Mesoporous Silica As An Emerging Platform In The Domain Of Nanomedicine

Cancer remains a highly lethal disease which tops the list of health concerns allover the world. The efficacy of cancer therapy is usually restricted by the lack ofspecificity of anticancer drugs which in turn results in the low therapeutic index andvery intolerable side effects. To solve this intractable health problem, advent andintegration of nanotechnology with biological systems has fortunately offered a lot ofnew possibilities to radically change cancer detection, diagnosis and treatment.Mechanistically, the architectural anarchy coupled with an overproduction ofpermeability enhancers and poor lymphatic drainage in cancer tissues in factfacilitates the nanoparticles to preferentially concentrate at cancer sites. Hence,variety of nanoparticle based drug delivery systems have been developed includingpolymeric conjugates, micelles, liposomes, dendrimers, carbon nanotubes andinorganic nanoparticles, to ferry cytotoxic drugs or therapeutic genes into malignantcells, while sparing healthy cells unharmed. Among all available nanoplatforms,mesoporous silica nanoparticles (MSNs) have been increasingly employed aspromising vehicles for anticancer drug delivery mainly because of theirbiocompatibility and high surface area. In addition, Mesoporous silica has also beenwidely explored as stimuli responsive drug delivery vehicle to minimize the prematurerelease of cytotoxic drugs. Likewise, the aim of this study was to design such smartmesoporous silica based nanoarchitectures that deliver highly cytotoxicchemotherapeutic drugs according to pathophysiological conditions.In the first study, acid-decomposable ZnO quantum dots (QDs) were used toblock the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit thepremature drug release of loaded anticancer drug. It was clearly demonstratedthrough various characterization techniques that after internalization into cancer cells, the ZnO QD lids were rapidly dissolved in response to acidic intracellular environ.The decomposition of ZnO nanolids resulted in the release of cytotoxic drug into thecytosol of cells from MSNs. In addition, ZnO QDs herein behaved as a dual-purposeentity that not only acted as a lid but also had a synergistic antitumor effect on cancercells. The capping of ZnO QD on anticancer-drug-loaded MSNs holds the potential toimprove the therapeutic index of drugs and lower their side effects.This system was later extended to deliver two drugs simultaneously inresponse to acidic conditions. A straightforward strategy was employed to engineerthis smart mesoporous architecture that integrated combinational therapy withnanotechnology to deliver two cytotoxic drugs in response to extracellular and/orintracellular acidic milieu in cancer cells. This novel approach involved first loading ofa campothetacin (hydrophobic topoisomerase I inhibitor) in the nanopores of MSNs.To achieve "zero release" of toxic drug before reaching the targeted sites, pHsensitive ZnO nanolids were similarly used to cap the drug loaded channels of MSNs.Subsequently, a hydrophilic drug Doxorubicin (potent DNA intercalating agent) wasimmobilized onto ZnO nanolids. Zinc oxide in that work concurrently acted asnanocaps to block the release of encapsulated drug and to provide conjugating sitefor loading another hydrophilic drug via coordinate bond. In contrast to mesoporoussilica, significant amount of doxorubicin (7.5%) was not only loaded onto ZnO surfacebut it also exhibited the highest percentage of cumulative burst release in responseto acidic environment. On the other hand, hydrophobic entrapped CPT was alsoreleased in controlled fashion but also in response to acidic conditions. Cell viability,confocal imaging along with other technique convincingly corroborated theapplicability and efficiency of resulting systems. Besides just drug delivery, focus ofresearch is increasingly being shifted towards imaging-assisted therapies to monitordrug distribution and subsequent therapeutic response as well. To realize imaging-assisted therapy and codelivery of multiple drugs through asingle nanocarrier, in the second study we engineered highly luminescent CdS-MSNs nanocomposite to codelivers two cytotoxic drugs simultaneously into cancercells in response to acidic endosomal environment. Quantum dots were conjugatedon the surface of the amine-functionalized MSNs via1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) activation chemistry. One anticancer drug(Campothetacin) was loaded into the nanopores of QDs@MSNs whereas; anotherfluorescent drug (doxorubicin)(DOX) was anchored onto the exterior surface ofQDs@MSNs through the establishment of dative covalent bond between DOX andCd2+.Conjugation of DOX resulted in the quenching of both fluorescent entities.However, exposure to mildly acidic environment caused a rapid recovery of thefluorescence of both components due to cleavage of metal complex. Thesefluorescent on-off states provided a unique opportunity to not only deliver anticancerdrugs but also sense the delivery of drugs and track the therapeutic responses ofchemotherapy. Cell experiments and drug release findings verified the efficiency ofnewly developed multifunctional nanoplatform.In the third study mesoporous silica based double drug carrying theranosticsystem was developed. The strategy is based on the fabrication of magnetiteembedded mesoporous silica nanoparticles (MSNs) whose internal porous structureand outer surface area were then respectively exploited to load two different cytotoxicdrugs. Hydrophobic camptothecin (CPT) was loaded into the nanopores of MSNswhereas arsenic trioxide "Delicious Poison was successfully immobilized onto thethiol functionalized external surface. CPT and Arsenic trioxide (ATO) loaded MSNsformulations exhibited a dose dependent cytotoxicity against cancer cells. On thecontrary, killing efficiency of dual drug formulation was expectedly higher than onedrug systems due to drug synergism. Moreover, the superparamagnetic feature ofembedded magnetite nanocrystals empowered the nanoparticles to be used as a contrast agent in magnetic resonance (MR) imaging for monitoring the eitherdiseased tissues or efficacy of chemotherapy. We expect that this integration of bothcombination therapy and nanotechnology coupled with its versatile magneticmanipulation may prove to be a significant step forward towards the development ofeffective theranostic agents.