pH-sensitive Mesoporous Silica Research Articles

A facile strategy of constructing pH-sensitive mesoporous silica nanoreservoirs and application in stimuli-responsive epoxy coatings

To prepare stimuli-responsive inhibitor-loaded mesoporous silica nanoreservoirs (MSNs), a facile strategy is proposed to construct the pH-sensitive stoppers. The positively charged Zn(OH)2 colloids can readily adsorb and deposit on the surface of the negatively charged MSNs to stop the self-release of the stored benzotriazoles (BTA). Due to the decomposition of Zn(OH)2 stoppers in weakly acidic solution, the on-command release of BTA from the MSN-BTA@Zn(OH)2 nanoreservoirs is achieved in the pH range from 8.0 to 2.0. The high pH sensitivity of the nanoreservoirs is confirmed. The cumulative release of BTA at pH 7.0 is over 80 % within 15 min in comparison with the release below 50 % at pH 8.0. Furthermore, the addition of the pH-sensitive nanoreservoirs to epoxy coatings enhances the corrosion resistance of the coatings and the well on-command releasing in 3.5 % NaCl solution is achieved. Apart from the released BTA, the Zn2+ ions from the dissolution of Zn(OH)2 stoppers could also play an important role in suppressing the corrosion of mild steel substrate in the scratched area.

PH-responsive mesoporous silica nanorod for high load and oral delivery of insulin

Diabetes is a metabolic disease often characterized by elevated blood sugar levels, which is mainly treated through external injection of insulin. However, long-term insulin injection in patients will produce many adverse side effects such as hypoglycemia, subcutaneous fat atrophy and prolonged absorption, resulting in poor patient compliance. In this work, mesoporous silica (SBA-15) nanorods with large surface area (541.8 m2/g) were prepared via soft-templating method, which retained a large number of ordered mesoporous structures as the drug delivery carrier for insulin. Insulin-loaded mesoporous silica (SBA-15/INS) particle was obtained by solvent adsorption, which was then coated with hydroxypropyl methylcellulose phthalate (HP55) to form pH-sensitive mesoporous silica nanoparticles (HP55@SBA-15/INS). The surface area, structure and morphology of silica particles were addressed by BET, FTIR, XRD, SEM and TEM, indicating that SBA-15/INS and HP55@SBA-15/INS maintained the rod-like and ordered white strips structure similar to SBA-15. Also, insulin was found to be present in the mesoporous silica nanoparticles, with loading capacity and encapsulation efficiency reaching 25.5 % and 80.9 %, respectively. The vitro release results revealed that insulin release in the simulated gastric fluid (SGF, pH = 1.2) was significantly slower than that in the simulated intestinal fluid (SIF, pH = 7.4). Compared with SBA-15/INS, the release percentages in 15 % HP55@SBA-15/INS decreased 30 % in SGF, while it increased approximately 10 % in SIF. Kinetics analysis showed that the release process in HP55@SBA-15/INS was a Fick diffusion in both SGF and SIF and HP55 was degraded in SIF, resulting in accelerated insulin release. The cytotoxicity evaluation results showed that the cell viability of 4T1 after 24 h incubated with SBA-15 and 15 % HP55@SBA-15/INS was both approximately 100 %, demonstrating that the facile manufactured method has great potential to prepare macromolecular drug nanoparticle for oral release.

Self-diagnosing and active protective dual-functional water-borne polyurethane coating based on smart mesoporous containers

In this work, a dual functional coating was constructed to possess self-diagnosing and active anti-corrosion protection using pH-sensitive mesoporous silica containers containing gallic acid (GA). The containers are capable of releasing the inner GA when corrosion occurs at the metal substrate/coating interface due to pH sensitivity. GA can react with the Fe3+ ions to form conspicuous purple color at damaged sites, which provides the coating with a fast and timely corrosion self-diagnosing function. It can also inhibit the expansion of corrosion and realize active corrosion protection. This work provides a new idea for the multifunctional design of smart coatings with a single substance that provides both self-diagnosing and active corrosion protection.

Chitosan-glucuronic acid conjugate coated mesoporous silica nanoparticles: A smart pH-responsive and receptor-targeted system for colorectal cancer therapy

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ± 0.43 nm, pore volume of 0.73 ± 0.21 cm3/g, and particle size of 245.24 ± 5.75 nm. A high loading of 180.51 ± 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosan-glucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer.

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents.

Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermo-sensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU–NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEU-NH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37°C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEU-NH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.

Facile development, characterization, and evaluation of novel bicalutamide loaded pH-sensitive mesoporous silica nanoparticles for enhanced prostate cancer therapy

It is a challenge to deliver therapeutics exclusively to cancer cells, while sparing the normal cells. However, pH-sensitive delivery systems have proved to be highly efficient in fulfilling this task due to their ability to provide on-demand and selective release of drug at acidic tumor sites. As a proof of concept, here pH responsive drug delivery system based on mesoporous core shell nanoparticles (NPs) surrounded with poly acrylic acid (PAA) layers were prepared employing a facile synthesis strategy. Bicalutamide (BIC) was encased into surface functionalized MCM-41 nanoparticles via electrostatic interactions. The synthesized NPs were characterized by nitrogen adsorption and desorption isotherms, SEM-EDS, TEM, LXRD, and WXRD. In vitro release studies demonstrated that BIC-MSN-PAA NPs exhibited a higher release in the acidic media which varied inversely with the increase in pH. Further, the results of cell cytotoxicity assay were evident that BICMSNs exhibited more potent killing of both PC-3 and LNCaP cells than free BIC. PAA-MSNs also exhibited an enhanced cellular uptake and prolonged circulation time in vivo. The results are suggestive of the fact that PAA functionalized MSNs can serve as an effective pH-responsive template and hold a great potential ahead in controlled release and effective cancer treatment.

Preparation and characterization of a pH-responsive mesoporous silica nanoparticle dual-modified with biopolymers

This study was aimed at preparing a highly dispersed and pH-sensitive mesoporous silica nanoparticles (MSNs) carrier via surface modification with polydopamine (PDA) and polyethylene glycol (PEG) i.e. MSNs@PDA-PEG. Small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) measurements suggested that hexagonally structured MSNs (type MCM-41) with the layer of PDA and PEG of thickness ∼20 nm were successfully prepared. Bovine serum protein (BSA) adsorption experiments showed that less protein was absorbed by MSNs@PDA-PEG after the anchoring of PEG, which confirmed the stealth properties of prepared carriers. Doxorubicin hydrochloride (DOX) was used as the model drug to be encapsulated into MSNs@PDA-PEG (DOX/MSNs@PDA-PEG). The DOX/MSNs@PDA-PEG had relatively high entrapment efficiency and drug loading up to 94.2% and 31.4%, respectively. The in vitro release profile of DOX/MSNs@PDA-PEG exhibited pH-responsive and gradual drug release. Cytotoxicity assay showed that DOX/MSNs@PDA-PEG had comparable cytotoxicity to A549 cells compared to pure DOX. The intracellular distribution of DOX/MSNs@PDA-PEG was imaged using confocal laser scanning microscope. It points that PDA and PEG can play “gatekeeper” and stealth roles for MSNs as promising nanocarrier for cancer treatment.

Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex

Co-delivery multiple drugs using nanocarriers has been recognized as a promising strategy for cancer treatment to enhance therapeutic efficacy. In this study, a pH sensitive mesoporous silica nanoparticles (MSN) based controlled release nanoparticles for co-delivery of sorafenib (SO), a multi-tyrosine kinase inhibitor, and ursolic acid (UA), a sensitive agent for SO, was developed, which was decorated with pH sensitive chitosan (CS) and lactobionic acid (LA) targeting to asialoglycoprotein receptor (ASGPR) over-expressing hepatocellar carcinoma cells (denoted as USMNs-CL). The nanocomplex enhanced bioavailability of hydrophobic drugs, efficient tumor cell targeting and exhibited pH-responsive function and sustained release profile. USMNs-CL showed synergistic cytotoxicity and could attenuate the adhesion, migration of ASGPR over-expressing liver cancer SMMC-7721cells at non-toxic concentrations. Moreover, the complex nanoparticles significantly increased the cellular apoptosis and down-regulated the expression of EGFR and VEGFR2 proteins related with cell proliferation and tumor angiogenesis. Invivo, compared with UA or SO alone, the nanocomplex significantly reduced the tumor burden in hepatocellular carcinoma (HCC) H22 tumor-bearing mice model and inhibited the lung metastasis in the H22 lung metastasis models. Overall, co-delivery of UA and SO by MSN-CS-LA nanocarriers could provide a promising strategy for HCC combinational therapy, especially for the HCC metastasis chemoprevention.

DOX-loaded pH-sensitive mesoporous silica nanoparticles coated with PDA and PEG induce pro-death autophagy in breast cancer

The development of multifunctional nano drug delivery carriers has been one of the most effective and prevailing approaches to overcome drug non-selectivity, low cell uptake efficiency and various side effects of traditional chemotherapy drugs.

PH-Sensitive mesoporous silica nanoparticles anticancer prodrugs for sustained release of ursolic acid and the enhanced anti-cancer efficacy for hepatocellular carcinoma cancer

Ursolic acid (UA) as a nature product exhibits good anti-cancer activity, low toxicity, and good liver protection features. However, the low-solubility and poor bioavailability restrict its further clinical application. To overcome this problem, a pH-sensitive prodrug delivery system (UA@MSN-UA) that incorporated acid-sensitive linkage between drug and silica-based mesoporous nanosphere (MSN) was successfully designed and synthesized. The physicochemical properties of the UA@MSN-UA nanoparticles were investigated for shape, particle size, zeta potential, nitrogen adsorption-desorption and infrared (IR) spectroscopy. The nanoparticles were further evaluated for in vitro cytotoxicity, including proliferation inhibition, cell cycle distribution and apoptotic effects against human hepatocellular carcinoma HepG2 cells. The TEM image showed that the size of synthesized MSN nanoparticle was a near-spherical shape with ~100nm diameter. In vitro cytotoxicity testing demonstrated that UA@MSN-UA nanoparticles prodrug exhibited higher proliferation inhibition, cell cycle arrest at the G2/M phase and significantly caused the early and late apoptosis in HepG2 cells, which would be contributed to high loading capacity, high cellular uptake and sustained release of UA. Overall, the UA-modified MSN prodrug delivery system can be a promising drug carrier for improving the bioavailability of UA, and further enhance its anti-cancer efficacy.

PH sensitive chitosan-mesoporous silica nanoparticles for targeted delivery of a ruthenium complex with enhanced anticancer effects.

Nanocarriers are widely used for delivering drugs to tumors and their development is progressing steadily. In this study, a pH sensitive mesoporous silica nanocarrier, RuNHC@MSNs-CTS-Biotin (CTS = chitosan), is developed for the targeted delivery and controlled release of a ruthenium(ii) N-heterocyclic carbene (RuNHC) complex. The RuNHC@MSNs-CTS-Biotin nanoparticles were composed of RuNHC loaded mesoporous silica nanoparticles (MSNs) coated with chitosan-biotin (CTS-Biotin) conjugates. CTS traps the RuNHC complex inside the mesopores and biotin is used as a targeting ligand to improve specific cell uptake. The particle size of RuNHC@MSNs-CTS-Biotin was around 90 nm with a zeta potential of 12.0 mV and the RuNHC loading capacity was 26.31%. The release of RuNHC from RuNHC@MSNs-CTS-Biotin was in a pH-dependent manner, and it exhibited a 59.71% terminal release ratio at pH 5.0, but almost no release under neutral conditions (pH 7.4). Its in vitro cellular uptake and anticancer activity revealed that RuNHC@MSNs-CTS-Biotin could be selectively internalized in cancer cells by biotin receptor-mediated endocytosis and this resulted in a significant improvement in anticancer activities as compared with the RuNHC complex. This multifunctional nanocarrier system provides a promising platform for the development of precisely controllable cancer therapy.

One-pot synthesis and loading of mesoporous SiO2 nanocontainers using micellar drugs as a template

A new approach is proposed for creating of pH-sensitive mesoporous silica nanocontainers with ultrahigh capacity for amphiphilic functional compounds.

Selective topotecan delivery to cancer cells by targeted pH-sensitive mesoporous silica nanoparticles

Topotecan targeted pH-sensitive delivery system based in mesoporous silica nanoparticles coated with a multifunctional biopolymer coating for cancer therapy.

Preparation of end-capped pH-sensitive mesoporous silica nanocarriers for on-demand drug delivery

Nanocarriers with a pH responsive behavior are receiving an ever growing attention due to their potential for promoting on-demand drug release and thus increase the therapeutic effectiveness of anti-tumoral pharmaceutics. However, the majority of these systems require costly, time-consuming and complex chemical modifications of materials or drugs to synthesize nanoparticles with pH triggered release. Herein, the development of dual drug loaded pH-responsive mesoporous silica nanoparticles (MSNs) with a calcium carbonate-based coating is presented as an effective alternative. This innovative approach allowed the loading of a non-steroidal anti-inflammatory drug (Ibuprofen) and Doxorubicin, with high efficiency. The resulting dual drug loaded MSNs have spherical morphology and a mean size of 171nm. Our results indicate that under acidic conditions the coating disassembles and the drugs are rapidly released, whereas at physiologic pH the release is slower and gradually increases with time. Furthermore, an improved cytotoxic effect was obtained for Doxorubicin–Ibuprofen MSNs coated with CaCO3 in comparison with non-coated particles. The cytotoxic effect of dual loaded carbonate coated particles, was similar to that of Doxorubicin+Ibuprofen free drug administration at 72h, even with the delivery of a significantly lower amount of drug by MSNs-CaCO3. These results suggest that the carbonate coating of MSNs is a promising approach to create a pH-sensitive template for a delivery system with application in cancer therapy.

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSN-Hydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo.