A report On Mesoporous Silica Nanoparticles AbstractThis Mini review contains the recent progress in Mesoporous Silica Nanoparticles (MSNs) as a drug delivery system. MSNs are one of the most promising nanocarriers for drug delivery because of their interesting physical and chemical properties, thermal and mechanical stability and Biocompatibility. MSNs possesses easily functionalizable surface. Due to this, large number of property modifications are possible which improves efficiency in this field. Surface of MSN can be functionalized with various polymers or proteins, vitamins.In this review we will focus on different stimuli method used for DDS. MSNs are considered for smart drug delivery system due to their biocompatibility and structure. There are various stimuli but we will focus on the internal stimuli such as pH, enzyme, temperature and external stimuli such as ultrasound, light and magnetic field for anti-cancer therapy. Table of Contents1.Table of content……………………………………………………………………………….32. Introduction…………………………………………………………………………………..4           2.1 Properties of MSNs……………………………………………………………………4           2.2 Applications of MSNs………………………………………………………………..4           2.3 Selective Targeting……………………………………………………………………5           2.4 Controlled dosage and Smart Behaviour……………………………………………..53.Internal Stimuli Responsive Drug Delivery…………………………………………………5         3.1 pH sensitive drug delivery……………………………………………………………..6         3.2 Redox responsive Drug delivery……………………………………………………….6         3.3 Enzyme Responsive Drug Delivery……………………………………………………7         3.4 Thermo Responsive Drug Delivery……………………………………………………74. External Stimuli Responsive Drug Delivery………………………………………………..8         4.1 Light Responsive drug delivery………………………………………………………..8         4.2 Ultrasound Drug delivery……………………………………………………………….9         4.3 Magnetic Responsive Drug delivery……………………………………………………95. Conclusion……………………………………………………………………………………116. References……………………………………………………………………………………12 1.IntroductionOver the last decade, Mesoporous Silica Nanoparticles( MSNs) have attracted great attention as a drug delivery system in biotechnology and nano- medical fields due to their unique and adjustable physiochemical properties. MSNs are solid are solid materials which Containing hundreds of empty( mesopores) channels arranged in a 2D network of honeycomb like porous structures. Mesoporous silica nanoparticles have many good properties which are helpful for Biomedical application of MSNs. It has high surface area and pore volume which can be used for drug loading. Due to large number of silanol groups on the surface, any functional group can be easily attached to MSNs. Silica is chemically inert material MSNs which show great biocompatibility.[5] large surface area and large pore volume are their biggest advantages.Due to this properties MSNs are considered as promising drug delivery carriers. Lot of research has been carried out on MSNs for use in biomedical field. Vallet-Regi’s work first reported the use of mesoporous silica as DDSs.2.1 Properties of Mesoporous Silica Nanoparticles:1.Tunable Particle size(50-300nm)2. Uniform and tunable pore size(2-6nm)3. large surface area (>700m2/g4. large pore volume >0.9cm3/g5. High thermal and chemical stability6. Dual tunable functional surface7. vivo biocompatibility and hemocompatibility.2.2 Applications of Mesoporous Silica Nanoparticles:1. Imaging and Diagnostic agents: MSNs are one of the widely used nanoparticles for imaging and diagnostics .There are different methods used for imaging. In one of the method MSNs are conjugated with organic dyes for fluorescent imaging. Also MSNs are conjugated with Magnetic nanoparticles for magnetic resonance imaging, quantum dots and central dots are used for imaging. The resulted MSNs give high resolution and Multichannel images.[5]2. Target Specificity: MSNs can be used for binding specific cell or tissue. Due to Target specificity of MSNs toxic effects of drug can be decreased.[5]3. Bio sensing and cell tracing: MSNs can be used for biosensing and cell tracing by loading its surface with cell recognising agents.[5]4. Use in Optoelectronic devices:  Polymer with High mechanical strength and low thermal expansion can be synthesized by modifying surface of MSNs which can be used in Solar cell and LED.[5]5. Loading and Delivering high concentration Molecules: Due to large surface area and pore volume high concentration molecules can be loaded and delivered using MSNs.[5]2.3 Selective targetingSelective targeting is widely used strategy to interact selectively with certain membrane receptors in which surface of mesoporous silica nanoparticles is coated.  Besides, it is possible to decorate MSNs with targeting ligands with affinity towards the blood vessels that irrigate the solid tumor, which disrupts its nutrients and oxygen supply triggering the tumor destruction. This method is known as active targeting. Till date lot of strategies have been developed to for active targeting using MSNs. Table (1) summerizes the different active targeting strategies for MSNs On the other hand, two targeting agents( dual targeting) can be engraved on the same nanocarrier in order to increase their selectivity even more. There are various examples of dual targeting ligands. For example, MSNs are modified with folic acid and dexamethasone to target the Hela cells, folic acid and triphenylphospine for sequential cells to organic targeting proposed.          Active Targeting                   Dual TargetingFig.1 (Left) schemtic representation of active targeting (Right) Schematic representation of dual targetingTargeting LigandTumor cell ReceptorTarget Cell lneRef.MethotrexateFR-aHela[7]AnisamideSigma receptorASPC-1[8]MABGNETNB1691-luc[9]HACD44MCF-7, MDA[10]ConASAHOS[11]Table 1.  Different active targeting strategies for MSNs2.4 Controlled Dosage and Smart Behavior: One of the good thing about MSNs is that there pores can be blocked by using different gatekeepers. Due to this advantage of MSNs stimuli responsive behavior can be achieved. Loaded drugs are released when MSNs are exposed to certain stimuli. There are diferent types of stimuli like pH, temperature, enzymes, magnetic field and light. This stimuli are mainly divided into internal stimuli and external stimuli. Internal stimuli are more beneficial because stimuli specificity is already present at physical sites. Due to this specificity nanoformulations release the cargo precisely at targated site which reduce the adverse effects. 3. Internal stimuli responsive The intrinsic properties such as pH, enzyme are the basis in the design of internal stimuli-responsive. There is difference between pH and temperature of normal tissues and pathological tissues. Many smart drug delivery systems are designed which able to respond this internal stimuli. This smart DDS mainly contains one or two elements. One is linker and second one is caping agent. Linker breaks down or degrade when exposed to appropriate stimuli. While capping agent acts as blocker which prevents the premature cargo release. Capping agents inorganic nanoparticles or polymers.3.1 pH sensitive drug delivery system:Various organs in human body has various pH. For example the extracellularpHoftumor tissues (6.5–7.0) or the pHof inflamed tissues and wounds (5.4–7.2) are more acidic thanthe pH of blood and normaltissues (7.4)   So to target the various cells and tissues pH sensitive drug delivery systems are employed. In addition, when inner cells are internalized, different pH depending on cell compartments can be exposed. In fact, the pH values in cytosol(7.4), Golgi apparatus( 6.4), endosomes( 5.5–6.0) and lysosomes( 5.0) differ considerably. Thus, pH- sensitive stoppers can be used as pore blockers to control the drug release response to these pH changes by functionalizing the MSNP surface with appropriate functionalitiesOne strategy is to engrave polymer chains that carry functional groups with basic properties that change their conformation to an external pH. Diverse pH- sensitive polymers, such as poly(4-vinylpyridine),poly(2-(diethylamino) ethylmethacrylate),chitosan, starch, or poly(styrene sulfonate), have been attached to MSNP surfaces. At neutral pH( 7.4), polymer chains are in a neutral and then interact with them by adopting a collapsed form on the MSNP surface, blocking pores and inhibiting drug release. Under mild acid conditions such as lysosome(pHca.5),the polymer chains are protonated and positively charged, leading to increased conformation allowing the cargo molecules to escape from the particles. In contrast,the neutral medium induces pore opening of MSNPs with polyamines. Pores can be capped using host-guest interactions using Polymacrocyclic molecules, such as CD or cucurbit, uril, that can form inclusion complexes with different immobilized organic molecules covalently attached to the external surface of MSNP which may dissociate from acid lysosomal pH exposure. Drugs like Doxorubicin or cis- platin can also be directly engraved on the surface using similar acid- sensitive functions. Another way is to functionalising the surface with pH decomposable inorganic coating which acts as gatekeeper.                   pH               Redox Potential        EnzymeFig.2 Mechanism of internal stimuli responsive drug delivery 3.2 Redox responsive drug deliveryOur body contains unique and intrinsic redox gradients. The GSH concentration varies between extracellular matrix and intracellular space. Also GSH concentration is different in tumor sites and normal tissues. Due to which redox sensitive nanocarriers are one of the promising intracellular drug delivery system. Disulfide bond has been proved to be the main redox-sensitive linker to develop redox-responsive nanocarriers. Disulfide bond in nanocarriers is stable in the external environments with low reduction level and is reduced to thiol groups by high concentration of GSH inside the cells, leading to the rupture and cleavage of nanoformulations and triggering drug release. Tremendous progress has been occurred in this polymeric drug delivery system using this method. One of the example is of amphiphilic PEI and poly(?-caprolactone) (PCL) grafted copolymers were synthesized via cystamine with disulfide bonds as the nanocarriers for the synergetic delivery of DOX and p53 plasmid DNA. The cumulative release of DOX showed a significant increase from 60 percent  to nearly 100 percent  within 48 h when the concentration of DTT increased from 0 to 10 mM. 3.3 Enzyme responsive drug deliveryEnzymatic activity dysregulation and an abnormal increase in enzymatic presence were observed in a number of diseased states that make enzymes interesting stimuli to trigger drug release using their biocatalytic actions. The first enzyme- sensitivegate on MSNPs was described by Stoddart and coworkers, who functionalized the nanoparticle surface with stalks encircledby cyclodextrins(CD) and incorporated an enzyme cleavable site, generally an ester function, with a bulky stopper. The responsive bond is loosened in the presence of esters, the molecular gate removed and the drug released. Biotin is also used to functionalise MSNs surface for enzyme responsive drug delivery. Other than functionalizing MSNs another way used is attaching enzyme sensitive cap.3.4 Thermo responsive drug deliveryThermo responsive drug delivery is another intrenal stimuli responsive system used for triggerd drug delivery. There is slight difference between temperature of physiological environment and disease sites. Normal body temprature is 37?c while temperature of disease site is 40?c to 42?c. Nanocariers remains stable at body temperature but when they are delivered to hyprthermal tissues they release the cargo. Poly(N-isopropylacrylamide) (PNIPAAm) is widely used polymer for thermo responsive drug delivery. There are many heat sensitive polymers used for functionalizing MSNs surface. Among them Pluronic is FDA approved thermo responsive polymer. poly(ethylene glycol)/poly(epsilon-caprolactone) (PEG/PCL) are also used to functionalise MSNs surface for this kind drug delivery.4 External Stimuli responsive drug delivery system:Different external stimuli responsive are used to for drug delivery. MSNs are developed in such a way that they respond when exposed to external stimuli. There are many external stimuli used for drug delivery like Ultrasound, magnetic field, Visible light etc.4.1 Light Responsive system:UV, NIR or visible light is used for external stimuli. Light activated drug release gives better control because light can be easily focused on small areas which reduces the side effects. There are some limitations of using UV/visible light for drug release. because Light can damage the cells also it cannot be penetrated deep inside the living tissues. There are many different examples of using light responsive systems. In one strategy silylated azobenzene is used to decorate the MSNs. Azobenzene acts as a pore keeper in the absence of light but when exposed to UV/visible radiation it acts as nanoimpeller. Which results in cis-trans photoisomerisation of N=N bond and dynamic motion is created and drug is released from the pores. Another strategy is grafting gatekeeper bearing a light sensitive linker. Pore blockers can be metal complexes, Cadmium sulfide/Gold nanoparticle. Photo cleavable linker can be o- nitrobenzylester, carbamate or o-methylbenzineamine. Also Thermo-sensitive polymers containing light sensitive groups can also be grafted on MSNs surface for Drug release. Figure(3) represents the visible light triggered drug release. In this example, MSNs are decorated with porphyrin nanocaps anchored through reactive oxygen species( ROS)-clear connections. When Vis light stimulus is used, porphyrin blocking caps cause singlet oxygen molecules that break the sensitive linker and trigger the opening of mesopores and allow the release of drugs 4.2 Ultrasound responsive System:Ultrasound responsive system are an effective method for achieving spatiotemporal drug control at the target site and preventing damage to healthy tissues. There are many advantages of using US triggered drug release. Because they are non-inasive, can be easily penetrated through tissues by tuning different parameters like frequency and exposure time. Also they lacks the ionizing radiation. Ultresound waves can trigger the drug release from MSNs through thermal effect. Mechanophores is chemical bond which splits when exposed to US radiation. This bond is used to design the Ultrasound triggered MSNs. Thus, 2-tetrahydropyranyl methacrylate, a hydrophobic monomer with a US- sensitive group, can thus transform into hydrophilic methacrylic acid. This phase transformation under the US stimulus was used to develop US- responsive drug delivery MSNs using mesopore gatekeepers. Figure(3) represents the mechanism of Ultrasound responsive system.4.3 Magnetic Field responsive System:Magnetic field responsive system are one of the promising external stimuli responsive system used for drug release. The advantages of using magnetic fields are due to the different effect they can have on MSNs, which can be magnetic guidance under a permanent magnetic field or an increase in temperature when applying an alternating magnetic field. Supermagnetic iron oxide is widely used magnetic nanoparticle for magnetic field stimuli responsive drug delivery system. The incorporation of SPIONs into MSNs allows AM fields to be used to increase temperature. MSNs may include temperature- responsive moieties acting as gatekeepers capable of undergoing physicochemical changes that cause pore opening and drug release. Figure(3) represents the example of drug loaded magnetic responsive MSNs. In this example pore outlets are grafted with single DNA strands .This hybridize with Fe3O4 SPIONs, which functionally acts as capping agents with a complementary DNA strand. Applying an AM field causes heat that triggers DNA dehybridization, allowing cargo release in a reversible way.Magnetic Field   Ultrasound      Visible lightFig.3 External stimuli responsive System[6] 5. ConclusionIn conclusion, we discussed progress in many stimuli responsive drug delivery systems. Due to versatile nature and even smaller size than eukaryotic cell, MSNs are excellent DDS. MSNs are excellent alternatives for conventional therapys. Zero premature drug release is biggest advantage and using external stimuli we can control the kinetic release of drug more efficiently. So far no clinical trials have been perfomed using MSNs. Silica is classified as “Genrally recognized safe” by FDA and used in cosmetics and food additive.  Some research has been carried out on mice using MSNs. Although the structure morphology, surface properties and size of MSNs were found to be suitable for controlled drug delivery and multifunctional drug delivery purposes; There are major concerns regarding the biocompatibility, toxicity, in vivo bio- distribution and efficacy of MSNs of various particle sizes, as knowledge on in vivo biocompatibility, toxicity and in vivo MSNs is still very limited. Most importantly, there is a lack of human clinical trials and the few existing animal model studies do not provide sufficient evidence for the safety of MSNs. Scale up is another major barrier. Most of the MSNs are synthesized in the lab. Where very few grams or milligram product is obtained. Reproducibility of MSNs at small scale is very easy but at large many factors it is very difficult. Total cost and reproducibility are major barriers in commercializing.   Several factors needed to be considered for scale up. Mesoporous silica nanoparticles are a promising and intelligent drug delivery system for different diseases, but significant clinical studies are still needed to further examine them for large- scale production and regulatory approvals.References Di-verse pH-sensitive polymers, such as poly(4-vinylpyridine),[71]poly(2-(diethylamino)ethylmethacrylate),[72]chitosan,[73]starch,[74]or poly(styrene sulfonate),[75]have been attached toMSNP surfaceIn addition, whennanoparticles are internalized inside cells, they can be exposedto different pH depending on the cell compartments. Indeed,pH values in cytosol(7.4), Golgi apparatus (6.4), endosomes(5.5–6.0) and lysosomes (5.0) are considerably differentIn addition, whennanoparticles are internalized inside cells, they can be exposedto different pH depending on the cell compartments. 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