Wenxiu Qi

pH-Triggered Controlled Drug Release from Mesoporous Silica Nanoparticles via Intracelluar Dissolution of ZnO Nanolids

Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity.

Acid degradable ZnO quantum dots as a platform for targeted delivery of an anticancer drug

Efficacious chemotherapy mainly hinges on the tumor-specific delivery of anticancer drugs. Herein we report a successful fabrication of highly photoluminescent and water dispersible ZnO quantum dotsvia a new ligand exchange free strategy. In addition to bioimaging, ZnO QDs have also been evaluated as a platform for targeted and pH responsive intracellular delivery of an anticancer drug. The cancer targeting feature is endowed by conjugating folic acid on to the surface of ZnO–NH2 QDs via an amidation reaction. Doxorubicin (DOX) is then successfully loaded onto the folic acid functionalized ZnO QDs by capitalizing on its marked tendency towards the formation of metal complexes. Drug loaded ZnO-FA QDs remain stable at physiological pH but readily disintegrate in the mildly acidic intracellular environment of cancer cells as validated by a drug release profile, confocal microscopy and a cell-cytotoxicity assay. Compared to the conventional drug nanovector, ZnO-FA QDs themselves manifest a significant therapeutic activity after reaching their targeted site, therefore, combined DOX and ZnO QDs can be more efficacious than either alone. Hence, this approach provides a valuable ZnO QDs-based nanovector that can simultaneously realize targeting, diagnosis, and therapy of cancer cells.

Intracellular antioxidants dissolve man-made antioxidant nanoparticles: using redox vulnerability of nanoceria to develop a responsive drug delivery system.

Regeneratable antioxidant property of nanoceria has widely been explored to minimize the deleterious influences of reactive oxygen species. Limited information is, however, available regarding the biological interactions and subsequent fate of nanoceria in body fluids. This study demonstrates a surprising dissolution of stable and ultrasmall (4 nm) cerium oxide nanoparticles (CeO2 NPs) in response to biologically prevalent antioxidant molecules (glutathione, vitamin C). Such a redox sensitive behavior of CeO2 NPs is subsequently exploited to design a redox responsive drug delivery system for transporting anticancer drug (camptothecin). Upon exposing the CeO2 capped and drug loaded nanoconstruct to vitamin c or glutathione, dissolution-accompanied aggregation of CeO2 nanolids unleashes the drug molecules from porous silica to achieve a significant anticancer activity. Besides stimuli responsive drug delivery, immobilization of nanoceria onto the surface of mesoporous silica also facilitates us to gain a basic insight into the biotransformation of CeO2 in physiological mediums.

pH dictates the release of hydrophobic drug cocktail from mesoporous nanoarchitecture.

Combination therapy has been a norm in clinical practice to effectively treat cancer. Besides polytherapy, nowadays, smart and nanobased drug carriers are extensively being explored to deliver drugs according to pathophysiological environment of diseases. In this regard, herein we designed intelligent mesoporous architecture, incorporating both combinational therapy with smart nanotechnology, to simultaneously deliver two highly hydrophobic chemotherapeutic drugs in response to extracellular and/or intracellular acidic environ of tumor. Novelty of the system lies in the employment of acid responsive ZnO QDs to clog not only the nanochannels of mesoporous silica, encapsulating one hydrophobic drug, but also exploitation of chelate forming propensity of another hydrophobic drug (curcumin) to load a significant quantity onto the surface of ZnO nanolids. Cell viability results revealed an extraordinarily high cytotoxic efficiency of that lethal drug cocktail even at a concentration as low as 3 μg/mL nanocarrier. We envision that this sophisticated nanocarrier, which utilizes both interior pore and exterior surface of nanolids for loading different hydrophobic guest molecules and their subsequent acid responsive release, will undoubtedly, illustrates its remarkable potential in targeted chemotherapy.

Using oxidant susceptibility of thiol stabilized nanoparticles to develop an inflammation triggered drug release system

Inflammation is a complex and dynamic defensive cellular approach to safeguard against deleterious agents; however, an overexpression of such responses frequently results in the development of a number of devastating diseases, such as atherosclerosis, cancer, inflammatory bowel, Alzheimers and Parkinsons diseases. At the site of the inflammation, excessive amount of reactive oxygen species (ROS) are produced, and therefore researchers are now earnestly trying to exploit ROS pathological signals to design oxidative triggered drug release systems. In this study, we report a straightforward strategy to develop an oxidative stress responsive drug release systems. Newly developed, ultra-small, and thiol stabilized zinc sulfide quantum dots (ZnS QDs) are used as nanocaps to regulate the release of anticancer drug (camptothecin) from mesoporous silica nanoparticles (MSNs) in response to oxidative environment. The exposure of capped nanocarrier to a higher concentration of H2O2 fails to open the drug loaded nanochannels; however, an addition of a minute amount of divalent iron, the most abundant transition-metal in the body, readily unseals the nanochannels at considerably lower H2O2 concentrations due to the generation of highly reactive hydroxyl radicals (˙OH). Thiol groups, which stabilize the ZnS nanolids, are actually oxidized by ˙OH and as a result unleash the loaded drug molecules from the channels of silica. In addition to the inflammation-induced drug delivery, this study also provides basic insight into the fate of thiol stabilized nanoparticles upon interaction with hydroxyl radicals.

Acid-induced release of curcumin from calcium containing nanotheranostic excipient.

Poor water solubility is believed one of the most critical problems of numerous promising pharmaceutical ingredients in their successful clinical utilization. Nanomedicine holds considerable promise to address this challenge, because it extends the therapeutic window of hydrophobic drugs through nanonization approach. Recently, the integration of diagnostic agents with smart therapeutic nanocarriers is also an emerging research arena to simultaneously visualize diseased tissues, achieve site specific drug release and track the impact of therapy. In this study, we have developed a biocompatible smart theranostic nanosystem which transports a highly promising hydrophobic drug (curcumin) in response to mildly acidic environment. As calcium is a main constituent of human body, hence we exploited the reversible calcium chelate formation tendency of divalent calcium to load and unload curcumin molecules. Moreover, an emerging T1 contrast agent is also tethered onto the surface of nanocarrier to realize MRI diagnosis application. In-vitro cell experiments revealed a significantly high chemotherapeutic efficiency of curcumin nanoformulation (IC50; 1.67 μg/mL), whereas free curcumin was found ineffective at the corresponding concentration (IC50; 29.72 μg/mL). MR imaging test also validated the performance of resulting system. Our strategy can be extended for the targeted delivery of other hydrophobic pharmaceutical ingredients.

Magnesium hydroxide nanoplates: a pH-responsive platform for hydrophobic anticancer drug delivery

The cost of conventional chemotherapeutic drugs is substantially high, and biomedical researchers are constantly hunting for cheap and effective chemotherapeutic alternatives. Recently, curcumin has emerged as a cost effective anticancer remedy, however, the low bioavailability of curcumin has been a major impediment to its successful utilization for disease management. In this work, we developed a highly biocompatible magnesium hydroxide as an intelligent nanocarrier for delivering curcumin into cancer cells. Curcumin was loaded onto magnesium hydroxide nanoplates via a complexation strategy. Furthermore, these drug conjugated nanoparticles not only achieve efficient loading of a highly hydrophobic drug, but also exhibit pH responsive release in extracellular or intracellular acid environments, validated by in vitro drug release, confocal microscopy and MTT assay. These biocompatible nanoplates can be promising candidates for the further development of smart drug delivery nanodevices.

Bleach etches nanosilver: HOCl-responsive drug delivery system to target leukemic cells

In addition to their well-known antibacterial property, silver nanoparticles (Ag NPs) have also been highlighted as anti-leukemic agents; however, the underlying mechanism responsible for inhibiting the growth of hematopoietic cancer cells is so far poorly understood. In previous reports, Ag NP-induced oxidative stress was implicated for therapeutic efficacy but the excessive production of ROS in several hematopoietic malignant cells, which can potentially induce the dissolution of Ag NPs, was not taken into consideration. In this study we proposed Ag NP dissolution, in response to increased oxidative stress in leukemic cells, as the most probable mechanism for their anticancer activity. Hypochlorous acid-mediated dissolution of therapeutically active and ultrasmall (<5 nm) Ag NPs was also exploited to develop an oxidant responsive combinatorial drug delivery system. When Ag-capped and anticancer drug loaded pores of mesoporous silica were exposed to HOCl, the ready disintegration of Ag NPs resulted in a controlled release of drug molecules. The drug release profile and growth inhibition of myeloperoxidase positive (MOLM-13) leukemic cells support the role of the oxidant in the dissolution of Ag NPs. Besides combinational chemotherapy, the current study also provides us with an opportunity to investigate the interaction of Ag NPs with biorelevant oxidants.