SVM Classification and CoMSIA Modeling of UGT1A6 Interacting Molecules

The human UDP-glucuronosyltransferase 1A6 (UGT1A6) plays important roles in elimination of many xenobiotics, including drugs. We have experimentally assessed inhibitory properties of 46 compounds toward UGT1A6 catalyzing the glucuronidation of 1-naphthol and built models for predicting compounds interactions with the enzyme. The tested compounds were divided into a training set (<i>n</i> = 31; evaluated by 10-fold cross-validation) and an external test set (<i>n</i> = 15), both of which yielded similar accuracies (80–81%) and Matthews correlation coefficients (0.61–0.63) when classified using support vector machines. Comparative molecular similarity index analysis (CoMSIA) modeling was conducted for nine methods of compound alignment. The most predictive CoMSIA model was analyzed in the light of a homology modeled UGT1A6 structure, with leave-one-out cross-validation, yielding a <i>q</i>² of 0.62 and <i>r</i>² of 0.91 on the training set and a <i>r</i>²_pred of 0.82 on the test set. The CoMSIA contour plots highlighted the importance of H-bond donors and electrostatic field interactions, accounting for 28% and 25% contribution of the model, respectively

Controlled Shape and Nucleation Switching of Interfacially Polymerizable Nanoassemblies by Methyl Substitution

Interfacial polymerization of uniform template-free nanostructures is very challenging since many factors play determinant roles in the final structure of the resulting nanoassemblies. Here, we present a single oxidative coupling method for the synthesis of different nanoshapes by addition or substitution of a methyl group on aniline monomers to freely alter the mechanism of monomer-to-polymer conversion. Well-defined nanotubes, nanohollows, and solid nanospheres are obtained from aniline, <i>N</i>-methylaniline, and 2-methylaniline polymerizations, respectively. We found that the extent of hydrophobicity and protonation under mild acidic conditions determines the monomers’ arrangement in micelle or droplet form, reactivity, and nucleation mechanism. These can subsequently affect the final morphology through a fusion process to form tubular structures, external flux of monomers to form nanohollows, and intradroplet oxidation to form solid nanospheres. Altered biological responses, such as cytocompatibility, redox response, hemocompatibility, and cell proliferation, are also found to be dependent on the position of the methyl group in the nanostructures

SVM Classification and CoMSIA Modeling of UGT1A6 Interacting Molecules

The human UDP-glucuronosyltransferase 1A6 (UGT1A6) plays important roles in elimination of many xenobiotics, including drugs. We have experimentally assessed inhibitory properties of 46 compounds toward UGT1A6 catalyzing the glucuronidation of 1-naphthol and built models for predicting compounds interactions with the enzyme. The tested compounds were divided into a training set (<i>n</i> = 31; evaluated by 10-fold cross-validation) and an external test set (<i>n</i> = 15), both of which yielded similar accuracies (80–81%) and Matthews correlation coefficients (0.61–0.63) when classified using support vector machines. Comparative molecular similarity index analysis (CoMSIA) modeling was conducted for nine methods of compound alignment. The most predictive CoMSIA model was analyzed in the light of a homology modeled UGT1A6 structure, with leave-one-out cross-validation, yielding a <i>q</i>² of 0.62 and <i>r</i>² of 0.91 on the training set and a <i>r</i>²_pred of 0.82 on the test set. The CoMSIA contour plots highlighted the importance of H-bond donors and electrostatic field interactions, accounting for 28% and 25% contribution of the model, respectively

Cyclodextrin-Modified Porous Silicon Nanoparticles for Efficient Sustained Drug Delivery and Proliferation Inhibition of Breast Cancer Cells

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

Platelet Lysate-Modified Porous Silicon Microparticles for Enhanced Cell Proliferation in Wound Healing Applications

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 <i>in vitro</i> and <i>ex vivo</i> 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 <i>in vitro</i> wound healing assay. Finally, the PL-modified PSi microparticles were evaluated in an <i>ex vivo</i> 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 <i>ex vivo</i> 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

A Versatile Carbonic Anhydrase IX Targeting Ligand-Functionalized Porous Silicon Nanoplatform for Dual Hypoxia Cancer Therapy and Imaging

Hypoxia occurs in most solid tumors, and it has been shown to be an independent prognostic indicator of a poor clinical outcome for patients with various cancers. Therefore, constructing a nanosystem specifically targeting cancer cells under hypoxia conditions is a promising approach for cancer therapy. Herein, we develop a porous silicon (PSi)-based nanosystem for targeted cancer therapy. VD11-4-2, a novel inhibitor for carbonic anhydrase IX (CA IX), is anchored on PSi particles (VD-PSi). As CA IX is mainly expressed on the cancer cell membrane under hypoxia condition, this nanocomplex inherits a strong affinity toward hypoxic human breast adenocarcinoma (MCF-7) cells; thus, a better killing efficiency for the hypoxia-induced drug resistance cancer cell is observed. Furthermore, the release of doxorubicin (DOX) from VD-PSi showed pH dependence, which is possibly due to the hydrogen-bonding interaction between DOX and VD11-4-2. The fluorescence resonance energy transfer effect between DOX and VD11-4-2 is observed and applied for monitoring the DOX release intracellularly. Protein inhibition and binding assays showed that VD-PSi binds and inhibits CA IX. Overall, we developed a novel nanosystem inheriting several advantageous properties, which has great potential for targeted treatment of cancer cells under hypoxic conditions

Amine Modification of Thermally Carbonized Porous Silicon with Silane Coupling Chemistry

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 (−NH₂) 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/nm², 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

Core/Shell Nanocomposites Produced by Superfast Sequential Microfluidic Nanoprecipitation

Although a number of techniques exist for generating structured organic nanocomposites, it is still challenging to fabricate them in a controllable, yet universal and scalable manner. In this work, a microfluidic platform, exploiting superfast (milliseconds) time intervals between sequential nanoprecipitation processes, has been developed for high-throughput production of structured core/shell nanocomposites. The extremely short time interval between the sequential nanoprecipitation processes, facilitated by the multiplexed microfluidic design, allows us to solve the instability issues of nanocomposite cores without using any stabilizers. Beyond high throughput production rate (∼700 g/day on a single device), the generated core/shell nanocomposites harness the inherent ultrahigh drug loading degree and enhanced payload dissolution kinetics of drug nanocrystals and the controlled drug release from polymer-based nanoparticles

Microfluidic Templated Mesoporous Silicon–Solid Lipid Microcomposites for Sustained Drug Delivery

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

Confinement Effects on Drugs in Thermally Hydrocarbonized Porous Silicon

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 ¹H transverse relaxation times (<i>T</i>₂) 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