pH-Responsive Inorganic/Organic Nanohybrids System for Controlled Nicotinic Acid Drug Release.

Although nicotinic acid (NA) has several clinical benefits, its potency cannot be fully utilized due to several undesirable side effects, including cutaneous flushing, GIT-associated symptoms, etc. To overcome such issues and improve the NA efficacy, a new inorganic-organic nanohybrids system was rationally designed. For making such a hybrid system, NA was intercalated into LDH through a coprecipitation technique and then coated with Eudragit® S100 to make the final drug delivery system called Eudragit® S100-coated NA-LDH. The as-made drug delivery system not only improved the NA release profile but also exhibited good bio-compatibility as tested on L929 cells. Such an inorganic-organic nanohybrid drug delivery agent is expected to reduce the undesirable side effects associated with NA and hopefully improve the pharmacological effects without inducing any undesirable toxicity.

Stimuli-Responsive Drug Delivery of Doxorubicin Using Magnetic Nanoparticle Conjugated Poly(ethylene glycol)-g-Chitosan Copolymer.

Stimuli-responsive nanoparticles are regarded as an ideal candidate for anticancer drug targeting. We synthesized glutathione (GSH) and magnetic-sensitive nanocomposites for a dual-targeting strategy. To achieve this goal, methoxy poly (ethylene glycol) (MePEG) was grafted to water-soluble chitosan (abbreviated as ChitoPEG). Then doxorubicin (DOX) was conjugated to the backbone of chitosan via disulfide linkage. Iron oxide (IO) magnetic nanoparticles were also conjugated to the backbone of chitosan to provide magnetic sensitivity. In morphological observation, images from a transmission electron microscope (TEM) showed that IO nanoparticles were embedded in the ChitoPEG/DOX/IO nanocomposites. In a drug release study, GSH addition accelerated DOX release rate from nanocomposites, indicating that nanocomposites have redox-responsiveness. Furthermore, external magnetic stimulus concentrated nanocomposites in the magnetic field and then provided efficient internalization of nanocomposites into cancer cells in cell culture experiments. In an animal study with CT26 cell-bearing mice, nanocomposites showed superior magnetic sensitivity and then preferentially targeted tumor tissues in the field of external magnetic stimulus. Nanocomposites composed of ChitoPEG/DOX/IO nanoparticle conjugates have excellent anticancer drug targeting properties.

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance.

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.

Aripiprazole-montmorillonite: a new organic-inorganic nanohybrid material for biomedical applications.

Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ-MMT). To further improve the efficacy of this taste masking and drug solubility, APZ-MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA-coated APZ-MMT was greatly suppressed (<1%) for the first 3 min, thus suggesting that AEA-coated APZ-MMT has strong potential for the taste masking of APZ. Notably, in simulated gastric juice at pH 1.2, the total percentage of APZ that was released within the first 2 h increased up to 95% for AEA-coated APZ-MMT. Furthermore, this in vitro release profile was also similar to that of Abilify®, a commercially available medication. In vivo experiments by using Sprague-Dawley rats were also performed to compare the pharmacokinetics of AEA-coated APZ-MMT and Abilify®. AEA-coated APZ-MMT exhibited about 20% higher systemic exposure of APZ and its metabolite, dehydro-APZ, compared with Abilify®. Therefore, a new MMT-based nanovehicle, which is coated with a cationic polymer, can act as a promising delivery system for both taste masking and for enhancing the bioavailability of APZ.

NOAEL cancer therapy: a tumor targetable docetaxel-inorganic polymer nanohybrid prevents drug-induced neutropenia.

To date, cancer therapies largely consist of five pillars: surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. Still, researchers are trying to innovate the current cancer therapies to pursue an ideal one without side effects. For developing such a therapy, we designed a chemically well-defined route to a PEG- and docetaxel (DTX)-conjugated inorganic polymer, polyphosphazene, named "polytaxel (PTX)" with a prolonged blood circulation time and tumor localization. Here, we conducted the proof-of-concept study of the ideal therapy in orthotopic and xenograft pancreatic cancer models. We found that the average tumor inhibition rates of PTX were similar to those of DTX without any DTX toxicity-related side effects, such as neutropenia and weight loss. In conclusion, PTX met the requirements of an ideal anticancer drug with high anticancer efficacy and 100% survival rate. PTX is expected to replace any existing anticancer therapies in clinical practice.

Inhibitory effect of Acer tegmentosum maxim extracts on P. gingivalis LPS-induced periodontitis.

OBJECTIVE: Periodontitis disease is a chronic inflammation, and the prevention or treatment of periodontal disease is important for improving oral health and averting systemic diseases.Acer tegmentosum Maxim (ATM) is a type of deciduous tree in Korea. ATM extracts have been traditionally used to treat various dieases. This study investigated the effects of ATM extract on mitigation of periodontitis in vitro and in vivo. DESIGN: The current study investigated whether extracts ofAcer tegmentosum Maxim (ATM) attenuated periodontitis induced by Porphyromonas gingivalis-derived lipopolysaccharide (LPS) in vitro and in vivo. We used a rat model of experimental periodontitis that received oral administration of 1 mg/kg P. gingivalis-derived LPS for 10 days. Periodontitis models was treated with two different dosages of ATM (30 or 100 mg/kg) during the same period of periodontal induction for histological analysis. RESULTS: The results indicated that aqueous ATM extracts effectively ameliorated ligature-induced periodontitis through of the antibacterial, anti-oxidative, and anti-inflammatory activities. CONCLUSION: These pre-clinical results suggest the need for further studies on the anti-periodontitis effect of ATM in humans. Thus, ATM could be used as a natural anti-periodontitis agent for the treatment of periodontitis.

Brimonidine-montmorillonite hybrid formulation for topical drug delivery to the eye.

Brimonidine (BMD) is often prescribed as an eye drop to reduce the intraocular pressure (IOP) for glaucoma treatment. However, eye drops are limited by rapid clearance from the preocular surface, and hence a low ocular drug bioavailability. Therefore, in this study, we propose montmorillonite (MMT), as a delivery carrier, hybridized with BMD (BMD-MMT) for topical drug delivery to the eye. The BMD-MMT hybrid was prepared by intercalating the BMD molecules in the interlayer space of the MMT lattice via ion-exchange reaction; it was then formulated with polyvinyl alcohol (PVA) to produce a dry tablet (i.e., BMD-MMT@PVA). The BMD-MMT@PVA hybrid drug released BMD in a sustained manner for more than 5 h under in vitro conditions. When the hybrid drug was administered to rabbit eyes in vivo, 43% and 18.5% BMD-MMT still remained on the preocular surface for 10 and 60 min after administration, respectively. Thus, the BMD-MMT@PVA hybrid drug exhibited a prolonged decrease in IOP, that is, for 12 h, which was approximately two times longer than that observed with the commercially available BMD eye drop, Alphagan® P.

Theranostic Bioabsorbable Bone Fixation Plate with Drug-Layered Double Hydroxide Nanohybrids.

A bioabsorbable polymeric bone plate enabled with both diagnostic and therapeutic functionalities (radiopacity and sustained drug release, respectively) is proposed. To this end, a drug-inorganic nanohybrid (RS-LDH) is examined as a theranostic agent by intercalating an anti-resorptive bone remodeling drug, risedronate (RS) into a layered double hydroxide (LDH) via an ion-exchange reaction. The RS-LDH is prepared as a sheet with a biodegradable polymer, poly(lactic-co-glycolic acid), and is then attached onto the clinically approved bioabsorbable bone plate to produce the theranostic plate. Because of the presence of the metals in the LDH, the theranostic plate results in discernible in vivo X-ray images for up to four weeks after implantation. Concurrently, bone regeneration is also significantly improved compared with the other control groups, likely because of this material's sustained drug-release property. The theranostic plate is also largely biocompatible, similar to the plate already approved for clinical use. It is concluded that the combination of a biodegradable bone plate with RS-LDH nanohybrids can constitute a promising system with theranostic ability in both X-ray diagnosis and expedited bone repair.

2D Inorganic-Antimalarial Drug-Polymer Hybrid with pH-Responsive Solubility.

Artesunic acid (ASH), an antimalarial drug, has low oral bioavailability due to its low aqueous solubility. To overcome this problem, artesunate (AS) was intercalated into zinc basic salt (ZBS) via co-precipitation. AS was immobilized with a tilted double layer arrangement, which was also confirmed by XRD and 1-D electron density mapping. In order to decrease the release rate of AS under gastrointestinal conditions and to simultaneously increase the release rate of AS under intestinal conditions, ZBS-AS was coated with EUDRAGIT L100 (ZBS-AS-L100). Finally, we performed an in-vivo pharmacokinetic study to compare the oral bioavailability of AS of ZBS-AS-L100 with that of ASH. Surprisingly, it was found that the former is 5.5 times greater than the latter due to an enhanced solubility of AS thanks to the ternary hybridization with ZBS and EUDRAGIT L100. Therefore, the present ZBS-AS-L100 system has a great potential as a novel antimalarial drug formulation with pH selectivity and enhanced bioavailability.

A nanohybrid system for taste masking of sildenafil.

A nanohybrid was prepared with an inorganic clay material, montmorillonite (MMT), for taste masking of sildenafil (SDN). To further improve the taste-masking efficiency and enhance the drug-release rate, we coated the nanohybrid of SDN-MMT with a basic polymer, polyvinylacetal diethylaminoacetate (AEA). Powder X-ray diffraction and Fourier transform infrared experiments showed that SDN was successfully intercalated into the interlayer space of MMT. The AEA-coated SDN-MMT nanohybrid showed drug release was much suppressed at neutral pH (release rate, 4.70 ± 0.53%), suggesting a potential for drug taste masking at the buccal cavity. We also performed in vitro drug release experiments in a simulated gastric fluid (pH = 1.2) and compared the drug-release profiles of AEA-coated SDN-MMT and Viagra(®), an approved dosage form of SDN. As a result, about 90% of SDN was released from the AEA-coated SDN-MMT during the first 2 hours while almost 100% of drug was released from Viagra(®). However, an in vivo experiment showed that the AEA-coated SDN-MMT exhibited higher drug exposure than Viagra(®). For the AEA-coated SDN-MMT, the area under the plasma concentration- time curve from 0 hours to infinity (AUC(0-∞)) and maximum concentration (C(max)) were 78.8 ± 2.32 µg · hour/mL and 12.4 ± 0.673 µg/mL, respectively, both of which were larger than those obtained with Viagra(®) (AUC(0-∞) = 69.2 ± 3.19 µg · hour/mL; C(max) = 10.5 ± 0.641 µg/mL). Therefore, we concluded that the MMT-based nanohybrid is a promising delivery system for taste masking of SDN with possibly improved drug exposure.

Inorganic-polymer nanohybrid carrier for delivery of a poorly-soluble drug, ursodeoxycholic acid.

Delivery of poorly soluble drugs has been problematic due to its low absorption profile and bioavailability. In this work, ursodeoxycholic acid (UDCA), a poorly-soluble drug, was intercalated into inorganic nanovehicle, layered double hydroxides (LDHs), with a molecular level to enhance its solubility in biological fluid. The UDCA-loaded nanovehicle (i.e., UDCA-LDHs) was also coated with an anionic polymer, Eudragit(®) S100, to increase the dissolution rate of UDCA. According to the powder X-ray diffraction (PXRD) patterns of UDCA-LDHs, the gallery height of LDHs was expanded from 3.6Å to 28.3Å, indicating that the UDCA molecules were successfully intercalated into the interlayer space of LDHs. Fourier transform infrared (FT-IR) spectra also revealed that the UDCA molecules were well stabilized in the LDHs through electrostatic interaction. The in vitro dissolution test in a simulated biological fluid (pH=6.8) showed that the total dissolved fraction of UDCA for the first 2h was about 60.2% for the Eudragit(®) S100 coated UDCA-LDHs, which was a dramatic increase as compared with 19.0% dissolution from intact UDCA. It is, therefore, concluded that LDHs nanovehicle coated with an anionic polymer is a promising delivery system for improving aqueous solubility of poorly soluble drugs.