Evaluation of nanoherbal gel for anti-warts activity

In the present experimental investigation a novel nanoherbal gel containing iron nanoparticles and extract from Cuscuta reflexa was used as a drug. Synthesized nanoherbal increased the drug solubility and penetration in the skin and is useful as a novel delivery system for better anti-warts activity. The experimental work includes preformulation studies of drug (Cuscuta reflexa) which include organoleptic properties, identification and solubility studies. Spectroscopy characterization was performed for identification of drug. The iron nanoparticles were evaluated for their characteristic such as appearance, viscosity and odor. Various formulations F1–F5 was prepared using different formulation variables based on experiment design. The result showed that the formulation F-5 provide the better release using 5.5 pH acetate buffer and at 37 °C temperature for anti-warts activity. The maximum drug release through synthesized nanoherbal gel was found to be 91.3%. Nanoherbal formulation was evaluated for physical appearance, pH, consistency, spreadibility and drug content. Stability study of formulation F5 was carried out for a period of 3 months to determine the percentage release and the results revealed that the formulation is stable under varied humidity and temperature condition and there was no major change in the amount of drug release during the storage condition, which reflected the stability of F5 formulation.     

Improved peptide mass fingerprinting matches via optimized sample preparation in MALDI mass spectrometry

Peptide mass fingerprinting (PMF) is a powerful technique in which experimentally measured m/z values of peptides resulting from a protein digest form the basis for a characteristic fingerprint of the intact protein. Due to its propensity to generate singly charged ions, along with its relative insensitivity to salts and buffers, matrix-assisted laser desorption and ionization (MALDI)-time-of-flight mass spectrometry (TOFMS) is the MS method of choice for PMF. The qualitative features of the mass spectrum can be selectively tuned by employing different methods to prepare the protein digest and matrix for MALDI-TOFMS. The selective tuning of MALDI mass spectra in order to optimize PMF is addressed here. Bovine serum albumin, carbonic anhydrase, cytochrome c, hemoglobin alpha- and beta-chain, and myoglobin were digested with trypsin and then analyzed by MALDI-TOFMS. 2,5-dihydroxybenzoic acid (DHB) and alpha-cyano-4-hydroxycinnamic acid (CHCA) were prepared using six different sample preparation methods: dried droplet, application of protein digest on MALDI plate followed by addition of matrix, dried droplet with vacuum drying, overlayer, sandwich, and dried droplet with heating. Improved results were obtained for the matrix alpha-cyano-4-hydroxycinnamic acid using a modification of the died droplet method in which the MALDI plate was heated to 80 °C prior to matrix application, which is supported by observations from scanning electron microscopy. Although each protein was found to have a different optimum sample preparation method for PMF, in general higher sequence coverage for PMF was obtained using DHB. The best PMF results were obtained when all of the mass spectral data for a particular protein digest was convolved together.     

Development of a chemoenzymatic strategy for the synthesis of optically active and orthogonally protected polyamines

The chemical preparation and stereoselective enzymatic desymmetrization of a series of prochiral 2-substituted-1,3-propanediamines have been carried out using Pseudomonas cepacia lipase as biocatalyst. Syntheses of novel optically active orthogonally protected di- or triamines have been achieved for the first time with different grade of enantiodiscrimination depending on the C-2 substitution of the propane-1,3-diamine fragment. Final monoselective deprotection reactions of (S)-3-allyl-2-tert-butyl-1-(9-fluorenylmethyl)propane-1,2,3-triyltriscarbamate have allowed us to obtain a panel of novel enantiomerically enriched disubstituted triamines, compounds of difficult access by conventional synthetic methods.     

Topical Dosage Formulation of Lyophilized Philadelphus coronarius L. Leaf and Flower: Antimicrobial,Antioxidant and Anti-Inflammatory Assessment of the Plant

Philadelphus coronarius is a versatile plant and its use in folk medicine has a long tradition; however, scientifically, the medical utilization of the herb is a less explored research field. The aim of our study was to identify and determine the quantity of the bioactive compounds of both the leaf and the flower and prepare a lyophilized product of them, from which medical ointments were formulated, since the topical application of P. coronarius has also not been studied. In vitro drug release, texture analysis and biocompatibility experiments were carried out, as well as the investigation of microbiological, antioxidant and anti-inflammatory properties. According to our results the composition and the selected excipients of the ointments have a great impact on the drug release, texture and bioavailability of the preparation. During the microbiological testing, the P. coronarius leaf was effective against Escherichia coli and Staphylococcus aureus, but it did not significantly decrease IL-4 production when it was tested on HaCaT cells. P. coronarius is a promising herb, and its topical application in antimicrobial therapy can be a useful addition to modern medical therapy.     

Subtractive Genomics Approach to Identify Putative Drug Targets and Identification of Drug-like Molecules for Beta Subunit of DNA Polymerase III in Streptococcus Species

The prolonged use of the antibiotics over the years has transformed many organisms resistant to multiple drugs. This has made the field of drug discovery of vital importance in curing various infections and diseases. The drugs act by binding to a specific target protein of prime importance for the cell??s survival. Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes are the few gram positive organisms that have developed resistance to drugs. It causes pneumonia, meningitis, pharyngitis, otitis media, sinusitis, bacteremia, pericarditis, and arthritis infections. The present study was carried out to identify potential drug targets and inhibitors for beta subunit of DNA polymerase III in these three Streptococcus species that might facilitate the discovery of novel drugs in near future. Various steps were adopted to find out novel drug targets. And finally 3D structure of DNA polymerase III subunit beta was modeled. The ligand library was generated from various databases to find the most suitable ligands. All the ligands were docked using Molegro Virtual Docker and the lead molecules were investigated for ADME and toxicity.     

Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy

To fight against cancer, smarter drugs and drug delivery systems are required both to boost the efficiency of current treatments while reducing deleterious side effects, and combine diagnosis/monitoring with therapy (theranosis) in the search for the final goal of personalized medicine. This work presents the design, preparation, and proof-of-principle validation of a novel hybrid organic–inorganic nanocomposite joining together non-invasive imaging capabilities through magnetic resonance imaging and externally actuated therapeutic properties through a combination of chemo- and thermotherapy. The lipidic matrix of the nanocomposite was composed of carnauba wax, which was simultaneously dual loaded with magnetite nanoparticles and the anticancer drug Oncocalyxone A. Obtained formulations were fully characterized and showed outstanding performances as T₂-contrast agents in magnetic resonance imaging (r₂>800 mm ⁻¹ s⁻¹), heat generating sources in magnetic hyperthermia (specific absorption rate, SAR>200 W g⁻¹_Fe), and magnetically responsive drug delivery vehicles. The potential of the designed formulations as theranostic agents was validated in vitro and results indicated a synergistic thermo/chemotherapeutic effect derived from heat generation and controlled drug delivery to cancer growth. Thereby, this external control over the drug delivery profile and the integrated imaging capability open the door to personalized cancer medicine and real-time monitoring of tumor progression.     

Synthesis, characterization and bioevaluation of irinotecan-collagen hybrid materials for biomedical applications as drug delivery systems in tumoral treatments

The purpose of the present study is the preparation and characterization of collagen/antitumor drug hybrids as drug delivery systems. Materials used for obtaining collagen-based drug delivery systems were collagen type I (Coll) as matrix and irinotecan (I) as hydrophilic active substances. After incorporation of I into Coll in differing ratios, the obtained hybrid materials (Coll/I) could be used according to our results as potential drug delivery systems in medicine for the topical (local) treatment of cancerous tissues or bone. The released amount of I varies with amount of Coll from hybrid materials: the higher, the slower the release amount of irinotecan transferred is in the first 6 hours. The in vitro citotoxicity demonstrates an antitumoral activity of the obtained hybrid materials and their potential use for biomedical applications as drug delivery systems in tumoral treatments.      

Preparation and Characterization of a Novel Drug Delivery System: Biodegradable Nanoparticles in Thermosensitive Chitosan/Gelatin Blend Hydrogels

A novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels was developed for prolonged and sustained controlled drug release. Four different HTCC nanoparticles, prepared based on ionic process of HTCC and oppositely charged molecules such as sodium tripolyphosphate, sodium alginate and carboxymethyl chitosan, were incorporated physically into thermosensitive chitosan/gelatin blend solutions to form the novel DDSs. Resulting DDSs interior morphology was evaluated by scanning electron microscopy. The effect of nanoparticles composition on both the gel process and the gel strength was investigated from which possible hydrogel formation mechanisms were inferred. Finally, bovine serum albumin (BSA), used as a model protein drug, was loaded into four different HTCC nanoparticles to examine and compare the effects of controlled release of these novel DDSs. The results showed that BSA could be sustained and released from these novel DDSs and the release rate was affected by the properties of nanoparticle: the slower BSA release rate was observed from DDS containing nanoparticles with a positive charge than with a negative charge. The described injectable drug delivery systems might have great potential application for local and sustained delivery of protein drugs.     

Density functional and molecular docking studies towards investigating the role of single-wall carbon nanotubes as nanocarrier for loading and delivery of pyrazinamide antitubercular drug onto pncA protein

The potential biomedical application of carbon nanotubes (CNTs) pertinent to drug delivery is highly manifested considering the remarkable electronic and structural properties exhibited by CNT. To simulate the interaction of nanomaterials with biomolecular systems, we have performed density functional calculations on the interaction of pyrazinamide (PZA) drug with functionalized single-wall CNT (fSWCNT) as a function of nanotube chirality and length using two different approaches of covalent functionalization, followed by docking simulation of fSWCNT with pncA protein. The functionalization of pristine SWCNT facilitates in enhancing the reactivity of the nanotubes and formation of such type of nanotube-drug conjugate is thermodynamically feasible. Docking studies predict the plausible binding mechanism and suggests that PZA loaded fSWCNT facilitates in the target specific binding of PZA within the protein following a lock and key mechanism. Interestingly, no major structural deformation in the protein was observed after binding with CNT and the interaction between ligand and receptor is mainly hydrophobic in nature. We anticipate that these findings may provide new routes towards the drug delivery mechanism by CNTs with long term practical implications in tuberculosis chemotherapy.     

Synthesis and Characterization of Sterculia Gum Based pH Responsive Drug Delivery System for Use in Colon Cancer

The present study deals with the modification of sterculia gum to develop the novel colon specific delivery system for use in colon cancer. The sterculia and acrylic acid based hydrogels were synthesized and characterized with FTIR, SEMs, TGA and swelling behavior. Swelling studies of the hydrogels were carried out as a function of reaction parameters such as monomer concentration, initiator concentration, amount of sterculia gum and crosslinker concentration and nature of swelling mediums. Swelling kinetics of the hydrogels and in vitro release dynamics of anticancer model drug methotrexate from the hydrogels were studied to evaluate the swelling mechanism and drug release mechanism from the drug-loaded hydrogels. The values of diffusion exponent for the release of drug were 0.883, 0.910 and 0.787 in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The release of drug from the polymer matrix occurred through a non -Fickian type diffusion mechanism.     

Monte carlo simulation of diffusion-limited drug release from finite fractal matrices

How fast can drug molecules escape from a controlled matrix-type release system? This important question is of both scientific and practical importance, as increasing emphasis is placed on design considerations that can be addressed only if the physical chemistry of drug release is better understood. In this work, this problem is studied via Monte Carlo computer simulations. The drug release is simulated as a diffusion-controlled process. Six types of Menger sponges (all having the same fractal dimension, d _f = 2.727, but with different values of random walk dimension, d _w ∈ [2.028, 2.998]) are employed as models of drug delivery devices with the aim of studying the consequences of matrix structural properties (characterized by d _f and d _w ) on drug release performance. The results obtained show that, in all cases, drug release from Menger sponges follows an anomalous behavior. Finally, the influence of the matrix structural properties on the drug release profile is quantified.     

Designing of pH-responsive ketorolac tromethamine loaded hydrogels of alginic acid: Characterization,in-vitro and in-vivo evaluation

pH-responsive hydrogels based on alginic acid grafted with acrylic acid and ethylene glycol dimethylacrylate in the presence of ammonium persulfate were developed for controlled delivery of Ketorolac tromethamine. The alginic acid based hydrogels were prepared by free radical polymerization technique. Increase in gel fraction was observed with the increase in alginic acid, acrylic acid, and ethylene glycol dimethylacrylate content. The dynamic swelling and drug release studies were conducted at two different pH values (pH 1.2 and 7.4). Maximum swelling and drug release were observed at pH 7.4. The characterization of prepared hydrogels was carried out by using Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, powder x-ray diffraction, and scanning electron microscopy. Similarly, in-vivo study was performed on rabbits and greater plasma drug concentration was achieved by fabricated hydrogels as compared to drug solution and commercial product Keten. Conclusively, the fabricated hydrogels can be considered as a potential candidate for controlled delivery of Ketorolac tromethamine.     

An efficient mixed solid-liquid phase synthesis of a heterobifunctional amphiphilic PEG-NH2 derivative and its conjugation to folic acid

A very efficient, versatile as well as simple to perform procedure was developed in order to prepare a heterobifunctional amphiphilic PEG-NH₂ derivative which can be used for conjugation to a targeting ligand (such as folic acid). This method proceeds by a mixed solid-liquid phase strategy using a TentaGel^® PAP resin, a copolymer consisting of a polystyrene matrix on which a PEG (M_w 3400 Da) terminated by an amino function has been grafted. Solid phase chemistry was used for the conjugation of a highly hydrophobic moiety. After release from the resin, the amphiphilic PEG-OH conjugate was converted into its corresponding amphiphilic PEG-NH₂ derivative (four steps in 77% overall yields). This procedure allowed the preparation of ∼330 mg batches. This derivative was then coupled to folic acid, a ligand that is used for the targeting of drug (gene) carrier and delivery systems to cells over-expressing the folate receptor. The low and high molecular weight of folic acid and its amphiphilic PEG-folate conjugate, respectively, allowed easy purification by dialysis and led to the targeted compound with high recovery.     

The role of the cage dimer of formaldehyde in the photolysis of formaldehyde: Argon matrix at 12 K

Photolysis of H₂CO was carried out in an Ar matrix with different matrix ratios (M/R). The infrared (IR) absorption spectra of the initial matrix preparation show that the matrix isolated monomers are almost exclusively present at very high dilutions (M/R or 5000) whereas the cage dimers and higher multimers are present in significant amounts at lower dilutions. The post-photolysis IR spectra indicate that the photodecomposition of H₂CO is mainly effected with the cage dimer, and that CH₃OH and CO are formed as photoproducts. The majority of the photoproducts exist as cage dimers of CH₃OH/CO. Upon thermal annealing after photolysis, diffusion through the matrix leads to the additional formation of aggregates composed of CH₃OH/H₂CO as well as CH₃OH/CO.     

Synthesis and characterization of a pH responsive and mucoadhesive drug delivery system for the controlled release application of anti-cancerous drug

In this work a novel pH sensitive composite, polyacrylamide grafted succinyl chitosan intercalated bentonite (AAm-g-NB/SC) was prepared as a drug carrier system for the controlled delivery of paclitaxel. Characterization of the drug delivery system was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal analysis etc. The equilibrium swelling behaviour of the composite was studied and the result showed a maximum at pH 7.4. The in vitro drug release study of paclitaxel indicated that about 15.6% of drug release was found to be occurred at pH 1.2 within 16 h, whereas about 82.5% of drug release was occurred at the intestinal pH condition of 7.4. In vitro biocompatibility study was performed and the result showed good biocompatibility of the composite in the concentration range 6.25–100 µg/mL. The cytotoxicity assay was carried out in cancerous cell line of Human colorectal Adenocarcinoma. Mucous glycoprotein assay study showed that the drug delivery system having good apparent adhering property towards mucin. The investigation indicated that paclitaxel, an anticancer drug can be successfully entrapped in the AAm-g-NB/SC composite for the controlled and targeted delivery for colorectal cancer therapy.     

Preparation,Characterization, and Evaluation of Liposomes Containing Oridonin from Rabdosia rubescens

Due to the remarkable anti-tumor activities of oridonin (Ori), research on Rabdosia rubescens has attracted more and more attention in the pharmaceutical field. The purpose of this study was to extract Ori from R. rubescens by ultrasound-assisted extraction (UAE) and prepare Ori liposomes as a novel delivery system to improve the bioavailability and biocompatibility. Response surface methodology (RSM), namely Box-Behnken design (BBD), was applied to optimize extraction conditions, formulation, and preparation process. The results demonstrated that the optimal extraction conditions were an ethanol concentration of 75.9%, an extraction time of 35.7 min, and a solid/liquid ratio of 1:32.6. Under these optimal conditions, the extraction yield of Ori was 4.23 mg/g, which was well matched with the predicted value (4.28 mg/g). The optimal preparation conditions of Ori liposomes by RSM, with an ultrasonic time of 41.1 min, a soybean phospholipids/drug ratio of 9.6 g/g, and a water bath temperature of 53.4 °C, had higher encapsulation efficiency (84.1%). The characterization studies indicated that Ori liposomes had well-dispersible spherical shapes and uniform sizes with a particle size of 137.7 nm, a polydispersity index (PDI) of 0.216, and zeta potential of −24.0 mV. In addition, Ori liposomes presented better activity than free Ori. Therefore, the results indicated that Ori liposomes could enhance the bioactivity of Ori, being proposed as a promising vehicle for drug delivery.     

Investigation of the effects of 24 bio-matrices on the LC-MS/MS analysis of morinidazole

This study compares and evaluates the effect of various matrices on liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS) analysis. Permanent post-column infusion (PCI) was used to quantify matrix effects. In this way, the suppressed or enhanced signal of the target material resulting from different co-eluting matrix components could be assessed. Twenty-four biological samples from in vivo and in vitro experiments were selected for this study. In addition, 7 sample components were further analyzed after sample preparation by protein precipitation. Multiple regression analysis was used to investigate the collinear relationship between matrix effects and co-eluted components at different time intervals. We found that salt was the dominant factor which impacted changes in signal detection. In order to eliminate it, we used ammonium formate as a modifier of the mobile phase which resulted in charge-state redistribution profiles so that a homogeneous matrix formed. By employing pulse gradient chromatography in the presence of 5 mM ammonium formate, favorable improvements of enhanced signal intensity and reduced matrix effects were obtained. These experiments also indicated the feasibility of using analogue IS during bio-analysis which contributed to an overall faster assay that would be suitable for drug discovery and development purposes.     

Design and synthesis of hyaluronan-mimetic gemini disaccharides

An efficient strategy has been designed for the preparation of synthetic mimics of hyaluronan (HA, 1) and its dimerized (Gemini) disaccharides (2a,b) via n-pentenyl glycoside formation. Construction of the target molecules was achieved through a combination of protection/deprotection protocols, imidate glycosylation methodology followed by ozonolysis, and reductive amination. These tailored synthetic mimics could act as versatile building blocks with therapeutic applications in tissue engineering, treatment of cancer and as drug delivery agents.     

A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

The antibody–drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this has been challenging to carry out; with few exceptions, increasing the drug-to-antibody ratio (DAR) above ∼4 typically destroys the biophysical properties and in vivo efficacy for ADCs. Herein, we describe the development of a novel bioconjugation platform combining cysteine-engineered (THIOMAB) antibodies and recombinant XTEN polypeptides for the unprecedented generation of homogeneous, stable “TXCs” with DAR of up to 18. Across three different bioactive payloads, we demonstrated improved AMD to tumors and Staphylococcus aureus bacteria for high-DAR TXCs relative to conventional low-DAR ADCs.

Efficiency of targeted cell delivery of small molecules was enhanced in cells and animals via a novel well-defined bioconjugation platform combining site-specific antibody conjugation and XTEN polypeptides to enable high payload loading.