Polyphosphazene-Based Biomaterials for Biomedical Applications.

Recently, synthetic polymers have attracted great interest in the field of biomedical science. Among these, polyphosphazenes (PPZs) are regarded as one of the most promising materials, due to their structural flexibility and biodegradability compared to other materials. PPZs have been developed through numerous studies. In particular, multi-functionalized PPZs have been proven to be potential biomaterials in various forms, such as nanoparticles (NPs) and hydrogels, through the introduction of various functional groups. Thus, PPZs have been applied for the delivery of therapeutic molecules (low molecular weight drugs, genes and proteins), bioimaging, phototherapy, bone regeneration, dental liners, modifiers and medical devices. The main goal of the present review is to highlight the recent and the most notable existing PPZ-based biomaterials for aforementioned applications, with future perspectives in mind.

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.

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.

Polylactic Acid/Chitosan Nanoparticles Loading Nifedipine: Characterization Findings and In Vivo Investigation in Animal.

This paper presents the results of zeta potential, water contact angle, atomic force microscopy image, in vitro solubility, and content of heavy metals in polylactic acid (PLA)/chitosan (CS) nanoparticles loading nifedipine. In addition, the In Vivo test of the PLA/CS nanoparticles loading nifedipine in the mice is also one of highlights of this work. The Zeta potential result shows that the charged surface of the PLA/CS nanoparticles loading nifedipine is neutral, negative or complex depending on nifedipine content. Nifedipine plays a role in increase of hydrophobic property, swelling degree and regular surface as well as decrease of surface rough of the nanoparticles. The PLA/CS/nifedipine nanoparticles are dissolved in the solutions with pH 6.8, pH 4.5 and pH 1.2. The In Vivo test of PLA/CS nanoparticles loading nifedipine on mice was evaluated by the change in diastolic pressure, systolic pressure, arterial pressure and heart rate. The obtained results confirm that the PLA/CS nanoparticles loading nifedipine is suitable to apply in the treatment of hypertension patients lately.

Biodegradable Inorganic Nanovector: Passive versus Active Tumor Targeting in siRNA Transportation.

The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system.

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.

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.

Fe3O4@polypyrrole core-shell nanohybrid for efficient DNA retrieval.

Core-shell nanohybrid, Fe3O4@PPY, which consists of superparamagnetic Fe3O4 core and DNA attractive polypyrrole, was successfully synthesized through the free radical polymerization. The DNA retrieval efficacy of the nanohybrid was found to be very high in DNA solution with low concentration (approximately 33% uptake in 100 microM).

Controlled release of donepezil intercalated in smectite clays.

The inorganic-organic hybrid for a drug delivery system was successfully realized by intercalating donepezil molecules into smectite clays (laponite XLG, saponite, and montmorillonite). According to the powder XRD patterns, TG profiles, and FT-IR spectra, it was confirmed that donepezil molecules were well stabilized in the interlayer space of clay via mono or double layer stacking. The adsorption amount and molecular structure of donepezil appeared to depend on the cation exchange capacity of the clay, which in turn, tailored the drug release patterns. Especially in the presence of a bulky cationic polymer (Eudragit E-100) in the release media, the release rate was found to be improved due to its effective replacement with intercalated donepezil molecules. Therefore, to formulate a complete drug delivery system, the hybrids were coated with Eudragit E-100 using a spray dryer, which also showed great enhancement in the release rate during a short period of time (180min).

One-pot synthetic route to polymer-silica assembled capsule encased with nonionic drug molecule.

A novel combinational drug delivery system, in which drug molecules could be dually encapsulated by soft (polymer) and hard (inorganic) vehicles has been successfully prepared via a simple one-pot synthesis; its improved chemotherapeutic efficacy has been verified through in vitro experiments.

Enhanced contrast of electrochromic full cell systems with nanocrystalline PEDOT-prussian blue.

Poly-(3,4-ethylenedioxythiophene) (PEDOT) is an ideal polymer for electrochromic (EC) devices due to its fast response time, high conductivity, and facile fabrication in a doped form except its demerit like an optical contrast limitation. In this study, we developed a simple way to overcome low coloration efficiency of PEDOT through fabricating a complementary PEDOT and prussian blue full cell system. Fundamental properties of EC displays, such as optical contrast, coloration efficiency, and switching speed, could be successfully optimized by controlling the deposition time and applied voltage during EDOT polymerization. In particular, UV transmittance spectra indicated that the optical contrast was enhanced up to 31 approximately 99% at the wavelength of 600 nm. Scanning electron microscopy images showed that the optimized PEDOT and prussian blue films were deposited on ITO glass substrate with an uniform thickness of approximately 180 nm and approximately 190 nm, respectively. Moreover, according to the circuit analysis, the average response time of electric current for the optimized full cell system was about 400 ms. It is, therefore, concluded that such a full cell system could have high potential applications as smart windows and/or optical devices.

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.

Layered double hydroxide as an efficient drug reservoir for folate derivatives.

Folic acid derivatives such as folinic acid and methotrexate (MTX) have been successfully hybridized with layered double hydroxide (LDH) by ion-exchange reaction. The X-ray diffraction patterns and spectroscopic analyses indicate that these molecules intercalated into the hydroxide interlayer space are stabilized in the tilted longitudinal monolayer mode by electrostatic interaction. No significant changes in their structural and functional properties are found in the hybrids. The cellular uptake test of MTX-LDH hybrid is carried out in the fibroblast (human tendon) and SaOS-2 cell line (Osteosarcoma, human) by in vitro MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide) assay. The initial proliferation of SaOS-2 cell is more strongly suppressed by treatment with MTX-LDH hybrid than with MTX alone. This study clearly shows that LDH not only plays a role as a biocompatible-delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency.

Drug-inorganic-polymer nanohybrid for transdermal delivery.

For transdermal drug delivery, we prepared a drug-inorganic nanohybrid (FB-LDH) by intercalating a transdermal model drug, flurbiprofen (FB), into the layered double hydroxides (LDHs) via coprecipitation reaction. The X-ray diffraction patterns and FT-IR spectra of the FB-LDH indicated that the FB molecules were successfully intercalated via electrostatic interaction within the LDH lattices. The in vitro drug release revealed that the Eudragit(®) S-100 in release media could facilitate the drug out-diffusion by effectively replacing the intercalated drug and also enlarging the lattice spacing of the FB-LDH. In this work, a hydrophobic gel suspension of the FB-LDH was suggested as a transdermal controlled delivery formulation, where the suspensions were mixed with varying amounts of Eudragit(®) S-100 aqueous solution. The Frantz diffusion cell experiments using mouse full-skins showed that a lag time and steady-state flux of the drug could be controlled from 12.8h and 3.28µgcm(-2)h(-1) to less than 1h and 14.57µgcm(-2)h(-1), respectively, by increasing the mass fraction of Eudragit(®) S-100 solution in gel suspensions from 0% to 20% (w/w), respectively. Therefore, we conclude gel formulation of the FB-LDH have a potential for transdermal controlled drug delivery.

Montmorillonite intercalated with glutathione for antioxidant delivery: synthesis, characterization, and bioavailability evaluation.

A most powerful antioxidant, glutathione (GSH), plays an important role in detoxification, immune response, and protection against reactive oxygen species. However, orally ingested GSH can be easily degradable to free amino acids by chemical and enzymatic hydrolysis, resulting in low bioavailability. The aim of this study was, therefore, to enhance GSH bioavailability by developing GSH-montmorillonite (MMT) hybrid system. It was also coated with polyvinylacetal diethylaminoacetate (AEA) for better stability. Both GSH-MMT and AEA-GSH-MMT hybrids were characterized by powder X-ray diffraction (PXRD), Fourier transformed infrared (FT-IR), and thermogravimetric analysis (TGA), indicating that GSH was successfully intercalated into the interlayer spaces of MMT. In vivo antioxidant activity assay revealed that AEA-GSH-MMT hybrid significantly increased antioxidant activity in the plasma after oral administration in mice. Pharmacokinetic study also indicated that AEA-GSH-MMT hybrid considerably increased the plasma concentration of GSH at 1h post-oral administration. Moreover, both the hybrid systems remarkably enhanced GSH delivery to the main target tissue, liver. All the results suggest that GSH-MMT hybrid systems have great potential to enhance bioavailability of oral GSH, providing new insight into their pharmaceutical application.

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.

A dual-polymer electrochromic device with high coloration efficiency and fast response time: poly(3,4-(1,4-butylene-(2-ene)dioxy)thiophene)-polyaniline ECD.

A new dual-polymer electrochromic device (ECD) composed of poly(3,4-(1,4-butylene-(2-ene)dioxy)thiophene) (PBueDOT) and polyaniline (PANI) with a hydrophobic molten salt electrolyte has been developed. To build this system, an alkylenedioxy ring in the BueDOT backbone was expanded to include a strongly electron-donating alkylenedioxy bridge, and the thickness and surface morphology of the corresponding PBueDOT film were controlled systematically. Not only the dual-electrochromic-polymer-electrode system, but also the expanded alkylenedioxy ring in the BueDOT backbone, synergistically improved the electrochromic performance. From the coloration efficiency (CE) value calculations, we found that the CE was enhanced up to 930 cm(2) C(-1). Furthermore, these ECDs showed an extremely fast response time of less than 80 ms.

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.