Chemotherapeutic Agent-Induced Vulvodynia, an Experimental Model.

Vulvodynia is a chronic clinical condition associated with vulvar pain that can impair the sexual, social, and psychological life of women. There is a need for more research to develop novel strategies and therapies for the treatment of vulvodynia. Vulvodynia in experimental animal models induced via infections, allergens, and diabetes are tedious and with lessor induction rate. The objective of the study was to explore the possibility of inducing vulvodynia using a chemotherapeutic agent in a rodent model. Paclitaxel is commonly used in treating breast and ovarian cancer, whose dose-limiting side effect is peripheral neuropathy. Studies have shown that peripheral neuropathy is one of the etiologies for vulvodynia. Following paclitaxel administration (2 mg/kg i.p.), the intensity of vulvar hypersensitivity was assessed using a series of von Frey filaments (0.008 to 1 g) to ensure the induction of vulvodynia. Vulvodynia was induced from day 2 and was well sustained for 11 days. Furthermore, the induced vulvodynia was validated by investigating the potentiation of a flinch response threshold, upon topical application and systemic administration of gabapentin, a commonly used medication for treating neuropathic pain. The results demonstrate that vulvodynia was induced due to administration of paclitaxel. The fact that chemotherapeutic agent-induced vulvodynia was responsive to topical and parenterally administered gabapentin provides validity to the model. The study establishes a new, relatively simple and reliable animal model for screening drug molecules for vulvar hypersensitivity.

Insight into hydroxyl radical-mediated cleavage of caged methylene blue: the role of Fenton's catalyst for antimalarial hybrid drug activation.

Methylene blue with a 10-N carbamoyl linkage was reported to be a hydroxyl radical triggered cleavable ligand. Probed by this platform, hemoproteins were demonstrated to be a much more efficient Fenton's catalyst than commonly used inorganic Fe(ii) salts. The applicability of this ligand was demonstrated through the capability of being triggered by elevated reactive oxygen species levels at diseased tissue, with malaria-parasitized erythrocytes as an in vitro model.

Methylene blue as a far-red light-mediated photocleavable multifunctional ligand.

Methylene blue (MB) with a 10-N-carbamoyl linkage was discovered and developed as a multifunctional far-red (660 nm) photocleavable ligand capable of rendering a series of MB-conjugated compounds with off-to-on fluorescence switch properties through the controlled release of MB.

Doxycycline Release of Dental Implants With Nanotube Surface, Coated With Poly Lactic-Co-Glycolic Acid for Extended pH-controlled Drug Delivery.

When dental implants become infected, the progression of the disease is rapid. Commercially available dental implant surfaces can be easily contaminated, resulting in rapid progression of peri-mucositis and peri-implantitis. The aim of this study was to evaluate, in vitro, the pattern of doxycycline release from by dental implants with titanium nanotube surface (DINS) at different pHs to examine novel drug loading and chemical coating techniques. Nine DINS were loaded with doxycycline and subsequently coated with polylactic-co-glycolic acid (PLGA). High-performance liquid chromatography (HPLC) was used to measure the amounts of released doxycycline in a 30-day period. Cytotoxicity of the DINS was evaluated by an assay using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT). The results showed that the experimental DINS coated with doxycycline and PLGA showed a mean drug release during the experimental period for the groups: pH 7.4 (8.39 µg/mL), pH 6.4 (8.63 µg/mL). The pH 5.4 (15.18 µl/mL) doxycycline release from DINS was faster at pH 5.4 than those at pHs 6.4 and 7.4 (P = .0031 and .0034, respectively). This new surface treatment of dental implants with titanium nanotubes and subsequent drug loading demonstrated biocompatibility and sustained doxycycline release over a 30-day period. Additional studies are needed in order to adopt a stable drug release at neutral pH environment while warranting a constant drug release in an acidic pH environment.

Pluronic-based dual-stimuli sensitive polymers capable of thermal gelation and pH-dependent degradation for in situ biomedical application.

Thermo-sensitive hydrogels are considered ideal for applications in the biomedical fields for their biocompatibility, flexibility, tissue-like water content, and reversible gelation property. By adjusting sufficient hydrophilic-hydrophobic balance in block copolymer structure, thermogel's critical gelation temperature can be modified to be near the physiological temperature, which makes it an appealing candidate for in situ gel depot. In this study, we report successful syntheses of novel multiple block copolymer compounds, denoted as dual-stimuli sensitive polymers (DSSPs), by copolymerizing Pluronic® P104 (7,100 Da) and 2,2-bis(aminoethoxy)propane (BAP) using diisocyanate linkers, L-lysine ethyl ester diisocyanate (DSSP-1) and 1,6-hexamethylene diisocyanate (DSSP-2). Through effective elongation of polymer chain lengths (DSSP-1: 41,760 Da, DSSP-2: 41,230 Da), Pluronic® P104's reversible thermal gelation properties were enhanced, as demonstrated by lowered critical gelation temperatures (DSSP-1: 36°C, DSSP-2: 38.7°C; 15 wt.%) that is near the physiological temperature. Furthermore, integration of acid-labile BAP allowed rapid pH-dependent degradation of the polymer, which was displayed by gel permeation chromatography (GPC) and release profiles of nile red and irinotecan from polymeric micelles and gels, respectively.

A highly GSH-sensitive SN-38 prodrug with an "OFF-to-ON" fluorescence switch as a bifunctional anticancer agent.

SN-38 (7-ethyl-10-hydroxy-camptothecin) is an active metabolite of irinotecan (CPT-11) and the most potent camptothecin analogue. In this study, 2,4-dinitrobenzene sulfonyl (DNS) was covalently conjugated as a GSH-sensitive trigger to 10'-OH of SN-38 to yield a GSH-sensitive prodrug, denoted as DNS-SN38, with virtually quenched fluorescence due to donor-excited photo-induced electron transfer (d-PeT). By investigating DNS-SN38's activation properties upon fluorescence restoration and cytotoxic potency against ovarian cancer cell lines (A2780 and m-Cherry + OCSC1-F2), its potential applicability as a useful chemotherapeutic agent was demonstrated.

Hemopressin-Based pH-Sensitive Hydrogel: A Potential Bioactive Platform for Drug Delivery.

Peptides with proper sequences are capable of self-assembling into well-defined nanostructures, which can subsequently grow and entangle into three-dimensional nanomatrices. In this study, hemopressin, a cannabinoid receptor-modulating peptide derived from the α-chain of hemoglobin known to self-assemble into nanofibrils, was examined for its potential applicability as a gelator. The results indicated that hemopressin's gel formation was dependent on pH and salt concentration. Although hemopressin's macroscopic states showed differences, its microscopic structure remained largely unchanged in which it consisted mainly of the antiparallel ß-sheet conformation as confirmed by FTIR (C=O stretch peaks at 1630 and 1695 cm-1) and CD (ß-sheet peak at 195 nm). The major difference between the gel and sol states was displayed in the fibril length in which the gelation at pH 7.4 resulted in 4 µm fibrils, whereas the solution at pH 5.0 showed 800 nm fibrils. The pH-dependent sol-gel phase transition property was then utilized for the investigation of the pH-responsive release of FITC-dextran (4-40 kDa) from hemopressin fibrillary gel. Finally, the biocompatibility of the peptide was demonstrated by proliferation assay of cultured bone marrow mesenchymal stem cells. Altogether, the results suggested that hemopressin is a potentially promising candidate as a therapeutically active platform for drug delivery.

Novel Biodegradable Polymer with Redox-Triggered Backbone Cleavage Through Sequential 1,6-Elimination and 1,5-Cyclization Reactions.

In the past decade, the self-immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self-immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox-sensitive polymer that can systemically degrade via sequential 1,6-elimination and 1,5-cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles.

Solid-state characterization of Felodipine-Soluplus amorphous solid dispersions.

The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus® (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters. The solubility of FEL within SOL was determined to be in the range of 6.2-9.9% (w/w). Various techniques were applied to characterize the solid-state properties of the amorphous SDs. These included Fourier Transform Infrared Spectrometry spectroscopy and Raman spectroscopy to detect the formation of hydrogen bonding between the drug and the polymer. Scanning electron microscopy was performed to study the morphology of the SDs. Among all the hot-melt extrudates, FEL was found to be molecularly dispersed within the polymer matrix for the extrudates containing 10% drug, while few small crystals were detected in the 30 and 50% extrudates. In conclusion, solubility of FEL was enhanced while a homogeneous SD was achieved for 10% drug loading.

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization.

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG750) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG750. PolyQPA-mPEG750 was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by (1)H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG750 underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG750 polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.

Nitroreductase-triggered activation of a novel caged fluorescent probe obtained from methylene blue.

A near-infrared fluorescent probe based on methylene blue (p-NBMB) was developed for the detection of nitroreductase. Conjugating methylene blue with a p-nitrobenzyl moiety enables it to be activated by nitroreductase-catalyzed 1,6-elimination, resulting in the release of an active methylene blue fluorophore.

Investigation of phase diagrams and physical stability of drug-polymer solid dispersions.

Solid dispersion technology has been widely explored to improve the solubility and bioavailability of poorly water-soluble compounds. One of the critical drawbacks associated with this technology is the lack of physical stability, i.e. the solid dispersion would undergo recrystallization or phase separation thus limiting a product's shelf life. In the current study, the melting point depression method was utilized to construct a complete phase diagram for felodipine (FEL)-Soluplus® (SOL) and ketoconazole (KTZ)-Soluplus® (SOL) binary systems, respectively, based on the Flory-Huggins theory. The miscibility or solubility of the two compounds in SOL was also determined. The Flory-Huggins interaction parameter χ values of both systems were calculated as positive at room temperature (25 °C), indicating either compound was miscible with SOL. In addition, the glass transition temperatures of both solid dispersion systems were theoretically predicted using three empirical equations and compared with the practical values. Furthermore, the FEL-SOL solid dispersions were subjected to accelerated stability studies for up to 3 months.

Controlled-release injectable containing terbinafine/PLGA microspheres for onychomycosis treatment.

Controlled-release drug delivery systems based on biodegradable polymers have been extensively evaluated for use in localized drug delivery. In the present study, intralesionally injectable poly (lactide-co-glycolide) (PLGA) microspheres for controlled release of terbinafine hydrochloride (TH) was developed for treating fungal toe/finger nail infections. TH-PLGA microspheres were formulated using O/W emulsification and modified solvent extraction/evaporation technique. Microspheres were evaluated for particle size and size distribution, encapsulation efficiency, surface, and morphology. The in vitro drug release profile was studied in aqueous media as well as in 1% agar gel. Microspheres system was also evaluated in excised cadaver toe model, and extent of TH accumulation in nail bed, nail plate, and nail matrix was measured at different time points. Microspheres were found to provide consistent and sustained TH release. Intralesional administration of controlled-release microspheres can be a potential alternative mode of treating fungus-infected toe and/or finger nails.

Minimally invasive transdermal delivery of iron-dextran.

Iron deficiency is one of the most prevalent and serious health issues among people all over the world. Iron-dextran (ID) colloidal solution is one among the very few US Food and Drug Administration (FDA)-approved iron sources for parenteral administration of iron. Parenteral route does not allow frequent administration because of its invasiveness and other associated complications. The main aim of this project was to investigate the plausibility of transdermal delivery of ID facilitated by microneedles, as an alternative to parenteral iron therapy. In vitro permeation studies were carried out using freshly excised hairless rat abdominal skin in a Franz diffusion apparatus. Iron repletion studies were carried out in hairless anemic rat model. The anemic rats were divided into intact skin (control), microneedle pretreated, and intraperitoneal (i.p.) groups depending on the mode of delivery of iron. The hematological parameters were measured intermittently during treatment. There was no improvement in the hematological parameters in case of control group, whereas, in case of microneedle pretreated and i.p. group, there was significant improvement within 2-3 weeks. The results suggest that microneedle-mediated delivery of ID could be developed as a potential treatment method for iron-deficiency anemia.

Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion.

The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH.

Microporation and 'iron'tophoresis for treating iron deficiency anemia.

PURPOSE: Iontophoretic mediated transdermal delivery of ferric pyrophosphate (FPP) in combination with microneedle pretreatment was investigated as a potential treatment for iron deficiency anemia (IDA). METHODS: In vitro transdermal delivery studies were performed using hairless rat skin and pharmacodynamic studies were performed in hairless anemic rat model. The hematological and biochemical parameters like hemoglobin, hematocrit and % serum transferrin were monitored in rats at healthy, anemic condition and post treatment. Micropores created by the microneedles were visualized in histological skin sections after staining with hemotoxylin and eosin. The recovery of micropores was investigated in vivo by measuring Transepidermal water loss (TEWL) at different time points. RESULTS: The passive, microneedle and iontophoresis mediated delivery did not lead to significant improvement in hematological and biochemical parameters in anemic rats, when used individually. When iontophoresis (0.15 mA/cm(2) for 4 hours) was combined with microneedle pretreatment (for 2 min), therapeutically adequate amount of FPP was delivered and there was significant recovery of rats from IDA. CONCLUSIONS: Microneedle and iontophoresis mediated delivery of iron via transdermal route could be developed as a potential treatment for IDA. The transdermal controlled delivery of iron could become a potential, safe and effective alternative to parenteral iron therapy.

Redox-sensitive polymeric nanoparticles for drug delivery.

Bioresponsive polymeric nanoparticles have been extensively pursued for the development of tumor-targeted drug delivery. A novel redox-sensitive biodegradable polymer with "trimethyl-locked" benzoquinone was synthesized for the preparation of paclitaxel-incorporated nanoparticles. The synthesized redox-sensitive nanoparticles released paclitaxel in response to chemically triggered reduction.

Drug release from a pH-sensitive multiblock co-polymer thermogel.

A Pluronic(®)-based pH-sensitive multiblock co-polymer thermogel has been proposed for sustained release of therapeutic agents. Hydrophobic small-molecule drugs (paclitaxel and camptothecin) and model hy-drophilic macromolecules (fluorescein-labeled dextrans of molecular mass 10, 20, 40, 150 and 250 kDa) were successfully loaded into and released from the thermogels. Drug-loaded polymer solutions were characterized for gelation behavior and micelle size. Drug loading increased the size of the multiblock co-polymer micelles from 20 to 100 nm. The co-polymer improved paclitaxel and camptothecin loading in an aqueous solution by 6900- and 1050-fold, respectively, compared to their solubility in water. The ther-mogels released loaded drugs in a pH-dependent fashion, regardless of their properties. At pH 5.0 and 6.5, paclitaxel and camptothecin completely released in 4 and 15 days, respectively, by a combined mechanism of diffusion and erosion. At neutral pH, diffusion predominated gel erosion to sustain the drug release up to 40 days. Fluorescein-labeled dextran release from the thermogels showed a similar pH-dependent trend as the hydrophobic small molecule drugs. However, dextran release at neutral pH was entirely dependent on the molecular mass of the dextran. Low-molecular-mass (10 and 20 kDa) dextrans were completely released in 12 and 21 days, respectively, while high-molecular-mass (⩾40 kDa) dextrans being continuously released over 36 days, indicating that the threshold of molecular weight necessary for sustained release of a hydrophilic macromolecule from this thermogel (e.g., enzymes, monoclonal antibodies and immunotoxins) is 40 kDa. Taken together, the MBCP thermogel showed potential as a controlled drug-delivery system that showed sustained release of both hydrophilic and lipophilic molecules.

NONOates--polyethylenimine hydrogel for controlled nitric oxide release and cell proliferation modulation.

In recent years, numerous research activities have been devoted to the controlled release of nitric oxide (NO) due to its potential as a restenosis inhibitor which inhibits the proliferation of vascular smooth muscle cells, the apoptosis of vascular endothelial cells, and aggregation of platelets. This work has demonstrated the development of a novel NO-conjugated gel system comprising of thermosensitive Pluronic F127, branched polyethylenimine (BPEI), and diazeniumdiolates (NONOates). Synthesis of conjugated Pluronic-BPEI-NONOates involved coupling of activated F127 to BPEI followed by the installation of NONOates at the secondary amine sites of branched PEI backbone under high pressure. NO-conjugated gel system, F127-BPEI-NONOates, reduced the initial burst of NO release and prolonged NO release. Furthermore, F127-BPEI-NONOates polymer coated on cell culture dish displayed much higher increase of endothelial cell proliferation and reduction of smooth muscle cell proliferation than that exhibited by non-NO releasing control. Such an NO-releasing device can operate locally and has a great potential in several biomedical applications due to high biocompatibility imparted by the conjugated F127.

Matrix metalloproteinase-sensitive thermogelling polymer for bioresponsive local drug delivery.

Development of a successful bioresponsive drug delivery system requires exquisite engineering of the materials so that they are able to respond to signals stemming from the physiological environment. In this study we propose a new Pluronic(®) based thermogelling system containing matrix metalloproteinase-2 (MMP2) responsive peptide sequences. A novel thermosensitive multiblock co-polymer comprising an MMP2-labile octapeptide (Gly-Pro-Val-Gly-Leu-Ile-Gly-Lys) was synthesized from a Pluronic(®) triblock co-polymer. The polymer was designed to form a thermogel at body temperature and degrade in the presence of MMP overexpressed in a tumor. The synthesized polymer was a multiblock co-polymer with ∼2.5 U of Pluronic(®). The multiblock co-polymer solutions exhibited reverse thermal gelation around body temperature. The gelation temperatures of the multiblock co-polymer solutions were lower than those of the corresponding Pluronic(®) monomer at a particular concentration. The cytotoxicity of the synthesized polymer was lower compared with the monomer. The solubility of the hydrophobic anticancer drug paclitaxel was enhanced in the polymer solutions by micelle formation. The synthesized polymer was preferentially degraded in the presence of MMP. Paclitaxel release was dependent on the enzyme concentration. These findings suggest that the synthesized polymer has potential as a controlled drug delivery system due to its unique phase transition and bioresponsive behavior.