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Porous silicon (PSi) nanoparticles have been applied in various fields, such as catalysis, imaging, and biomedical applications, because of their large specific surface area, easily modifiable surface chemistry, biocompatibility, and biodegradability. For biomedical applications, it is important to precisely control the surface modification of PSi-based materials and quantify the functionalization density, which determines the nanoparticle's behavior in the biological system. Therefore, we propose here an optimized solution to quantify the functionalization groups on PSi, based on the nuclear magnetic resonance (NMR) method by combining the hydrolysis with standard 1 H NMR experiments. We optimized the hydrolysis conditions to degrade the PSi, providing mobility to the molecules for NMR detection. The NMR parameters were also optimized by relaxation delay and the number of scans to provide reliable NMR spectra. With an internal standard, we quantitatively analyzed the surficial amine groups and their sequential modification of polyethylene glycol. Our investigation provides a reliable, fast, and straightforward method in quantitative analysis of the surficial modification characterization of PSi requiring a small amount of sample.

Background: Approximately 80% of brain tumours are gliomas. Despite treatment, patient mortality remains high due to local metastasis and relapse. It has been shown that transferrin-functionalised porous silicon nanoparticles (Tf@pSiNPs) can inhibit the migration of U87 glioma cells. However, the underlying mechanisms and the effect of glioma cell heterogeneity, which is a hallmark of the disease, on the efficacy of Tf@pSiNPs remains to be addressed., Results: Here, we observed that Tf@pSiNPs inhibited heterogeneous patient-derived glioma cells' (WK1) migration across small perforations (3 μm) by approximately 30%. A phenotypical characterisation of the migrated subpopulations revealed that the majority of them were nestin and fibroblast growth factor receptor 1 positive, an indication of their cancer stem cell origin. The treatment did not inhibit cell migration across large perforations (8 μm), nor cytoskeleton formation. This is in agreement with our previous observations that cellular-volume regulation is a mediator of Tf@pSiNPs' cell migration inhibition. Since aquaporin 9 (AQP9) is closely linked to cellular-volume regulation, and is highly expressed in glioma, the effect of AQP9 expression on WK1 migration was investigated. We showed that WK1 migration is correlated to the differential expression patterns of AQP9. However, AQP9-silencing did not affect WK1 cell migration across perforations, nor the efficacy of cell migration inhibition mediated by Tf@pSiNPs, suggesting that AQP9 is not a mediator of the inhibition., Conclusion: This in vitro investigation highlights the unique therapeutic potentials of Tf@pSiNPs against glioma cell migration and indicates further optimisations that are required to maximise its therapeutic efficacies.

Porous silicon (PSi) is a biocompatible and biodegradable material, which can be utilized in biomedical applications. It has several favorable properties, which makes it an excellent material for building engineered nanosystems for drug delivery and diagnostic purposes. One significant hurdle for commercial applications of PSi is the lack of industrial scale production of nanosized PSi particles. Here, we report a novel two-step production method for PSi nanoparticles. The method is based on centrifuge chemical vapor deposition (cCVD) of elemental silicon in an industrial scale reactor followed by electrochemical post-processing to porous particles. Physical properties, biocompatibility and in vivo biodistribution of the cCVD produced nanoparticles were investigated and compared to PSi nanoparticles conventionally produced from silicon wafers by pulse electrochemical etching. Our results demonstrate that the cCVD production provides PSi nanoparticles with comparable physical and biological quality to the conventional method. This method may circumvent several limitations of the conventional method such as the requirements for high purity monocrystalline silicon substrates as starting material and the material losses during the top-down milling process of the pulse-etched films to porous nanoparticles. However, the electroless etching required for the porosification of cCVD-produced nanoparticles limited control over the pore size, but is amenable for scaling of the production to industrial requirements., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Porous silicon (PSi) nanoparticles are capable of delivering therapeutic payloads providing targeted delivery and sustained release of the payloads. In this work we describe the development and proof-of-concept in vivo evaluation of thermally hydrocarbonized porous silicon (PSi) nanoparticles that are implanted with radioactive 155 Tb atoms and coated with red blood cell (RBC) membrane ( 155 Tb-THCPSi). The developed nanocomposites can be utilized as an intravenous delivery platform for theranostic radionuclides., Methods: THCPSi thin films were implanted with 155 Dy ions that decay to 155 Tb at the ISOLDE radioactive ion-beam (RIB) facility at CERN. The films were processed to nanoparticles by ball-milling and sonication, and subsequently coated with either a solid lipid and RBC membrane or solely with RBC membrane. The nanocomposites were evaluated in vitro for stability and in vivo for circulation half-life and ex vivo for biodistribution in Balb/c mice., Results: Nanoporous THCPSi films were successfully implanted with 155 Tb and processed to coated nanoparticles. The in vitro stability of the particles in plasma and buffer solutions was not significantly different between the particle types, and therefore the RBC membrane coated particles with less laborious processing method were chosen for the biological evaluation. The RBC membrane coating enhanced significantly the blood half-life compared to bare THCPSi particles. In the ex vivo biodistribution study a pronounced accumulation to the spleen was found, with lower uptake in the liver and a minor uptake in the lung, gall bladder and bone marrow., Conclusions: We have demonstrated, using 155 Tb RIB-implanted PSi nanoparticles coated with mouse RBC membranes, the feasibility of using such a theranostic nanosystem for the delivery of RIB based radionuclides with prolonged circulation time., Advances in Knowledge and Implications for Patient Care: For the first time, the RIB implantation technique has been utilized to produce PSi nanoparticle with a surface modified for better persistence in circulation. When optimized, these particles could be used in targeted radionuclide therapy with a combination of chemotherapeutic payload within the PSi structure., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. Nanoparticles hold tremendous promise to overcome the pharmacokinetic challenges and off-target adverse effects. However, an inhibitory effect of nanoparticles by themselves on metastasis has not been explored. In this study, we developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Tf@pSiNP were colloidally stable, biocompatible, and their uptake into GBM cells was enhanced by receptor-mediated internalisation. The migration of Tf@pSiNP-exposed cells across the confined microchannels was suppressed, but unconfined migration was unaffected. The pSiNP-induced destabilisation of focal adhesions at the leading front may partially explain the migration inhibition. More corroborating evidence suggests that pSiNP uptake reduced the plasticity of GBM cells in reducing cell volume, an effect that proved crucial in facilitating migration across the tight confined tracts. We believe that the inhibitory effect of Tf@pSiNP on cell migration, together with the drug-delivery capability of pSiNP, could potentially offer a disruptive strategy to treat GBM.

There is a dire need to develop more effective therapeutics to combat brain cancer such as glioblastoma multiforme (GBM). An ideal treatment is expected to target deliver chemotherapeutics to glioma cells across the blood-brain barrier (BBB). The overexpression of transferrin (Tf) receptor (TfR) on the BBB and the GBM cell surfaces but not on the surrounding cells renders TfR a promising target. While porous silicon nanoparticles (pSiNPs) have been intensely studied as a delivery vehicle due to their high biocompatibility, degradability, and drug-loading capacity, the potential to target deliver drugs with transferrin (Tf)-functionalized pSiNPs remains unaddressed. Here, we developed and systematically evaluated Tf-functionalized pSiNPs (Tf@pSiNPs) as a glioma-targeted drug delivery system. These nanoparticles showed excellent colloidal stability and had a low toxicity profile. As compared with nontargeted pSiNPs, Tf@pSiNPs were selective to BBB-forming cells and GBM cells and were efficiently internalized through clathrin receptor-mediated endocytosis. The anticancer drug doxorubicin (Dox) was effectively loaded (8.8 wt %) and released from Tf@pSiNPs in a pH-responsive manner over 24 h. Furthermore, the results demonstrate that Dox delivered by Tf@pSiNPs induced significantly enhanced cytotoxicity to GBM cells across an in vitro BBB monolayer compared with free Dox. Overall, Tf@pSiNPs offer a potential toolbox for enabling targeted therapy to treat GBM.

Two automatic methodologies were developed to perform the loading and release assays of drugs from porous silicon (PSi) nanoparticles. 5-Fluorouracil (5-FU) was selected as a model drug, and different functionalized PSi nanoparticles were used. While for drug loading studies the reproducible characteristics of flow systems were explored regarding mixture and volumes taken, in the drug release flow methodology versatility in accommodating different devices around the valve were tested. Fluorescent properties of 5-FU were used with detection limit of 9 × 10 -4 mg L -1 and a linear response up to 5 mg L -1 The drug loading and release procedures were optimized in sequential injection analysis (SIA) systems obtaining a huge economy regarding the time spent (4 min towards 2 h). Batch and SIA methods were tested and compared for the different behaviours of the PSi nanoparticles towards both methodologies and no noteworthy differences were obtained with Student's t-test for loading with a calculated t value of 2.04 showing the absence of statistical differences. All the results present a RSD less than 10%. So, the developed automatic methodologies are a viable alternative to load drugs and to study the release profiles from PSi nanoparticles., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mesoporous silicon (PSi) is biocompatible and tailorable material with high potential in drug delivery applications. Here, we report of an evaluation of PSi as a carrier platform for theranostics by delivering a radioactive ion beam- (RIB-) based radioactive lanthanoid into tumors in a mouse model of prostate carcinoma. Thermally hydrocarbonized porous silicon (THCPSi) wafers were implanted with 159 Dy at the facility for radioactive ion beams ISOLDE located at CERN, and the resulting [ 159 Dy]THCPSi was postprocessed into particles. The particles were intratumorally injected into mice bearing prostate cancer xenografts. The stability of the particles was studied in vivo , followed by ex vivo biodistribution and autoradiographic studies. We showed that the process of producing radionuclide-implanted PSi particles is feasible and that the [ 159 Dy]THCPSi particles stay stable and local inside the tumor over seven days. Upon release of 159 Dy from the particles, the main site of accumulation is in the skeleton, which is in agreement with previous studies on the biodistribution of dysprosium. We conclude that THCPSi particles are a suitable platform together with RIB-based radiolanthanoids for theranostic purposes as they are retained after administration inside the tumor and the radiolanthanoid remains embedded in the THCPSi.

Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell-penetrating peptide (virus-1 transactivator of transcription)-conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high-efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3-fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real-time US imaging-guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug-loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Microfluidics technology is emerging as a promising strategy in improving the oral delivery of proteins and peptides. Herein, a multistage drug delivery system is proposed as a step forward in the development of noninvasive therapies. Undecylenic acid-modified thermally hydrocarbonized porous silicon (UnPSi) nanoparticles (NPs) were functionalized with the Fc fragment of immunoglobulin G for targeting purposes. Glucagon-like peptide-1 (GLP-1) was loaded into the NPs as a model antidiabetic drug. Fc-UnPSi NPs were coated with mucoadhesive chitosan and ultimately entrapped into a polymeric matrix with pH-responsive properties by microfluidic nanoprecipitation. The final formulation showed a controlled and narrow size distribution. The pH-responsive matrix remained intact in acidic conditions, dissolving only in intestinal pH, resulting in a sustained release of the payload. The NPs presented high cytocompatibility and increased levels of interaction with intestinal cells when functionalized with the Fc fragment, which was supported by the validation of the Fc-fragment integrity after conjugation to the NPs. Finally, the Fc-conjugated NPs showed augmented GLP-1 permeability in an intestinal in vitro model. These results highlight the potential of microfluidics as an advanced technique for the preparation of multistage platforms for oral administration. Moreover, this study provides new insights on the potential of the Fc receptor transcytotic capacity for the development of targeted therapies.

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection-based delivery of insulin. Neonatal Fc receptor (FcRn)-mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn-targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH-responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH-sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn-targeted NPs. Overall, these FcRn-targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Engineered nanoparticles are increasingly used as drug carriers in pharmaceutical formulations. This study focuses on the hitherto unaddressed impact of porous silicon (PSi) nanoparticles on human cytochrome P450 (CYP) metabolism, which is the major detoxification route of most pharmaceuticals and other xenobiotics. Three different surface chemistries, including thermally carbonized PSi (TCPSi), aminopropylsilane-modified TCPSi (APTES-TCPSi) and alkyne-terminated thermally hydrocarbonized PSi (Alkyne-THCPSi), were compared for their effects on the enzyme kinetics of the major CYP isoforms (CYP1A2, CYP2A6, CYP2D6, and CYP3A4) in human liver microsomes (HLM) in vitro. The enzyme kinetic parameters, K m and V max , and the intrinsic clearance (CL int ) were determined using FDA-recommended, isoenzyme-specific model reactions with and without PSi nanoparticles. Data revealed statistically significant alterations of most isoenzyme activities in HLM in the presence of nanoparticles at 1mg/ml concentration, and polymorphic CYP2D6 was the most vulnerable to enzyme inhibition. However, the observed CYP2D6 inhibition was shown to be dose-dependent in case of TCPSi and Alkyne-THCPSi nanoparticles and attenuated at the concentrations below 1μg/ml. Adsorption of the probe substrates onto the hydrophobic Alkyne-THCPSi particles was also observed and taken into account in the determination of the kinetic parameters. Three polymer additives commonly used in pharmaceutical nanoformulations (Pluronics F68 and F127, and polyvinylalcohol) were also separately screened for their effects on CYP isoenzyme activities. These polymers had less effect on the enzyme kinetic parameters, and resulted in increased activity rather than enzyme inhibition, in contrast to the PSi nanoparticles. Although the chosen subcellular model (HLM) is not able to predict the cellular disposition of PSi nanoparticles in hepatocytes and thus provides limited information of probability of CYP interactions in vivo, the present study suggests that mechanistic interactions by the PSi nanoparticles or the polymer stabilizers may appear if these are effectively uptaken by the hepatocytes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bioresponsive cytosolic nanobased multidelivery has been emerging as an enormously challenging novel concept due to the intrinsic protective barriers of the cells and hardly controllable performances of nanomaterials. Here, we present a new paradigm to advance nano-in-nano integration technology amenable to create multifunctional nanovehicles showing considerable promise to overcome restrictions of intracellular delivery, solve impediments of endosomal localization and aid effectual tracking of nanoparticles. A redox responsive intercalator chemistry comprised of cystine and 9-aminoacridine is designed as a cross-linker to cap carboxylated porous silicon nanoparticles with DNA. These intelligent nanocarriers are then encapsulated within novel one-pot electrostatically complexed nano-networks made of a zwitterionic amino acid (cysteine), an anionic bioadhesive polymer (poly(methyl vinyl ether-alt-maleic acid)) and a cationic endosomolytic polymer (polyethyleneimine). This combined nanocomposite is successfully tested for the co-delivery of hydrophobic (sorafenib) or hydrophilic (calcein) molecules loaded within the porous core, and an imaging agent covalently integrated into the polyplex shell by click chemistry. High loading capacity, low cyto- and hemo-toxicity, glutathione responsive on-command drug release, and superior cytosolic delivery are shown as achievable key features of the proposed formulation. Overall, formulating drug molecules, DNA and imaging agents, without any interference, in a physico-chemically optimized carrier may open a path towards broad applicability of these cost-effective multivalent nanocomposites for treating different diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

One of the most challenging obstacles in nanoparticle's surface modification is to achieve the concept that one ligand can accomplish multiple purposes. Upon such consideration, 3-aminopropoxy-linked quercetin (AmQu), a derivative of a natural flavonoid inspired by the structure of dopamine, is designed and subsequently used to modify the surface of thermally hydrocarbonized porous silicon (PSi) nanoparticles. This nanosystem inherits several advanced properties in a single carrier, including promoted anticancer efficiency, multiple drug resistance (MDR) reversing, stimuli-responsive drug release, drug release monitoring, and enhanced particle-cell interactions. The anticancer drug doxorubicin (DOX) is efficiently loaded into this nanosystem and released in a pH-dependent manner. AmQu also effectively quenches the fluorescence of the loaded DOX, thereby allowing the use of the nanosystem for monitoring the intracellular drug release. Furthermore, a synergistic effect with the presence of AmQu is observed in both normal MCF-7 and DOX-resistant MCF-7 breast cancer cells. Due to the similar structure as dopamine, AmQu may facilitate both the interaction and internalization of PSi into the cells. Overall, this PSi-based platform exhibits remarkable superiority in both multifunctionality and anticancer efficiency, making this nanovector a promising system for anti-MDR cancer treatment., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Recently, we reported that the loading of ETH into thermally carbonized-porous silicon (TCPSi) nanoparticles enhanced the solubility and permeability of ETH at different pH-values and also increased its metabolization process. Based on these results, we synthesized carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) conjugated with ETH and its antimicrobial effect was evaluated against Mycobacterium tuberculosis strain H37Rv. The activity of the conjugate was increased when compared to free-ETH, which suggests that the nature of the synergy between the NPs and ETH is likely due to the weakening of the bacterial cell wall that improves conjugate-penetration. These ETH-conjugated NPs have great potential in reducing dosing frequency of ETH in the treatment of multidrug-resistant tuberculosis (MDR-TB)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Immunoadjuvant porous silicon (PSi)-based nanovaccines are prepared by nanoprecipitation in a glass capillary microfluidics device. Vesicles, derived from cancer cell membranes encapsulating thermally oxidized PSi nanoparticles or PSi-polymer nanosystems binding a model antigen, are biocompatible over a wide range of concentrations, and show immunostimulant properties in human cells, promoting the expression of co-stimulatory signals and the secretion of pro-inflammatory cytokines., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The effect of adsorption and confinement on ibuprofen was studied by immersion loading the molecules into porous silicon (PSi) microparticles. The PSi microparticles were modified into thermally oxidized PSi (TOPSi) and thermally hydrocarbonized PSi (THCPSi) to evaluate the effects of the loading solvent and the surface chemistry on the obtainable drug payloads. The payloads, location, and the molecular state of the adsorbed drug were evaluated using thermal analysis. The results showed that after the adsorption of ∼800 mg/cm 3 (w drug /v pores ) of drug into the mesopores, depending on the solvent used in the immersion, the drug began to rapidly recrystallize on the external surface of the particles. Moderate concentrations, however, enabled payloads of 800-850 mg/cm 3 without excessive surface crystallization, and thus, there was no need for rinsing the samples to remove the externally crystallized portion. The results showed that the confined ibuprofen forms nanocrystals inside of the mesopores after approximately 200 mg/cm 3 payloads were obtained, accounting for half of the adsorbed drug amount. The presence of both crystalline and noncrystalline phases was further characterized using variable temperature solid-state nuclear magnetic resonance (NMR) measurements. The interactions between the drug molecules and the pore walls of TOPSi and THCPSi were observed using Fourier transform infrared and 1 H NMR spectroscopies, and the hydrogen bonding between the silanol groups of TOPSi and the adsorbed ibuprofen was confirmed, but having only limited effect on the overall state of the confined drug. In vitro drug permeation studies in Caco-2 and Caco-2/HT29 cocultures showed that the adsorption onto hydrophilic or hydrophobic PSi microparticles had no significant effects on the ibuprofen permeation, whether the drug was partially nanocrystalline or completely in a liquidlike state.

Gold nanorods, DNA origami, and porous silicon nanoparticle-functionalized biocompatible double emulsion are developed for versatile molecular targeted therapeutics and antibody combination therapy. This advanced photothermal responsive all-in-one biocompatible platform can be easily formed with great therapeutics loading capacity for different cancer treatments with synergism and multidrug resistance inhibition, which has great potential in advancing biomedical applications., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The new frontier in the treatment of chronic nonhealing wounds is the use of micro- and nanoparticles to deliver drugs or growth factors into the wound. Here, we used platelet lysate (PL), a hemoderivative of platelets, consisting of a multifactorial cocktail of growth factors, to modify porous silicon (PSi) microparticles and assessed both in vitro and ex vivo the properties of the developed microsystem. PL-modified PSi was assessed for its potential to induce proliferation of fibroblasts. The wound closure-promoting properties of the microsystem were then assessed in an in vitro wound healing assay. Finally, the PL-modified PSi microparticles were evaluated in an ex vivo experiment over human skin. It was shown that PL-modified PSi microparticles were cytocompatible and enhanced the cell proliferation in different experimental settings. In addition, this microsystem promoted the closure of the gap between the fibroblast cells in the wound healing assay, in periods of time comparable with the positive control, and induced a proliferation and regeneration process onto the human skin in an ex vivo experiment. Overall, our results show that PL-modified PSi microparticles are suitable microsystems for further development toward applications in the treatment of chronic nonhealing wounds.

In this study, thermally hydrocarbonised porous silicon nanoparticles (THCpSiNPs) capped with polyethylenimine (PEI) were fabricated, and their potential for small interfering RNA (siRNA) delivery was investigated in an in vitro glioblastoma model. PEI coating following siRNA loading enhanced the sustained release of siRNA, and suppressed burst release effects. The positively-charged surface improved the internalisation of the nanoparticles across the cell membrane. THCpSiNP-mediated siRNA delivery reduced mRNA expression of the MRP1 gene, linked to the resistence of glioblastoma to chemotherapy, by 63% and reduced MRP1-protein levels by 70%. MRP1 siRNA loaded nanoparticles did not induce cytotoxicity in glioblastoma cells, but markedly reduced cell proliferation. In summary, the results demonstrated that non-cytotoxic cationic THCpSiNPs are promising vehicles for therapeutic siRNA delivery.

Over the past decade, the potential of polymeric structures has been investigated to overcome many limitations related to nanosized drug carriers by modulating their toxicity, cellular interactions, stability, and drug-release kinetics. In this study, we have developed a successful nanocomposite consisting of undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with an anticancer drug, sorafenib, and surface-conjugated with heptakis(6-amino-6-deoxy)-β-cyclodextrin (HABCD) to show the impact of the surface polymeric functionalization on the physical and biological properties of the drug-loaded nanoparticles. Cytocompatibility studies showed that the UnTHCPSi-HABCD NPs were not toxic to breast cancer cells. HABCD also enhanced the suspensibility and both the colloidal and plasma stabilities of the UnTHCPSi NPs. UnTHCPSi-HABCD NPs showed a significantly increased interaction with breast cancer cells compared to bare NPs and also sustained the drug release. Furthermore, the sorafenib-loaded UnTHCPSi-HABCD NPs efficiently inhibited cell proliferation of the breast cancer cells.

Porous silicon (PSi) nanoparticles' tunable properties are facilitating their use at highly challenging medical tasks such as peptide delivery. Because of many different mechanisms that are affecting the interaction between the peptide and the particle, the drug incorporation into the mesoporous delivery system is not straightforward. We have studied the adsorption and loading of incretin hormone glucagon like peptide 1 (GLP-1) on PSi nanoparticles. The results show that the highest loading degree can be achieved in pH values near the isoelectric point of peptide, and the phenomenon is independent of the surface's zeta potential. In order to study the interaction between the peptide and the nanoparticle, we studied the adsorption with lower concentrations and noticed that also non-Coulombic forces have a big role in adsorption of GLP-1. Adsorption is effective and pH-independent especially on low peptide concentrations and onto more hydrophobic nanoparticles. Reversibility of adsorption was studied as a function of buffer pH. When the loading is compared to the total mass of the formulation, the loading degree is 29%, and during desorption experiments 25% is released in 4 h and can be considered as a reversible loading degree. Thus, the peptides adsorbed first seem to create irreversibly adsorbed layer that facilitates reversible adsorption of following peptides.

An advanced nanocomposite consisting of an encapsulated porous silicon (PSi) nanoparticle and an acid-degradable acetalated dextran (AcDX) matrix (nano-in-nano), was efficiently fabricated by a one-step microfluidic self-assembly approach. The obtained nano-in-nano PSi@AcDX composites showed improved surface smoothness, homogeneous size distribution, and considerably enhanced cytocompatibility. Furthermore, multiple drugs with different physicochemical properties have been simultaneously loaded into the nanocomposites with a ratiometric control. The release kinetics of all the payloads was predominantly controlled by the decomposition rate of the outer AcDX matrix. To facilitate the intracellular drug delivery, a nona-arginine cell-penetrating peptide (CPP) was chemically conjugated onto the surface of the nanocomposites by oxime click chemistry. Taking advantage of the significantly improved cell uptake, the proliferation of two breast cancer cell lines was markedly inhibited by the CPP-functionalized multidrug-loaded nanocomposites. Overall, this nano-in-nano PSi@polymer composite prepared by the microfluidic self-assembly approach is a universal platform for nanoparticles encapsulation and precisely controlled combination chemotherapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The wound healing stands as very complex and dynamic process, aiming the re-establishment of the damaged tissue's integrity and functionality. Thus, there is an emerging need for developing biopolymer-based composites capable of actively promoting cellular proliferation and reconstituting the extracellular matrix. The aims of the present work were to prepare and characterize biopolymer-functionalized porous silicon (PSi) microparticles, resulting in the development of drug delivery microsystems for future applications in wound healing. Thermally hydrocarbonized PSi (THCPSi) microparticles were coated with both chitosan and a mixture of chondroitin sulfate/hyaluronic acid, and subsequently loaded with two antibacterial model drugs, vancomycin and resveratrol. The biopolymer coating, drug loading degree and drug release behavior of the modified PSi microparticles were evaluated in vitro. The results showed that both the biopolymer coating and drug loading of the THCPSi microparticles were successfully achieved. In addition, a sustained release was observed for both the drugs tested. The viability and proliferation profiles of a fibroblast cell line exposed to the modified THCPSi microparticles and the subsequent reactive oxygen species (ROS) production were also evaluated. The cytotoxicity and proliferation results demonstrated less toxicity for the biopolymer-coated THCPSi microparticles at different concentrations and time points comparatively to the uncoated counterparts. The ROS production by the fibroblasts exposed to both uncoated and biopolymer-coated PSi microparticles showed that the modified PSi microparticles did not induce significant ROS production at the concentrations tested. Overall, the biopolymer-based PSi microparticles developed in this study are promising platforms for wound healing applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA(+)) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA(+) nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA(+) relies on the capability of the conjugated HA(+) to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA(+)-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.

A multifunctional nano-in-micro drug delivery platform is developed by conjugating the porous silicon nanoparticles with mucoadhesive polymers and subsequent encapsulation into a pH-responsive polymer using microfluidics. The multistage platform shows monodisperse size distribution and pH-responsive payload release, and the released nanoparticles are mucoadhesive. Moreover, this platform is capable of simultaneously loading and releasing multidrugs with distinct properties., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH-responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi-drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH-response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH-values, and enhances their release at higher pH-values, which can be further used for colon cancer prevention and treatment. Overall, the pH-responsive polymer/PSi-based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The research on porous silicon (PSi) materials for biomedical applications has expanded greatly since the early studies of Leigh Canham more than 25 years ago. Currently, PSi nanoparticles are receiving growing attention from the scientific biomedical community. These nanostructured materials have emerged as promising multifunctional and versatile platforms for nanomedicine in drug delivery, diagnostics and therapy. The outstanding properties of PSi, including excellent in vivo biocompatibility and biodegradability, have led to many applications of PSi for delivery of therapeutic agents. In this review, we highlight current advances and recent efforts on PSi nanoparticles regarding the production properties, efficient drug delivery, multidrug delivery, permeation across biological barriers, biosafety and in vivo tracking for biomedical applications. The constant boost on successful preclinical in vivo data reported so far makes this the 'golden age' for PSi, which is expected to finally be translated into the clinic in the near future.

Thermally hydrocarbonized porous silicon (THCPSi) microparticles were loaded with indomethacin (IMC) and griseofulvin (GSV) using three different payloads between 6.2-19.5 and 6.2-11.4 wt %, respectively. The drug loading parameters were selected to avoid crystallization of the drug molecules on the external surface of the particles that would block the pore entrances. The successfulness of the loadings was verified with TG, DSC, and XRPD measurements. The effects of the confinement of IMC and GSV into the small mesopores of THCPSi were analyzed with helium pycnometry, FTIR, and NMR spectroscopy. The results showed the density of the THCPSi loaded drugs to be ca. 10% lower than the bulk crystalline forms, while a melt quenched amorphous drugs showed a density reduction of 3-7.5%. DSC and FTIR results confirmed that the drugs reside in an amorphous form within the THCPSi pores. Similar results were obtained with NMR, which also indicated that IMC may reside as both amorphous clusters and individual molecules within the pores. The (1)H transverse relaxation times (T2) of amorphous and THCPSi loaded drugs showed IMC relaxation times of 0.28 ms for both the cases, whereas for GSV the values were 0.32 and 0.39 ms, respectively, indicating similar limited mobility in both cases. The results indicated that strong drug-carrier interactions were not necessary for stabilizing the amorphous state of the adsorbed drug. Dissolution tests using biorelevant media, fasted state simulated intestinal fluid (FaSSIF) and simulated gastric fluid (SGF), showed that THCPSi-loaded IMC and GSV were rapidly released in FaSSIF with comparable rates to the amorphous forms, whereas in SGF the THCPSi reduced the pH dependency in the dissolution of IMC.

Currently, developing a stable nanocarrier with high cellular internalization and low toxicity is a key bottleneck in nanomedicine. Here, we have developed a successful method to covalently conjugate poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of (3-aminopropyl)triethoxysilane-functionalized thermally carbonized porous silicon nanoparticles (APSTCPSi NPs), forming a surface negatively charged nanovehicle with unique properties. This polymer conjugated NPs could modify surface smoothness, charge, and hydrophilicity of the developed NPs, leading to considerable improvement in the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the polymer-conjugated NPs, the cellular internalization was increased in both MDA-MB-231 and MCF-7 breast cancer cells. These results provide a proof-of-concept evidence that such polymer-based PSi nanocomposite can be extensively used as a promising candidate for intracellular drug delivery., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A major challenge for a drug-delivery system is to engineer stable drug carriers with excellent biocompatibility, monodisperse size, and controllable release profiles. In this study, we used a microfluidic technique to encapsulate thermally hydrocarbonized porous silicon (THCPSi) microparticles within solid lipid microparticles (SLMs) to overcome the drawbacks accompanied by THCPSi microparticles. Formulation and process factors, such as lipid matrixes, organic solvents, emulsifiers, and methods to evaporate the organic solvents, were all evaluated and optimized to prepare monodisperse stable SLMs. FTIR analysis together with confocal images showed the clear deposition of THCPSi microparticles inside the monodisperse SLM matrix. The formation of monodisperse THCPSi-solid lipid microcomposites (THCPSi-SLMCs) not only altered the surface hydrophobicity and morphology of THCPSi microparticles but also remarkably enhanced their cytocompatibility with intestinal (Caco-2 and HT-29) cancer cells. Regardless of the solubility of the loaded therapeutics (aqueous insoluble, fenofibrate and furosemide; aqueous soluble, methotrexate and ranitidine) and the pH values of the release media (1.2, 5.0, and 7.4), the time for the release of 50% of the payloads from THCPSi-SLMC was at least 1.3 times longer than that from the THCPSi microparticles. The sustained release of both water-soluble and -insoluble drugs together with a reduced burst-release effect from monodisperse THCPSi-SLMC was achieved, indicating the successful encapsulation of THCPSi microparticles into the SLM matrix. The fabricated THCPSi-SLMCs exhibited monodisperse spherical morphology, enhanced cytocompatibility, and prolonged both water-soluble and -insoluble drug release, which makes it an attractive controllable drug-delivery platform.

Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Influenza A viruses (IAVs) cause recurrent epidemics in humans, with serious threat of lethal worldwide pandemics. The occurrence of antiviral-resistant virus strains and the emergence of highly pathogenic influenza viruses have triggered an urgent need to develop new anti-IAV treatments. One compound found to inhibit IAV, and other virus infections, is saliphenylhalamide (SaliPhe). SaliPhe targets host vacuolar-ATPase and inhibits acidification of endosomes, a process needed for productive virus infection. The major obstacle for the further development of SaliPhe as antiviral drug has been its poor solubility. Here, we investigated the possibility to increase SaliPhe solubility by loading the compound in thermally hydrocarbonized porous silicon (THCPSi) nanoparticles. SaliPhe-loaded nanoparticles were further investigated for the ability to inhibit influenza A infection in human retinal pigment epithelium and Madin-Darby canine kidney cells, and we show that upon release from THCPSi, SaliPhe inhibited IAV infection in vitro and reduced the amount of progeny virus in IAV-infected cells. Overall, the PSi-based nanosystem exhibited increased dissolution of the investigated anti-IAV drug SaliPhe and displayed excellent in vitro stability, low cytotoxicity, and remarkable reduction of viral load in the absence of organic solvents. This proof-of-principle study indicates that PSi nanoparticles could be used for efficient delivery of antivirals to infected cells.

Thermally carbonized porous silicon (TCPSi) microparticles were chemically modified with organofunctional alkoxysilane molecules using a silanization process. Before the silane coupling, the TCPSi surface was activated by immersion in hydrofluoric acid (HF). Instead of regeneration of the silicon hydride species, the HF immersion of silicon carbide structure forms a silanol termination (Si-OH) on the surface required for silanization. Subsequent functionalization with 3-aminopropyltriethoxysilane provides the surface with an amine (-NH(2)) termination, while the SiC-type layer significantly stabilizes the functionalized structure both mechanically and chemically. The presence of terminal amine groups was verified with FTIR, XPS, CHN analysis, and electrophoretic mobility measurements. The overall effects of the silanization to the morphological properties of the initial TCPSi were analyzed and they were found to be very limited, making the treatment effects highly predictable. The maximum obtained number of amine groups on the surface was calculated to be 1.6 groups/nm(2), corresponding to 79% surface coverage. The availability of the amine groups for further biofunctionalization was confirmed by successful biotinylation. The isoelectric point (IEP) of amine-terminated TCPSi was measured to be at pH 7.7, as opposed to pH 2.6 for untreated TCPSi. The effects of the surface amine termination on the cell viability of Caco-2 and HT-29 cells and on the in vitro fenofibrate release profiles were also assessed. The results indicated that the surface modification did not alter the loading of the drug inside the pores and also retained the beneficial enhanced dissolution characteristics similar to TCPSi. Cellular viability studies also showed that the surface modification had only a limited effect on the biocompatibility of the PSi.

Recently, highly promising results considering the use of porous silicon (PSi) nanoparticles as a controlled and targeted drug delivery system have been published. Drugs are typically loaded into PSi nanoparticles by electrostatic interactions, and the drug-loaded nanoparticles are then administered parenterally in isotonic solutions. Zeta potential has an important role in drug adsorption and overall physical stability of nanosuspensions. In the present study, we used zeta potential measurements to study the impact of the formulation components to the nanosuspension stability. The impact of medium was studied by measuring isoelectric points (IEP) and zeta potentials in isotonic media. The role of drug adsorption was demonstrated with gastrointestinal peptides GLP-1(7-37) and PYY (3-36) and the selection of isotonic additive was demonstrated with peptide-loaded PSi nanoparticles. The results show the notable effect of isotonic solutions and peptide adsorption on zeta potential of PSi nanosuspensions. As a rule of thumb, the sugars (sucrose, dextrose and mannitol) seem to be good media for negatively charged peptide-loaded particles and weak acids (citric- and lactic acid) for positively charged particles. Nevertheless, perhaps the most important rule can be given for isotonic salt solutions which all are very poor media when the stability of nanosuspension is considered., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Multidrug-resistant tuberculosis (MDR-TB) has become a worldwide problem and a major public health concern. The mechanisms of resistance are fairly well characterized for most agents, but MDR limits the therapeutic usefulness of both new and classical medicines against TB. Ethionamide (ETA) is a thioamide antibiotic and one of the most widely used drugs as second line agent for the treatment of MDR-TB. Over the years, some studies have emerged to improve the bioavailability of this drug and of its active metabolites. However, inactive metabolites of ETA are still a major drawback in its application against TB. Porous silicon (PSi) materials can be applied to improve the dissolution behavior of poorly water-soluble compounds and to overcome toxicity and other drug-related problems in oral delivery. In the present work, we have loaded ETA into thermally carbonized-PSi (TCPSi) microparticles and studied the solubility, toxicity, permeability, and metabolic profiles of the PSi-loaded drug. The solubility and permeability of ETA was clearly enhanced after loaded into TCPSi particles at different pH-values. ETA was in general toxic at concentrations above 0.50mM to HepG2, Caco-2, and RAW macrophage cells, but the toxicity was drastically reduced when the drug was loaded into the microparticles. ETA showed a fast metabolization process in the presence of the TCPSi particles. In addition, new thiolated metabolites were identified from incubation of ETA-loaded PSi with HepG2 liver cells, which opens new perspectives toward both the understanding of ETA metabolism and the development of novel ETA-based systems with improved efficacy against MDR-TB., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this study, the self-assembly of hydrophobin class II (HFBII) on the surface of thermally hydrocarbonized porous silicon (THCPSi) nanoparticles was investigated. The HFBII-coating converted the hydrophobic particles into more hydrophilic ones, improved the particles' cell viability in both HT-29 and Caco-2 cell lines compared to uncoated particles, and enhanced the particles' cellular association. The amount of HFBII adsorbed onto the particles was also successfully quantified by both the BCA assay and a HPLC method. Importantly, the permeation of a poorly water-soluble drug, indomethacin, loaded into THCPSi particles across Caco-2 monolayers was not affected by the protein coating. In addition, (125)I-radiolabelled HFBII did not extensively permeate the Caco-2 monolayer and was found to be stably adsorbed onto the THCPSi nanoparticles incubated in pH 7.4, which renders the particles the possibility for further track-imaging applications. The results highlight the potential of HFBII coating for improving wettability, increasing biocompatibility and possible intestinal association of PSi nanoparticulates for drug delivery applications.

Rapid immune recognition and subsequent elimination from the circulation hampers the use of many nanomaterials as carriers to targeted drug delivery and controlled release in the intravenous route. Here, we report the effect of a functional self-assembled protein coating on the intravenous biodistribution of (18)F-labeled thermally hydrocarbonized porous silicon (THCPSi) nanoparticles in rats. (18)F-Radiolabeling enables the sensitive and easy quantification of nanoparticles in tissues using radiometric methods and allows imaging of the nanoparticle biodistribution with positron emission tomography. Coating with Trichoderma reesei HFBII altered the hydrophobicity of (18)F-THCPSi nanoparticles and resulted in a pronounced change in the degree of plasma protein adsorption to the nanoparticle surface in vitro. The HFBII-THCPSi nanoparticles were biocompatible in RAW 264.7 macrophages and HepG2 liver cells making their intravenous administration feasible. In vivo, the distribution of the nanoparticles between the liver and spleen, the major mononuclear phagocyte system organs in the body, was altered compared to that of uncoated (18)F-THCPSi. Identification of the adsorbed proteins revealed that certain opsonins and apolipoproteins are enriched in HFBII-functionalized nanoparticles, whereas the adsorption of abundant plasma components such as serum albumin and fibrinogen is decreased.

Purpose: To achieve sustained peptide delivery via mesoporous silicon (PSi) microparticles and to evaluate the effects of different surface chemistries on peptide YY3-36 (PYY3-36) delivery., Methods: PYY3-36 was loaded into thermally oxidized (TOPSi), thermally hydrocarbonized (THCPSi) and undecylenic acid treated THCPSi (UnTHCPSi) microparticles with comparable porous properties. In vitro, PYY3-36 release was investigated by centrifuge. In vivo, PYY3-36 plasma concentrations were analyzed after delivery in microparticles or solution., Results: Achieved loading degrees were high (12.2 - 16.0% w/w). PYY3-36 release was sustained from all microparticles; order of PYY3-36 release was TOPSi > THCPSi > UnTHCPSi both in vitro and in vivo. In mice, PSi microparticles achieved sustained PYY3-36 release over 4 days, whereas PYY3-36 solution was eliminated in 12 h. In vitro, only 27.7, 14.5 and 6.2% of loaded PYY3-36 was released from TOPSi, THCPSi and UnTHCPSi, respectively. Absolute PYY3-36 bioavailabilities were 98, 13, 9 and 38% when delivered subcutaneously in TOPSi, THCPSi, UnTHCPSi and solution, respectively. The results clearly demonstrate improved bioavailability of PYY3-36 via TOPSi and the importance of surface chemistry of PSi on peptide release., Conclusions: PSi represents a promising sustained and tailorable release system for PYY3-36.

In this study, indomethacin-loaded thermally oxidized mesoporous silicon microparticles (TOPSi-IMC) were formulated into tablets with excipients in order to improve the dissolution and permeability properties of the poorly soluble drug. Formulations of TOPSi-IMC particles and excipients were prepared at different TOPSi-IMC particle ratios (25, 30 and 35%). The formulations were compressed by direct compression technique with a single punch tablet machine. For comparison, a formulation containing the bulk IMC (indomethacin) and the same excipients without thermally oxidized mesoporous silicon microparticles particles (TOPSi) was prepared and compressed into tablets. The TOPSi-IMC tablets were characterised according to weight, thickness, crushing strength, disintegration time and dissolution rate. The results of this study show that TOPSi-IMC particles can be compressed to a conventional tablet. The release rate of the drug and its permeation across intestinal cells model (Caco-2) from TOPSi-IMC tablets was improved compared to the bulk IMC tablets. The dissolution rate and permeability of IMC from the tablets decreased with increasing ratio of the TOPSi-IMC particles in the formulation. The phenomenon is, presumably, a result of the loss of unique pore structure of the particles due to deformation of the particles under the compression load., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Porous silicon (PSi) particles have been widely used in modulating the dissolution rate of various types of drugs loaded within its mesopores. This material can be surface treated in order to vary its hydrophobicity and several other properties, such as drug loading degree and release rate. Hydrophobins are a family of self-assembling proteins of fungal origin which have the ability to form layers on hydrophobic materials. This type of protein layer can modify the characteristics and control the binding properties of the surface on which it assembles. In this study, we have developed a procedure to coat thermally hydrocarbonized-PSi microparticles with hydrophobin II (HFBII) in order to modify the particles' hydrophobicity and to improve their biocompatibility, while maintaining intact the advantageous drug releasing properties of the PSi. The HFBII content adsorbed onto the particles was successfully quantified by a protein assay. Drug dissolution and permeation across Caco-2 cell monolayers were also conducted, together with viability studies in AGS, Caco-2 and HT-29 cells. The characterization and coating stability assessment showed that the HFBII-coating desorbs partially from the particles' surface as the pH increases. The HFBII coating also improved the biocompatibility of the particles without compromising the enhanced drug permeation or release., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mesoporous materials have an ability to enhance dissolution properties of poorly soluble drugs. In this study, different mesoporous silicon (thermally oxidized and thermally carbonized) and non-ordered mesoporous silica (Syloid AL-1 and 244) microparticles were compared as drug carriers for a hydrophobic drug, itraconazole (ITZ). Different surface chemistries pore volumes, surface areas, and particle sizes were selected to evaluate the structural effect of the particles on the drug loading degree and on the dissolution behavior of the drug at pH 1.2. The results showed that the loaded ITZ was apparently in amorphous form, and that the loading process did not change the chemical structure/morphology of the particles' surface. Incorporation of ITZ in both microparticles enhanced the solubility and dissolution rate of the drug, compared to the pure crystalline drug. Importantly, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. After storage under stressed conditions (3 months at 40 °C and 70% RH), the loaded silica gel particles showed practically similar dissolution profiles as before the storage. This was not the case with the loaded mesoporous silicon particles due to the almost complete chemical degradation of ITZ after storage., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Mesoporous silicon particles hold great potential in improving the solubility of otherwise poorly soluble drugs. To effectively translate this feature into the clinic, especially via oral or parenteral administration, a thorough understanding of the interactions of the micro- and nanosized material with the physiological environment during the delivery process is required. In the present study, the behaviour of thermally oxidized porous silicon particles of different sizes interacting with Caco-2 cells (both non-differentiated and polarized monolayers) was investigated in order to establish their fate in a model of intestinal epithelial cell barrier. Particle interactions and TNF-α were measured in RAW 264.7 macrophages, while cell viabilities, reactive oxygen species and nitric oxide levels, together with transmission electron microscope images of the polarized monolayers, were assessed with both the Caco-2 cells and RAW 264.7 macrophages. The results showed a concentration and size dependent influence on cell viability and ROS-, NO- and TNF-α levels. There was no evidence of the porous nanoparticles crossing the Caco-2 cell monolayers, yet increased permeation of the loaded poorly soluble drug, griseofulvin, was shown., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We report here the in vitro cytotoxicity of mesoporous silicon (PSi) microparticles on the Caco-2 cells as a function of particle size fractions (1.2-75 microm), particle concentration (0.2-4 mg ml(-1)) and incubation times (3, 11 and 24 h). The particle size (smaller PSi particles showed higher cytotoxicity) and the surface chemistry treatment of the PSi microparticles were considered to be the key factors regarding the toxicity aspects. These effects were significant after the 11 and 24 h exposure times, and were explained by cell-particle interactions involving mitochondrial disruption resulting from ATP depletion and reactive oxygen species production induced by the PSi surface. These events further induced an increase in cell apoptosis and consequent cell damage and cell death in a dose-dependent manner and as a function of the PSi particle size. These effects were, however, less pronounced with thermally oxidized PSi particles. Under the experimental conditions tested and at particle sizes >25 microm, the non-toxic threshold concentration for thermally hydrocarbonized and carbonized PSi particles was <2 mg ml(-1), and for thermally oxidized PSi microparticles was <4 mg ml(-1)., (Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Porous silicon (PSi) particles have been studied for the effects they elicit in Caco-2 and RAW 264.7 macrophage cells in terms of toxicity, oxidative stress, and inflammatory response. The most suitable particles were then functionalized with a novel (18)F label to assess their biodistribution after enteral and parenteral administration in a rat model. The results show that thermally hydrocarbonized porous silicon (THCPSi) nanoparticles did not induce any significant toxicity, oxidative stress, or inflammatory response in Caco-2 and RAW 264.7 macrophage cells. Fluorescently labeled nanoparticles were associated with the cells surface but were not extensively internalized. Biodistribution studies in rats using novel (18)F-labeled THCPSi nanoparticles demonstrated that the particles passed intact through the gastrointestinal tract after oral administration and were also not absorbed from a subcutaneous deposit. After intravenous administration, the particles were found mainly in the liver and spleen, indicating rapid removal from the circulation. Overall, these silicon-based nanosystems exhibit excellent in vivo stability, low cytotoxicity, and nonimmunogenic profiles, ideal for oral drug delivery purposes.

Mesoporous silicon microparticles with three various surface chemistries and eight different average pore diameters for each surface modification, ranging from 11 to 75 nm, were loaded with ibuprofen. The loaded batches were characterized using thermal analysis and nitrogen sorption. Three thermodynamically different states of ibuprofen were found in the samples: a crystalline state outside the pores, a crystalline state inside the pores, and a disordered state inside the pores. Both the crystalline and disordered ibuprofen were found in the pores in all of the batches. Crystalline ibuprofen outside the pores was only found in two batches and in negligible amounts. The results supported the assumption that there is a layer of disordered ibuprofen adjacent to the pore wall (i.e., delta layer), in which the thickness is not strongly depending upon the pore size. The thickness of the disordered layer varied depending upon the surface chemistry of the pore wall and was 1.2, 1.5, and 2.0 nm for hydrogen-terminated, thermally oxidized, and thermally carbonized surfaces, respectively. The method gave detailed information on the physical state of ibuprofen in the batches. It can be used with any drug compound that is able to form crystals inside the mesopores and can be a useful tool in determining the optimal surface chemistry and pore size of a mesoporous drug-carrier material.

In the present work, porous silicon (PS) based Bragg reflectors are fabricated, and the reactive PS surface is passivated by means of thermal carbonization (TC) by acetylene decomposition. The gas sensing properties of the reflectors are studied with different gas compositions and concentrations. Based on the results it can be concluded that thermally carbonized Bragg reflectors provide an easy and inexpensive means to produce chemically stable high quality PS reflectors with good gas sensing properties, which differ from those of unpassivated PS reflectors.