cellular uptake of the nanocarriers.1.An MSNs-based reactive oxygen species response free-blockage drug controlled release system was designed and constructed,which realized controlled drug release by controlling the wetting behavior of the inner surface of nanopores on MSNs.This wettability-driven,free-blockage controlled release system was prepared by one-step co-condensation strategy and loaded drug by simple ultrasound,which defuses the limitations and potential side effects of traditional entity structure physical blockage drug controlled release system and will play an important role in promoting the clinical design and application of drug controlled release systems in the future.2.Based on the above work,a functional molecule of phenylboronic acid(PBA)that can respond to glucose under physiological conditions and has a hydrophilic-hydrophobic conversion property of glucose response was designed and synthesized.The co-condensation method was used to prepare MSNs with the inner surface of the nanochannels specifically modified by PBA functional molecules.This kind of MSNs-based drug controlled release platform not only can control the drug release behavior through its own nanochannel’s wettability conversion but also the preparation and operation process are simple and effective,which provide a new possibility for the construction of molecular transport platform from the perspective of surface wettability in the future.3.Although we have solved the troublesome of using additional nano"gatekeeper" in the traditional MSNs-based drug controlled release system through the above two works,we still need to pay enough attention to the dilemma of low cellular uptake efficiency and refractory degradation faced by MSNs nanocarriers for promoting the clinical transformation of MSNs-based drug controlled release system.Herein,inspired by sea urchins,we innovated from the source of the material,designed and prepared sub-50 nm urchin-like biodegradable MONs(UMONs)with a rough surface and spiky tubular morphology that can enhance cell uptake.Next,L-Arginine(a typical NO donor with high stability and biocompatibility)was loaded in the nanopores of the UMONs,and ultrasmall gold nanoparticles with glucose oxidase(GOx)-mimicking catalytic activity were modified on the external surface to construct a pH/GSH dual-responsive urchin-like biodegradable MONs nanomedicine for enhanced cellular internalization and nanocatalysis-enhanced NO gas therapy.4.Through the above three work,we have overcome the limitations of the nano "gatekeeper" entity structure physical blockage drug controlled release system and solved the problems of low cellular uptake efficiency and difficult degradation of the nanocarriers.However,if the drug-loaded MONs cannot accumulation and retention in the tumor site for a long time after it penetrates the tumor tissue,it cannot be effectively uptake by the cells to complete drug delivery.In this way,the two problems we have solved before can only be regarded as "armchair theory",and there is no way to promote the clinical transformation of MONs-based nanomaterials.As a consequence,based on the sub-40 nm HMONs,we proposed an acid-induced HMONs system aggregation strategy,which enables the HMONs system to have longer tumor retention abilitity,and provides a solid foundation for the effective cell uptake of drug-loaded nanocarriers.The tumor acidic microenvironment-triggered aggregation strategy of nanocarriers opens a new paradigm to promote the clinical transformation of MSNs-based nanomedicine.