pH-responsive Mesoporous Silica Nanoparticles Research Articles

Biosynthesis of pH-Responsive Mesoporous Silica Nanoparticles from Cucumber Peels for Targeting 3D Lung Tumor Spheroids.

Lung adenocarcinoma is considered to be one of the primary causes of cancer-related deaths globally. Conventional treatments, such as chemotherapy and radiation therapy taken together, have not significantly lowered mortality rates. Repositioning of authorized anticancer medications supported by nanotechnology has therefore emerged as an effective strategy to close such gaps. In this context, mesoporous silica nanoparticles (MSNs) were biosynthesized from cucumber peels and were loaded with doxorubicin, a common anticancer drug to form doxorubicin-bound mesoporous silica nanoparticles (DMSNs). The study addresses a sustainable method for turning waste materials into MSNs, which can be used to create multifunctional nanosystems. The therapeutic module (DMSNs) was designed specifically to target 2D monolayer cells and 3D tumor spheroids of lung adenocarcinoma cancer. The DMSNs demonstrated notable antiproliferative activity and effective intracellular localization in addition to being biocompatible and innately fluorescent. Subsequent investigations revealed significant antibacterial activity against Staphylococcal infection, which is primarily prevalent in lung cancer patients. Thus, the developed MSNs held promising potential for anticancer drug delivery systems and have antibacterial potential to treat bacterial infections in patients with lung cancer. Furthermore, the cucumber peel-mediated synthesis of MSNs could also aid in the management of food waste and promote the adoption of the waste-to-health paradigm for sustainable solutions.

PH-Responsive Mesoporous Silica Nanoparticles Loaded with Naringin for Targeted Osteoclast Inhibition and Bone Regeneration.

It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research. First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo. CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent. Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.

Unravelling pH/pKa influence on pH-responsive drug carriers: Insights from ibuprofen-silica interactions and comparative analysis with carbon nanotubes, sulfasalazine, and alendronate

This study employs density functional theory to explore the interaction between ibuprofen (IBU) and silica, emphasizing the influence of the trimethylsilyl (TMS) functional group for designing pH-responsive drug carriers. The surface (S) and drug (D) molecules' neutral (0) or deprotonated (−1) states were taken into consideration during the investigation. The likelihood of these states was determined based on the pKa values and the desired pH conditions. To calculate the pH-dependent interaction energy (EintpH), four different situations have been identified: S0D0, S0D−1, S−1D0, and S−1D−1.The electrostatic component of interaction energy aligns favorably with its theoretical value in both the Debye-Hückel and Grahame models. The investigation has gathered first-hand experimental data on the drug loading and release of pH-responsive mesoporous silica nanoparticles. Effective drug loading was observed in the acidic environment of the stomach (pH 2–5), followed by a release in the slightly basic to neutral pH of the small intestine (pH 7.4), These findings align with existing literature. The results revealed horizontal drug adherence on silica surfaces, improving binding capabilities. Comparisons were made with combinations involving carboxylated carbon nanotubes and ibuprofen, silica, and sulfasalazine, and silica and alendronate, exploring drug loading/release dynamics associated with positive/negative interaction energies. The investigation, supported by experimental data, contributes valuable insights into pH-responsive mesoporous silica nanoparticles, offering new design possibilities for drug carriers.

A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis.

Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR. We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR. The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox. We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.

Delivery of chiral D-cysteine by pH-responsive mesoporous silica nanoparticles for effective bacterial inhibition

Efficient and highly controllable antibacterial effects, as well as good biocompatibility, are required for antibacterial materials to overcome multi-drug resistance in bacteria. Herein, mesoporous silica nanomaterials (MSNs) carriers with a particle mean size of 60 nm and pore size of 7.9 nm were prepared, which was followed by loading with D-cysteine (D-Cys) and modified with Polyethyleneimine (PEI) molecules on the outer surface (named as D@MSNs-P). The prepared D@MSNs-P showed a good pH response in the range of 5–7, and the rate of antibacterial agent D-Cys released from nanocarriers was much faster at lower pH (pH 5) than that at higher pH (pH 6–7), which favors the rapid control of the pathogenic bacteria. In a working pH (pH 5), D@MSNs-P exhibited broad-spectrum antibacterial activities against Escherichia coli, Staphylococcus aureus, Salmonella enteritidis, and Listeria monocytogenes with the highest antibacterial efficiency of 99.9%, 99.8%, 98.1%, and 96.2%, respectively, which is much higher than that of pure D-Cys, pure MSNs, D@MSNs, and PEI group. The outstanding antibacterial activity of D@MSNs-P was attributed to the synergistic effect of the unique structure of MSNs and chiral D-Cys molecules. In addition, the prepared D@MSNs-P has no cytotoxicity to HepG2 cells (Human hepatoma cells) at the concentration of 0.4–12.8 mg/mL and even can promote cell proliferation at high concentrations. Our results open a new door for designing the most promising nanomaterials for pH response release and controllable antimicrobial.

Drug delivery system with dual imaging and dual response control drug release functions for chemo-photodynamic synergistic therapy

Traditional treatment of cancers such as chemotherapy still causes many side effects after the treatment even nowadays, therefore combination therapies by using drug delivery systems are valued by more and more scientists. However, loading multiple drugs in the nanoparticles for drug delivery system may cause insufficient drugs or functional groups, which might let the nanomaterial have fewer functions. Therefore, making the mesoporous silica nanoparticles (MSNs) have photodynamic therapy function by “doping “ lanthanide ions into the material structure, can evade this problem. Moreover, with the doping of lanthanide metals, the MSNs can have not only dual imaging functions of both magnetic resonance imaging and fluorescence, but also achieve photodynamic function. To feature the material with more function, chemotherapeutic drug-doxorubicin was loaded into the pores of MSNs and then bonded hyaluronic acid which is the active target and a gatekeeper, on the surface of MSNs. Finally, an all-in-one drug delivery system” Hyaluronidase and pH-responsive mesoporous silica nanoparticles with dual-imaging activity for chemo-photodynamic therapy” is synthesized. The first part in this experiment was to confirm the physical properties of the lanthanides dopped MSN and its photodynamic treatment effect. The second part was to confirm that each organic molecule had been successfully bonded to the surface of the MSN and achieve pH and Hyaluronidase response drug release effect, The last part was to prove that the drug delivery system had a significant anticancer effect through cell experiments.

A pH-responsive mesoporous silica nanoparticle-based drug delivery system for targeted breast cancer therapy.

In order to make the drug specifically aggregate at the tumor site, we had developed a targeted drug delivery system based on pH responsive mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-COOH) were prepared and doxorubicin (DOX) was loaded into the pores of MSN-COOH, and then polyethyleneimine (PEI) and anisamide (AA) were modified on the surface of mesoporous silica, named DOX@MSN-PEI-AA(DMPA). DMPA specifically entered tumor cells through AA-mediated receptor endocytosis; PEI dissociated from the surface of the MSN in the acidic environment of cellular lysosomes/endosomes due to protonation of PEI, resulting in steady release of the encapsulated DOX from the pores of MSN in the cytoplasm of the target cells. In vitro and in vivo anti-tumor experiments and hemolytic experiments indicated that DMPA can accurately target breast cancer cells and show excellent safety at the same time, showing great potential for tumor therapy.

Delivery of Chiral D-Cysteine by Ph-Responsive Mesoporous Silica Nanoparticles for Effective Bacterial Inhibition

Delivery of Chiral D-Cysteine by Ph-Responsive Mesoporous Silica Nanoparticles for Effective Bacterial Inhibition

Costunolide Loaded in pH-Responsive Mesoporous Silica Nanoparticles for Increased Stability and an Enhanced Anti-Fibrotic Effect.

Liver fibrosis remains a significant public health problem. However, few drugs have yet been validated. Costunolide (COS), as a monomeric component of the traditional Chinese medicinal herb Saussurea Lappa, has shown excellent anti-fibrotic efficacy. However, COS displays very poor aqueous solubility and poor stability in gastric juice, which greatly limits its application via an oral administration. To increase the stability, improve the dissolution rate and enhance the anti-liver fibrosis of COS, pH-responsive mesoporous silica nanoparticles (MSNs) were selected as a drug carrier. Methacrylic acid copolymer (MAC) as a pH-sensitive material was used to coat the surface of MSNs. The drug release behavior and anti-liver fibrosis effects of MSNs-COS-MAC were evaluated. The results showed that MSNs-COS-MAC prevented a release in the gastric fluid and enhanced the dissolution rate of COS in the intestinal juice. At half the dose of COS, MSNs-COS-MAC still effectively ameliorated parenchymal necrosis, bile duct proliferation and excessive collagen. MSNs-COS-MAC significantly repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers in LX-2 cells and liver tissue. These results suggest that MSNs-COS-MAC shows great promise for anti-liver fibrosis treatment.

PH-Sensitive Drug Delivery System Based on Mesoporous Silica Modified with Poly-L-Lysine (PLL) as a Gatekeeper.

In this work, we synthesized a novel pH-triggered drug delivery system to enhance the bioavailability of the anticancer drug doxorubicin (DOX) through the gatekeeper poly-L-lysine (PLL) on the pore entrances of mesoporous silica nanoparticles (MSNs). Firstly, mesoporous silica was selected as the inorganic support for drug loading. Secondly, PLL was employed as the gatekeeper to control the cargo transport. In a neutral environment, the PLL brushes became shrunken and formed a dense barrier on the pore entrances of PLL/MSNs, which closed the pores and thus prevented the release of cargo. In an acidic environment, the cargo was released from the carrier PLL/MSNs because the pore entrances were opened by the swollen PLL brushes. The DOX-loaded PLL/MSNs (PLL/MSNs-DOX) showed 1.5 times higher drug release under acidic condition (pH = 4) than under neutral condition (pH = 7). During the drug release experiment for 48 h under acidic condition, PLL/MSN-DOX released about 50% of the drug after 9 h and approximately 85% after 24 h, whereas pristine MSNs loaded with DOX (MSNs-DOX) released about 50% of the drug after 30 min and reached equilibrium after 24 h. The MSNs also demonstrated their effectiveness in storing anticancer drugs until the desired environmental trigger is present. Therefore, the pH-responsive MSNs have great potential as a targeting cancer therapy.

A facile strategy to fabricate a pH-responsive mesoporous silica nanoparticle end-capped with amphiphilic peptides by self-assembly.

A facile strategy with no modification processes was demonstrated to fabricate a pH-responsive end-capped mesoporous silica nanoparticle (MSN)-based drug delivery system (DDS). The simple but smart nanovalve systems were constructed by the self-assembly behavior of unbonded peptide-based amphiphile (P45) in the presence of Doxorubicin hydrochloride (Dox). A series of characterizations confirmed that the DDSs had been successfully fabricated. Dox molecules were entrapped by nanovalves in the pores of MSNs, and an in vitro release experiment demonstrated that the P45/Dox@MSNs exhibited "zero premature release" in the physical environment. However, an accelerated release was triggered by an acidic atmosphere in cellular cytosol. Moreover, detailed investigations confirmed that the enhanced cellular uptake of P45/Dox@MSNs due to the RGD motif of the nanovalves, exhibiting an obvious toxicity to cancer cells. Therefore, the DDSs constructed here can serve as a promising platform to realize targeted drug delivery and controlled drug release by using diversified bioactive native amphiphilic peptide.

Zwitterionic carbon dot-encapsulating pH-responsive mesoporous silica nanoparticles for NIR light-triggered photothermal therapy through pH-controllable release.

Here, we designed a pH-responsive Indocyanine Green (ICG)-loaded zwitterion fluorescent carbon dot (CD)-encapsulating mesoporous silica nanoparticle (MSN) for pH-tunable image-guided photothermal therapy. ICG was loaded into MSN(CD) via hydrophobic and electrostatic interactions between zwitterionic CDs and ICG to achieve a controlled photothermal temperature with a fluorescent "off/on" system. The porosity of the MSNs was altered after ICG loading because of intermolecular interactions between the CDs and ICG inside the MSN shell and core, which blocked the MSN pore. The acidic environment pH affected the fluorescent signals of the ICG-MSN(CD), reflecting the "off-on" characteristics of the synthesized MSN, which then induced the release of ICG from the matrices. Moreover, the photothermal conversion of ICG-MSN(CD) showed sufficient heat generation to kill cancer cells at an acidic pH with low-temperature elevation at physiological pH. ICG-MSN(CD) demonstrated good cell viability of MDA-MB-231 cells without irradiation; however, high necrosis was observed when the environment was adjusted to acidic pH and after near-infrared irradiation. These pH-responsive photothermal mesoporous silica nanoparticles may have applications in biomedicine, particularly for cancer treatment.

Formulation and development of smart pH responsive mesoporous silica nanoparticles for breast cancer targeted delivery of anastrozole: In vitro and in vivo characterizations

Abstract In the present study, pH responsive, breast cancer targeted mesoporous silica nanoparticles (MSNs) have been developed as a carrier with a view to overcome problems such as non-selectivity, low cellular uptake and side effects associated with traditional chemotherapeutic drugs and improve their therapeutic efficacy. MCM-41 type of MSNs was synthesized using modified Stober's process and further modified by first reacting with (3-aminopropyl)triethoxysilane (APTES) and then succinic anhydride (SA) in order to obtain carboxylic acid functionalized MSN-COOH. Anastrozole was loaded into the MSNs and then capped with chitosan-folate conjugate. The MSNs were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential analysis, small angle x-ray scattering (SAXS), nitrogen adsorption/desorption analysis, differential scanning calorimetry (DSC), HPLC and UV-visible spectroscopy. In vitro release studies confirmed triggered drug release from these nanoparticles under acidic (pH 5.5) environment. Hemolysis study proved that the formulation was safe for intravenous administration. The formulation exhibited 1.5 folds higher cytotoxicity as compared to free drug indicating its improved therapeutic potency. The in-vivo anticancer activity of formulations was studied against Ehrlich Ascites Carcinoma (EAC) induced breast cancer in Balb C mice in which these nanoparticles showed superior anticancer activity. Excellent tumor suppressing activity was demonstrated by these nanoparticles against EAC induced breast cancer model.

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.

Lectin-conjugated pH-responsive mesoporous silica nanoparticles for targeted bone cancer treatment.

The development of highly selective and efficient tumor-targeted smart drug delivery nanodevices remains a great challenge in nanomedicine. This work reports the design and optimization of a multifunctional nanosystem based on mesoporous silica nanoparticles (MSNs) featuring selectivity towards human osteosarcoma cells and pH-responsive antitumor drug delivery capability. The novelty and originality of this manuscript relies on proving that the synergistic assembly of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards healthy cells, which constitutes a new paradigm in targeted bone cancer therapy.

Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography

Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor-targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7×) and 6.5 (20×); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery.

Synergistic combination cancer therapy based in lectin-targeted pH-responsive mesoporous silica nanoparticles

Event Abstract Back to Event Synergistic combination cancer therapy based in lectin-targeted pH-responsive mesoporous silica nanoparticles Marina Martínez-Carmona1, 2, 3, 4, Montserrat Colilla1, 2, 3, 4, Daniel Lozano1, 2, 3 and María Vallet-Regí1, 2, 3, 4 1 Universidad Complutense de Madrid, Química Inorgánica y Bioiniorgánica, Facultad de Farmacia, Spain 2 Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12, Spain 3 Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain 4 CEI Campus Moncloa, UCM-UPM, Spain Introduction: The main challenge in the treatment of cancer therapy is the development of nanocarriers able to selectively transport and release cytotoxic drugs once the target has been reached[1]. Mesoporous silica nanoparticles (MSNs) have emerged as promising candidates to develop targeted stimuli-responsive drug delivery devices for the treatment of solid tumors[2]-[5]. Some specific combinations of cytotoxic agents exhibiting synergistic effects results in the increase of the tumor cell kill capability and the decrease of side effects[6]. Herein we propose the development of a targeted-pH-responsive mesoporous core@shell silica@polymer nanosystem entrapping the antitumor drug doxorubicin (Dox) and incorporating the lectin Concanavalin A (Con-A) in its outermost surface (Fig. 1). The use of Con-A aims at playing a dual role by acting as targeting ligand and therapeutic agent, thus improving the antitumor ability of the nanosystem. Materials and Methods: Pure silica MSNs were synthetized following the well-known modified Stöber method. Then MSNs were grafter with 3,9-Bis(3-aminopropyl)2,4,8-10-tetraoxaspiro[5,5] undecane (ATU), an acid cleavable linker[7], and loaded with Dox by soaking in a concentrated aqueous drug solution. The capping of the pores was accomplished using a polyacrylic acid polymer (PAA). Con-A was attached to the PAA shell via an EDC/NHS crosslinking method. The materials were characterized by TG, FTIR, 13C solid state NMR, N2 adsorption, SEM, HR-TEM, zeta-potential and DLS. The pH-responsive drug delivery behavior of the nanosystem was tested in vial. Finally, the in vitro behavior of the nanosystems regarding cell internalization and killing capability was evaluated in healthy (MC3T3-E1) and tumor (HOS) cell cultures. Results and Discussion: The physical-chemical, structural and textural characterization of the materials allowed confirming the successful incorporation of the different molecules to the spherical 2D-hexagonal MCM-41 type MSNs after each synthesis step. The amounts of PAA and Con-A grafted to MSNs were ca. 7% and 10% in weight, respectively, which accounts for the suitability of the functionalization methods here reported. The amount of Dox loaded was ca. 7%. The drug delivery behavior of the full nanosystem evaluated in vial showed that nearly 4-fold higher release was obtained in acidic media than in neutral pH, which demonstrates the pH-responsive drug release ability of the system (Fig. 2A). This finding proves the suitability of the nanosystem for smart Dox delivery system capable of releasing the drug in the acidic environment of the endosomes/lysosomes once it has been internalized by the cell. The in vitro tests indicated that the presence of Con-A as targeting ligand leads to higher nanosystem internalization degree in HOS than in MC3T3-E1 cells. Moreover, the cancer cell killing capability of Dox was synergistically enhanced by the presence of Con-A (Fig. 2B), as derived from cell viability assays. Conclusion: We have developed a novel pH-responsive drug delivery nanosystem incorporating Con-A and Dox. The combination of these two elements into the same nanosystem synergistically enhances its antitumor capacity in a selective fashion. These findings open promising expectations for the further in vivo evaluation of the nanosystems. Authors acknowledge Ministerio de Economía y Competitividad (MINECO), Secretaría de Estado de Investigación, Desarrollo e Innovación (SEIDI) supporting through projects MAT201235556 and CSO201011384E (Agening Network of Excellence). Marina MartínezCarmona acknowledges Moncloa Campus of International Excellence (UCM/UPM-ISCIII) for a PICATA predoctoral fellowship. Daniel Lozano acknowledges MINECO/SEIDI for a Postdoctoral Juan de la Cierva grant

Tannin as a gatekeeper of pH-responsive mesoporous silica nanoparticles for drug delivery

Tannin grafted on mesoporous silica nanoparticles (tannin-MSNs) was synthesized by the amidation reaction of carboxyl benzyl borate with amino group modified MSN.

Dual pH-responsive mesoporous silica nanoparticles for efficient combination of chemotherapy and photodynamic therapy.

A kind of dual pH-responsive mesoporous silica nanoparticle (MSN)-based drug delivery system, which can respond to the cancer extracellular and intercellular pH stimuli, has been fabricated for synergistic chemo-photodynamic therapy. By grafting histidine onto the silica surface, the acid sensitive PEGylated tetraphenylporphyrin zinc (Zn-Por-CA-PEG) can be used as a gatekeeper to block the nanopores of MSNs by the metallo-supramolecular-coordinated interaction between Zn-Por and histidine. This gatekeeper is stable enough to prevent the loaded drug from leaching out in healthy tissue. However, at cancer extracellular pH (∼6.8) the conjugated acid sensitive cis-aconitic anhydride (CA) between Zn-Por and PEG will cleave and the surface of Zn-Por will be amino positively charged to facilitate cell internalization. Furthermore, the metallo-supramolecular-coordination will disassemble in intracellular acidic microenvironments (∼5.3) to release the carried drug and Zn-Por due to the removal of the gatekeeper. The photosensitivity of Zn-Por further makes it possible to combine chemotherapy and photodynamic therapy. This dual pH-sensitive MSN-based drug delivery system showed higher in vitro cytotoxicity than the single chemotherapy of free DOX or photodynamic therapy of Zn-Por, presenting its great potential for cancer treatment to overcome the challenges in efficient delivery in the site and ideal anti-cancer efficacy.

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.