Biodegradation Of Silica-based Nanoparticles And Tumor-specific Nanotherapy

The fast development of medicine and nanomaterials have promoted the emergence and promotion of nanomedicine,among which various nanomaterials and tumor therapeutic strategies have been explored.Silica-based and carbon-based nanomaterials have been attracting ever-increasing attention in nanomedicine.Featuring high biosafety,controlled morphology and dimensions,extremely high specific surface area,tunable pore size,and easy functionalization,silica-based nanomaterials have been widely applied in drug delivery,biological sensing,tissue engineering and biological imaging.However,biological safety evaluations of silica-based nanomaterials have been far from sufficient,especially its biodegradation research,and the current degradation issue has been being one of the major obstacles for its further clinical transformation.The chemical/physiological stability of inorganic MSNs is regarded as its intrinsic advantage facilitating sustained drug releasing and corresponding chemotherapy,but will,unfortunately,result in undesirable low biodegradability,the consequent accumulation of the nanocarriers within the body,and thereby the potential biosafety risk.Therefore,the biodegradation control of MSNs is now one of the major challenges in determining the further clinical translation potential of these inorganic nanocarriers.Inorganic doping endows the inert silica framework not only accelerated biodegradation but also functional biomedical applications.With the development of bioscience and biotechnology,tumor initiation and progression now can be understood ever more comprehensively and accurately.Tumor microenvironment plays a vital role in tumor occurrence,effective drug resistance,high radio-resistance,adaptive metastasis,thus will strongly deteriorate the therapeutic outcomes and promote tumor recurrence.Tumor microenvironment features hypoxia,mild acidity,over-expressed hydrogen peroxide and exhaustive energy supply-demand relationship.Fortunately,these distinct TME may provide theranostic opportunities specifically and/or selectively against malignant tumor cells,rendering TME a double-edged sword.Additionally,along with the rapid development of nanoscience and nanotechnology on biomedicine and pharmacy,a number of novel but highly effective anticancer nanotherapies have been reported very recently.By exploiting the metabolic features in TME,significant progress have been achieved on antitumor chemotherapy,chemodynamic therapy（CDT）,radiotherapy（RT）,photodynamic therapy（PDT）,photothermal therapy,sonodynamic therapy or their synergistic therapies.Tumor microenvironment-responsive nanotherapies have high tumor selectivity and specificity and are also capable of modulating the microenvironment as feedback.In this paper,we mainly focus on the following topics.（1）The biodegradation behavior of MSNs and the tumor therapy by using CTAC@MSNs,where CTAC is a pore directing agent/surfactant used in the synthesis of MSNs)as the nanomedicine without the need of surfactant extraction and drug loading.（2）coordination-accelerated“iron extraction”promoted biodegradation of Fe-doped hollow mesoporous silica nanoparticles（Fe-HMSNs）.（3）Fe^II-engineered hollow mesoporous silica nanocatalyst with a biodegradable and catalytically active framework for tumor-specific therapy via Fe^II-catalyzed Fenton reactions.（4）One step in situ synthesis of tumor microenvironment-responsive biodegradable organic silica nanoparticles as novel drug delivery systems.1.The biodegradation behavior of MSNs and CTAC@MSNs nanomedicine.Being one of the most widely applied inorganic nanomaterials,biodegradability of MSNs is of great importance for biosafety and further clinical translation.In this chapter,MSNs synthesized after longer hours was found to show slower degradation in simulated body fluid,which mainly originates from the more densified framework and less Si-OH groups on the surface at prolonged synthesis.MSNs degradation also shows pH-dependence,quicker degradation has been observed in neural condition than in the acidic SBF.Degradation behavior of MSNs is mainly determined by the framework integrity,amount of Si-OH group and pH value of degradation fluid.We further evaluated anticancer effect of CTAC@MSNs nanomedicine with the CTAC surfactant used in the synthesis of MSNs remained in the mesopore system,thus avoiding the redundant procedures of CATC extraction,surface modification and drug loading in traditional nanomedicine construction.CTAC@MSNs showed relatively high cytotoxicity in vitro but rather low anticancer effect in vivo due to low tumor distribution.After cascade targeting modification of RGD and TAT peptides,CTAC@MSNs show much enhanced antitumor effect but have a quite high half lethal dose.2.Coordination-accelerated“iron extraction”enables fast biodegradation of Fe^Ⅲ-doped hollow mesoporous silica nanoparticles.An iron doped hollow mesoporous silica nanoparticles（Fe-HMSNs）were constructed,and its coordination responsive biodegradability and drug loading and release properties were further evaluated.Fe-HMSNs were obtained after hydrothermal treatment of MSNs with urea and iron precursor,via a dissolution-regrowth strategy.PEGylation was carried out for further cellular and in vivo assays,followed by drug loading of DOX.It was found that iron ions in the framework is easy to be extracted by protein coordination,and leave the framework with plenty of vacancies,which further accelerates the residual silica framework degradation.Moreover,the complexation-responsive degradation of framework further accelerates DOX release.3.Fe^Ⅱ-engineered hollow mesoporous silica nanocatalyst with biodegradable and catalytically active framework for tumor-specific therapy via Fe^II-catalyzed Fenton reactions.In this research,ferrous iron-doped hollow mesoporous silica nanoparticles（rFeO_x-HMSNs）were obtained by the partial reduction of Fe-HMSNs,which work as an efficient organic nanocatalyst similar to natural peroxidase.The tumor microenvironment is featured with mild acidity and over-expressed H₂O₂,which enables rFeO_x-HMSN nanocatalyst to catalyze the decomposition of H₂O₂ and production of highly toxic hydroxyl radicals to kill cancer cells by Fenton reaction.This nanocatalytic tumor therapy strategy has advantages of high biosafety and selectivity,and enhanced therapeutic outcomes in comparison with traditional chemotherapy using toxic chemodrugs because rFeO_x-HMSN could only catalyze the Fenton reaction in mildly acidic tumor microenvironment rather than in neutral normal tissues.This inorganic nanocatalyst show high catalytic activity following the Michaelis-Menten kinetics.Besides,rFeO_x-HMSNs also show complexation-responsive biodegradability,indicating its high biosafety in vitro and in vivo.4.One step in situ synthesis of tumor microenvironment responsive biodegradable organic silica nanoparticles as novel drug delivery systems.Drug molecules were encapsulated in the framework of silica nanoparticles,which also act as defects generator in the nanoparticles for accelerated silica degradation.Such a nanomedicine obtained by one step in-situ synthesis approach avoids the use of high-cost surfactant and necessitates no procedures such as surfactant removal,surface modification and drug loading used in traditional MSN based drug delivery systems.In addition,the organic functional group introduction endows the nanoparticles with glutathione-responsive biodegradation and drug release in tumor tissues.The drug loaded silica show much-enhanced biodegradability in comparison to traditional MSNs.Moreover,high drug loading efficiency and drug loading capacity were realized by this strategy,indicating enhanced cellular cytotoxicity and in vivo anticancer effect.