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1.
Tian Luo Johannes Magnusson Véronique Préat Raphael Frédérick Cameron Alexander Cynthia Bosquillon Rita Vanbever 《Pharmaceutical research》2016,33(7):1671-1681
Purpose
Pulmonary drug delivery is considered an attractive route of drug administration for lung cancer chemotherapy. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lung. Therefore, achieving a sustained presence of chemotherapeutics in the lung is very challenging. In this study, we synthesized two different polyethylene glycol-paclitaxel ester conjugates with molecular weights of 6 and 20 kDa in order to achieve sustained release of paclitaxel in the lung.Methods
One structure was synthesized with azide linker using “click” chemistry and the other structure was synthesized with a succinic spacer. The physicochemical and biological properties of the conjugates were characterized in vitro.Results
Conjugation to polyethylene glycol improved the solubility of paclitaxel by up to four orders of magnitude. The conjugates showed good stability in phosphate buffer saline pH 6.9 (half-life ≥72 h) and in bronchoalveolar lavage (half-life of 3 to 9 h) at both molecular weights, but hydrolyzed quickly in mouse serum (half-life of 1 to 3 h). The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than free paclitaxel or Taxol, the commercial paclitaxel formulation.Conclusions
These properties imply that the conjugates have the potential to retain paclitaxel in the lung for a prolonged duration and to sustain its release locally for a better efficacy.2.
Purpose
To develop a biomaterial composite for promoting proliferation and migration of neural stem cells (NSCs), as well as angiogenesis on the materials, to rescue central nervous system (CNS) injuries.Methods
A delivery system was constructed based on cross-linked hyaluronic acid (HA) hydrogels, containing embedded BDNF and VEGF-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery and support for NSCs in the CNS. The surface morphologies were evaluated by SEM and AFM, mechanical property was investigated by rheological tests, and release kinetics were performed by ELISA. Bioactivity of released BDNF and VEGF was assessed by neuron and endothelial cell culture, respectively. Compatibility with NSCs was studied by immunofluorescent staining.Results
Release kinetics showed the delivery of BDNF and VEGF from PLGA microspheres and HA hydrogel composite were sustainable and stable, releasing ~20–30% within 150 h. The bioactivities preserved well to promote survival and growth of the cells. Evaluation of structure and mechanical properties showed the hydrogel composite possessed an elastic scaffold structure. Biocompatibility assay showed NSCs adhered and proliferated well on the hydrogel.Conclusions
Our created HA hydrogel/PLGA microsphere systems have a good potential for controlled delivery of varied biofactors and supporting NSCs for brain repair and implantation.3.
Antony V. Samrot Ujjala Burman Padmanaban S P. Yamini Arul Maximus Rabel 《Toxicology and Environmental Health Sciences》2018,10(3):162-167
Objective
To evaluate the toxicity of the silver nanoparticle against earthworms - Eudrilus eugeniae, a model for soil organism.Methods
Silver nanoparticles were synthesised by chemical reduction and further characterised by UV Visible Spectroscopy and FeSEM. Earthworms were allowed to interact with different concentrations of the synthesized silver nanoparticles. After exposure period, histology and inductively coupled plasma optical emission spectrometry (ICP-OES) were done to determine the accumulation and toxic effects exhibited by the nanoparticle on earthworms.Results
The synthesized nanoparticle was found to be between the size of 180 and 200 nm. Histology studies revealed that silver nanoparticles to cause fibrosis, lipofuscin-like deposits and also gut disruption in earthworms.Conclusion
Silver nanoparticles were found to be toxic to Eudrilus eugeniae, which was evidenced by histology.4.
Dirk Bauerschlag Ivo Meinhold-Heerlein Nicolai Maass Andreas Bleilevens Karen Bräutigam Wa’el Al Rawashdeh Stefano Di Fiore Anke Maria Haugg Felix Gremse Julia Steitz Rainer Fischer Elmar Stickeler Stefan Barth Ahmad Fawzi Hussain 《Pharmaceutical research》2017,34(4):696-703
Purpose
Targeted theranostics is an alternative strategy in cancer management that aims to improve cancer detection and treatment simultaneously. This approach combines potent therapeutic and diagnostic agents with the specificity of different cell receptor ligands in one product. The success of antibody drug conjugates (ADCs) in clinical practice has encouraged the development of antibody theranostics conjugates (ATCs). However, the generation of homogeneous and pharmaceutically-acceptable ATCs remains a major challenge. The aim of this study is to detect and eliminate ovarian cancer cells on-demand using an ATC directed to EGFR.Methods
An ATC with a defined drug-to-antibody ratio was generated by the site-directed conjugation of IRDye®700 to a self-labeling protein (SNAP-tag) fused to an EGFR-specific antibody fragment (scFv-425).Results
In vitro and ex vivo imaging showed that the ATC based on scFv-425 is suitable for the highly specific detection of EGFR+ ovarian cancer cell, human tissues and ascites samples. The construct was also able to eliminate EGFR+ cells and human ascites cells with IC50 values of 45–66 nM and 40–90 nM, respectively.Conclusion
Our experiments provide a framework to create a versatile technology platform for the development of ATCs for precise detection and treatment of ovarian cancer cells.5.
Purpose
In the present investigation, we prepared and evaluated the paclitaxel loaded riboflavin and thiamine conjugated multi walled carbon nanotubes (PTX-Rf-MWCNTs and PTX-Tm-MWCNTs) for targeted delivery to cancer employing MCF-7 cancer cell lines.Methods
The developed conjugates were characterized using FTIR, NMR spectroscopy, electron microscopy drug loading, release, stability, hemolytic, ex vivo and in vivo studies etc.Results
The percent entrapment efficiency was found to be 87.92?±?0.48 and 82.75?±?0.47% of PTX-Tm-MWCNTs, PTX-Rf-MWCNTs, respectively. The percent hemolysis of purified MWCNTs, PTX-MWCNTs, PTX-Tm-MWCNTs and PTX-Rf-MWCNTs was found to be 20.49?±?0.97, 37.39?±?0.78, 14.61?±?0.84 and 11.17?±?0.77% respectively. The PTX-Tm-MWCNTs and PTX-Rf-MWCNTs showed more cytotoxic effect as compared to PTX and PTX-MWCNTs with PTX-Rf-MWCNTs exhibiting the maximum cytotoxic potential.Conclusion
Thus in final outcome, we concluded that the riboflavin and thiamine conjugated MWCNTs shown great promising potential in the treatment of cancer, but more exhaustive data is needed in future.6.
Julie Babyar 《Journal of pharmaceutical innovation》2017,12(2):185-187
Purpose
The purpose of this perspective piece is to address the potential for drug and medical product innovation through sound regulation and strengthened international harmonization.Methods
Current literature, recommendations and guidelines in regulatory agencies assisted in this perspective review.Results
Multiple guidelines and recommendations provide for strategic planning and process improvement capabilities at local, national and international levels.Conclusions
Seeking best practice starts with identifying and improving individual nation drug regulatory bodies, including the US Food and Drug Administration (FDA). Inefficiency causes and process improvement solutions have been suggested and outlined in strategic plans at the FDA as well as with multiple stakeholder organizations and public-private partnerships. Cohesively, these groups should be tasked with formal, consistent updates on improvement as well as ongoing supportive research and evaluation of the changes implemented. Simultaneously, the international community has a tremendous opportunity to act on best practice for drug and medical product innovation by aligning sound and consistent approach to regulation.7.
Shannon Ruzycki Mark Yarema Hossein Sadrzadeh Alain Tremblay 《Journal of medical toxicology》2016,12(2):185-188
Context
Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose.Case Details
A 45-year-old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient’s recovery revealed exposure to snorted fentanyl powder immediately prior to presentation.Discussion
Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication.Conclusions
Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses.8.
9.
Rizzo M Lamers CT Sauer CG Ramaekers JG Bechara A Andersen GJ 《Psychopharmacology》2005,179(3):559-566
Rationale
Illicit drug use can increase driver crash risk due to loss of control over vehicle trajectory. This study asks, does recreational use of ±3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) and tetrahydrocannabinol (THC; marijuana) impair cognitive processes that help direct our safe movement through the world?Objective
This study assesses the residual effects of combined MDMA/THC use, and of THC use alone, upon perceived trajectory of travel.Methods
Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles (1, 2, 4 and 8° to the left or right). On each trial, subjects reported if direction of travel was to the left or the right.Results
Results showed impairments in both drug groups, with the MDMA/THC group performing the worst.Conclusions
The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability.10.
Lisa-Marie Schaden Miriam Wimmer-Teubenbacher Johannes Poms Peter Laggner Karl Lohner Stephan Sacher Johannes G. Khinast Sharareh Salar-Behzadi 《Pharmaceutical research》2018,35(7):135
Purpose
The effect of different irradiation doses on the structure and activity of lyophilized powders of Hen Egg-White Lysozyme (HEWL) and alcohol dehydrogenase (ADH) was investigated using these substances as models for robust and sensitive proteins, respectively. Three doses were selected to cover the ranges of radio-sterilization (25kGy), treatment of blood products (25Gy) and annual background radiation dose (approximately 2mGy). The results offer an initial screening of different irradiation doses and support the development of X-ray imaging methods as non-destructive process analytical technology (PAT) tools for detecting the visible particulate matters in such products.Methods
HEWL and ADH were exposed to X-rays in the solid state. The effect of irradiation was determined directly after irradiation and after storage. Structural changes and degradation were investigated using SAXS, SDS-PAGE and HPLC-MS. Protein functionality was assessed via activity assays.Results
Lower irradiation doses of 25Gy and 2mGy had no significant impact on the structure and enzyme activity. The dose of 25kGy caused a significant decrease in the enzyme activity and structural changes immediately after irradiation of ADH and after storage of irradiated HEWL at ?20°C.Conclusion
The results emphasize the importance of careful selection of radiation doses for development of X-ray imaging methods as PAT tools inspection of solid biopharmaceutical products.11.
Pengkai Ma Huajun Yu Xuemei Zhang Hongjie Mu Yongchao Chu Ling Ni Pingping Xing Yiyun Wang Kaoxiang Sun 《Pharmaceutical research》2017,34(1):121-135
Purpose
A bifunctional RGDTAT peptide-modified PEG-PAMAM dendrimer conjugate RGDTAT-PEG-PAMAM (RTPP) was established for the targeted treatment of αvβ3-overexpressing tumor cells.Methods
The RGDTAT peptide was synthesized and attached to PAMAM using PEG to construct the RTPP conjugate. The methotrexate (MTX) encapsulated RTPPM complex was prepared and characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and in vitro release. The targeting ability was then studied in cells and tumor-bearing nude mice using fluorescence microscopy, confocal fluorescence microscopy, flow cytometry, and in vivo imaging. The cytotoxicity and pharmacokinetics of the RTPPM complex was also evaluated in cells and rats.Results
The successful synthesis of the RTPP conjugate was confirmed by 1H-NMR. DLS and TEM measurements revealed that the size was 37 nm and the complex had a spherical shape. RTPP and RTPPM were taken up by αvβ3-overexpressing cells more efficiently than by αvβ3-lowexpressing cells. The RTPP conjugate localized to the cell nucleus and accumulated in the tumor more efficiently than did the conjugates without RGDTAT. The pharmacokinetic study of the RTPPM complex showed sustained drug release.Conclusions
The bifunctional peptide-mediated dendrimer-based RTPP conjugate can serve as a promising nanocarrier for targeted drug delivery to improve anti-tumor activity.12.
Steven A. Giannos Edward R. Kraft Zhen-Yang Zhao Kevin H. Merkley Jiyang Cai 《Pharmaceutical research》2018,35(6):110
Purpose
Permeation studies, with near infrared (NIR) light and anti-aggregation antibody formulation, were used to investigate the in vitro permeation of bevacizumab, ranibizumab and aflibercept through human sclera.Methods
A vertical, spherical Franz cell diffusion apparatus was used for this scleral tissue permeation model. A photokinetic ocular drug delivery (PODD) testing device accommodated the placement of NIR LEDs above the donor chambers. An adjustable LED driver/square wave generator provided electrical energy with a variable pulse rate and pulse width modulation (duty cycle).Results
Exposure to non-thermal NIR light had no effect on mAbs with regard to monomer concentration or antibody binding potential, as determined by SE-HPLC and ELISA. The optimal LED wavelength was found to be 950 nm. Duty cycle power of 5% vs 20% showed no difference in permeation. When compared to controls, the combination of non-aggregating antibody formulation and NIR illumination provided an average transscleral drug flux enhancement factor of 3X.Conclusion
Narrow wavelength incoherent (non-laser) light from an NIR LED source is not harmful to mAbs and can be used to enhance drug permeation through scleral tissue. The topical formulation, combined with pulsed NIR light irradiation, significantly improved scleral permeation of three anti-VEGF antibody drugs.13.
Purpose
In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics.Methods
A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature.Results
The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations.Conclusions
The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.14.
15.
Purpose
Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution.Methods
Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively.Results
The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers.Conclusions
These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning.16.
Purpose
The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product.Methods
Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated.Results
Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions.Conclusions
The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.17.
Purpose
To compare traditional dialysis- and novel solvatofluorochromism (SFC)-based methods for accurate determination of drug release profiles for nanoparticle drug carriers.Methods
Polymer nanoassemblies (PNAs) varying in drug release patterns were prepared using poly(ethylene glycol), poly(ethylenimine), hydrophobic excipients (palmitate and deoxycholate), and model hydrophobic anticancer drugs with clinical relevance (carfilzomib and docetaxel). Nile blue (NB) was used as a model SFC dye quenching fluorescence in water yet emitting strong fluorescence in the presence of hydrophobic drugs within PNAs. Drug release kinetics were measured by dialysis- and SFC-based methods, and analyzed by mathematical modeling of free drug, spiked drug, and encapsulated drug release.Results
The dialysis method overestimated drug remaining in PNAs because it included released drug in measurements, whereas the SFC method successfully distinguished drugs entrapped in PNAs from released in solution and thus provided more accurate drug release patterns. However, mathematical modeling revealed that the dialysis method would be less influenced than the SFC method by hydrophobic excipients modulating drug diffusion within PNAs.Conclusions
In comparison to the dialysis-based method, the SFC-based method would allow for real-time spectroscopic determination of drug release from PNAs and potentially other nanoparticle drug carriers with improved convenience and accuracy.18.
Purpose
Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin.Methods
Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution.Results
Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions.Conclusions
Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.19.
Jessica Bane Olivier Mozziconacci Li Yi Y. John Wang Alavattam Sreedhara Christian Schöneich 《Pharmaceutical research》2017,34(1):229-242
Purpose
Triply oxidized histidine in an IgG1 monoclonal antibody was noticed when exposed to ICH light conditions. In order to understand the role of light source, irradiation wavelengths and primary sequence, specifically those of a nearby tryptophan, we synthesized and exposed several peptides to ICH light conditions and analyzed the products using LC-MS analysis.Methods
Protein and peptide samples were photo-irradiated under ICH conditions as well as with monochromatic light at λ?=?254 nm and analyzed using either LTQ Orbitrap or a LTQ-FT ion cyclotron resonance mass spectrometer respectively.Results
A triply oxidized His residue was detected along with a second doubly oxidized His residue in an IgG1. Both of these oxidized His residues are located near Trp residues. In order to investigate the role of Trp photosensitization in His oxidation we synthesized model peptides and Ala mutants. Peptides exposed to ICH light stress conditions revealed a small percent of triply oxidized His in the Trp-containing peptide sequences but not in their corresponding Ala mutants.Conclusions
The differences in product formation under different photo-irradiation conditions underline the importance of light source, irradiation wavelengths and primary sequence in the photosensitivity of proteins.20.