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Journal Cover Pharmaceutical Research
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
   Published by Springer-Verlag Homepage  [2354 journals]
  • Dissolving Microneedle Patches for Dermal Vaccination
    • Authors: M. Leone; J. Mönkäre; J. A. Bouwstra; G. Kersten
      Pages: 2223 - 2240
      Abstract: The dermal route is an attractive route for vaccine delivery due to the easy skin accessibility and a dense network of immune cells in the skin. The development of microneedles is crucial to take advantage of the skin immunization and simultaneously to overcome problems related to vaccination by conventional needles (e.g. pain, needle-stick injuries or needle re-use). This review focuses on dissolving microneedles that after penetration into the skin dissolve releasing the encapsulated antigen. The microneedle patch fabrication techniques and their challenges are discussed as well as the microneedle characterization methods and antigen stability aspects. The immunogenicity of antigens formulated in dissolving microneedles are addressed. Finally, the early clinical development is discussed.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2223-2
      Issue No: Vol. 34, No. 11 (2017)
  • BITC and S -Carvone Restrain High-Fat Diet-Induced Obesity and Ameliorate
           Hepatic Steatosis and Insulin Resistance
    • Authors: Sary Alsanea; Dexi Liu
      Pages: 2241 - 2249
      Abstract: Purpose To investigate the preventative activity of benzyl isothiocyante and S-carvone against high-fat diet-induced obesity and metabolic complications. Methods Ten-week-old C57BL/6 male mice were fed a high-fat diet and injected intraperitoneally twice per week with benzyl isothiocyante, S-carvone, or vehicle for 8 weeks. The body weight, food intake, and body composition were monitored, and glucose tolerance and insulin tolerance tests were performed at the end of the experiment. Serum and tissue samples were studied using serum biochemistry, histological, and gene expression analysis to define the effects of benzyl isothiocyante and S-carvone treatments on lipid and glucose metabolism and inflammatory responses. Results Benzyl isothiocyante and S-carvone blocked high-fat diet-induced weight gain, fat accumulation in the liver, and insulin resistance. The beneficial effects were found to be associated with an improvement of expression of macrophage marker genes in white adipose tissue, including F4/80, Cd11b, Cd11c, Cd206, and Tnf-α, and reduced expression of genes (Pparγ2, Scd1, Cd36) responsible for lipid synthesis and transport in the liver. Conclusion Benzyl isothiocyante and S-carvone block high-fat diet-induced obesity and metabolism disorders and can be considered for management of the obesity epidemic that affects approximately 36% of adults and 17% of children in the USA.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2230-3
      Issue No: Vol. 34, No. 11 (2017)
  • Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a
           Proof-of-Concept Pharmacokinetic Study
    • Authors: Joana Sousa; Gilberto Alves; Ana Fortuna; Amílcar Falcão
      Pages: 2260 - 2269
      Abstract: Purpose To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection. Methods Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used. Results Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points. Conclusion The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2232-1
      Issue No: Vol. 34, No. 11 (2017)
  • Precision Ocular Drug Delivery Via Aerosol Ring Vortices
    • Authors: Matthew J. Herpin; Hugh D. C. Smyth
      Pages: 2287 - 2294
      Abstract: Purpose Despite being the most prominent dosage form for topical ocular delivery, eye-drops have several well-recognized drawbacks. Addressing these limitations, in this work we introduce a novel method to accurately deliver ophthalmic medications to the surface of the eye at relatively low volume and low velocity. By aerosolizing a medicament and dispensing it in the form of a toroidal vortex, commonly known as a “smoke ring”, several major drawbacks associated with topical drug delivery can be avoided. Methods A device capable of emitting a toroidal vortex was developed such that actuation force and aerosol loading could be modulated. Different solution formulations were tested for deposited dose on an in vitro eye. Results It was found that the dose delivered to the surface of an in vitro eye was directly proportional to the velocity and the size of the droplets emitted from the device. With a dilute solution formulation (0.05% fluorescein sodium), doses could be reproducibly deposited by actuating the device at different velocities (from ~5 ng to ~18 ng per actuation). While a more concentrated solution of 0.5% fluorescein sodium, between 20 ng and 160 ng could be deposited depending on selected actuation velocity. And with the highest concentration, 5% fluorescein sodium, 1.15 +/− 0.075 μg was deposited. It was also shown that the amount of drug deposited onto the eye surface could be modulated by modulating the chamber fill time. Conclusion Precise toroidal vortex based aerosol delivery may facilitate optimized administration of medicines to the surface of the eye.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2236-x
      Issue No: Vol. 34, No. 11 (2017)
  • Novel Gemcitabine Conjugated Albumin Nanoparticles: a Potential Strategy
           to Enhance Drug Efficacy in Pancreatic Cancer Treatment
    • Authors: Varun Kushwah; Ashish Kumar Agrawal; Chander Parkash Dora; David Mallinson; Dimitrios A. Lamprou; Ramesh C. Gupta; Sanyog Jain
      Pages: 2295 - 2311
      Abstract: Purpose The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. Methods The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis. Further, BSA nanoparticles were developed from BSA-GEM conjugate and extensively evaluated against in-vitro pancreatic cancer cell lines to explore cellular uptake pathways and therapeutic efficacy. Results Various characterization techniques confirmed covalent conjugation of GEM with BSA. GEM-BSA conjugate was then transformed into NPs via high pressure homogenization technique with particle size 147.2 ± 7.3, PDI 0.16 ± 0.06 and ZP -19.2 ± 1.4. The morphological analysis by SEM and AFM revealed the formation of smooth surface spherical nanoparticles. Cellular uptake studies in MIA PaCa-2 (GEM sensitive) and PANC-1 (GEM resistant) pancreatic cell lines confirmed energy dependent clathrin internalization/endocytosis as a primary mechanism of NPs uptake. In-vitro cytotoxicity studies confirmed the hNTs independent transport of GEM in MIA PaCa-2 and PANC-1 cells. Moreover, DNA damage and annexin-V assay revealed significantly higher apoptosis level in case of cells treated with GEM-BSA NPs as compared to free GEM. Conclusions GEM-BSA NPs were found to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM and thus demonstrated promising therapeutic potential over free drug. Graphical ᅟ
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2238-8
      Issue No: Vol. 34, No. 11 (2017)
  • Rheological Characterization of Molten Polymer-Drug Dispersions as a
           Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability
    • Authors: Jeroen Van Renterghem; Chris Vervaet; Thomas De Beer
      Pages: 2312 - 2321
      Abstract: Purpose The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. Methods Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10–20–30–40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. Results Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. Conclusion The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2239-7
      Issue No: Vol. 34, No. 11 (2017)
  • Role of the OATP Transporter Family and a Benzbromarone-SensitiveEfflux
           Transporter in the Hepatocellular Disposition of Vincristine
    • Authors: Johan Nicolaï; Louise Thevelin; Qi Bing; Bruno Stieger; Hugues Chanteux; Patrick Augustijns; Pieter Annaert
      Pages: 2336 - 2348
      Abstract: Purpose Vincristine is known to interfere with OATP-mediated uptake of other compounds, hinting that vincristine itself could be a substrate of OATP transporters. The present study therefore aimed to investigate the role of OATP transporters in the hepatocellular disposition of vincristine. Methods Vincristine uptake was studied in suspended rat and human hepatocytes as well as OATP-transfected Chinese hamster ovary (CHO) cells in the absence and presence of OATP transporter inhibitors. Membrane vesicles containing MDR1 or MRP1/2/3 were used to directly assess the role of these efflux transporters in vincristine disposition. Results Uptake in suspended rat hepatocytes was temperature-dependent and could be inhibited by a range of OATP inhibitors. Furthermore, the MRP-inhibitor benzbromarone, but none of the tested MDR1 inhibitors, reduced vincristine efflux in rat and human suspended hepatocytes. OATP1B1-, OATP1B3- and OATP2B1- transfected CHO cells showed significantly increased vincristine uptake as compared to wild-type cells. Moreover, uptake in OATP-transfected CHO cells was reduced by OATP inhibitors. However, uptake studies in suspended human hepatocytes showed that only 10% of the total vincristine uptake process could be attributed to OATP-mediated transport. Studies with transporter-expressing membrane vesicles confirmed vincristine as an MDR1 substrate, while MRP1/2/3-mediated transport of vincristine could not be observed with this model system. Conclusions Our findings show the involvement of OATP transporters in the disposition of vincristine in rat and human hepatocytes. However, in both species, hepatic uptake is overshadowed by a benzbromarone-sensitive efflux mechanism, possibly MRP3.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2241-0
      Issue No: Vol. 34, No. 11 (2017)
  • In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1
           Knockout Mice Following Oral Dose Escalation
    • Authors: Bei Yang; David E. Smith
      Pages: 2349 - 2361
      Abstract: Purpose We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. Methods Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. Results Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. Conclusion The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2242-z
      Issue No: Vol. 34, No. 11 (2017)
  • Elucidation of the Mechanism of Increased Activity of Immunostimulatory
           DNA by the Formation of Polypod-like Structure
    • Authors: Kohta Mohri; Kengo Nagata; Shozo Ohtsuki; Shiori Toyama; Mao Nonomura; Yuki Takahashi; Yoshinobu Takakura; Makiya Nishikawa; Shinji Sakuma
      Pages: 2362 - 2370
      Abstract: Purpose We previously demonstrated that the immunostimulatory activity of CpG DNA is increased by the formation of polypod-like structures. The present study was designed to elucidate the mechanism underlying this increase. Methods Tripodna (three pods) and hexapodna (six pods) were prepared. The cellular uptake of Alexa Fluor 488-labeled DNA samples was examined in several cell lines by measuring the MFI of cells. TNF-α release from RAW264.7 cells was measured after addition of polypodna containing CpG motifs. Dissociation of double stranded DNA was evaluated using FRET. Results Tripodna and hexapodna were efficiently taken up by macrophage-like RAW264.7 cells and dendritic DC2.4 cells, but not by fibroblast or endothelial cell lines. The uptake by RAW264.7 cells was highest for hexapodna, followed by tripodna, dsDNA, and ssDNA. The release of TNF-α from RAW264.7 cells was also highest for hexapodna. The ratio of TNF-α release to cellular uptake was highest for ssDNA, and lowest for dsDNA. Tripodna and hexapodna were more easily dissociated into single strands after cellular uptake than was dsDNA. Conclusions The efficient cellular uptake and prompt dissociation into single strands can be directly related to the high immunostimulatory activity of polypod-like structured DNAs containing CpG motifs.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2243-y
      Issue No: Vol. 34, No. 11 (2017)
  • Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2,
           6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment
           of non-small Cell Lung Cancer
    • Authors: Nusrat Chowdhury; Imran Vhora; Ketan Patel; Ravi Doddapaneni; Arindam Mondal; Mandip Singh
      Pages: 2371 - 2384
      Abstract: Purpose Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX). Methods Cationic DTX liposomes complexed with pshPFKFB3 (PSH-DL) were developed. In vitro cell line studies were performed to evaluate transfection, PFKFB3 mRNA silencing, cytotoxicity, pGP inhibition, and protein markers expression. In vivo efficacy study was performed in A549 xenograft nude mice model. Results Cytotoxicity studies showed significantly enhanced anticancer activity of PSH-DL against individual treatment alone confirming the chemoenhancing effect of pshPFKFB3 on DTX activity. Fluorescence microscopy and RT-PCR showed effective transfection and RNAi by pshPFKFB3. pGP inhibition assay and western blotting revealed that PFKFB3 downregulation caused diminution of pGP activity leading to changes in cell cycle (Cdk2), survival (survivin), apoptosis (Bcl2 and cleaved caspase 3) and stress (p-JNK and p-p38) markers so that induces apoptosis by PSH-DL in NSCLC cells. PSH-DL also showed ~3.8-fold reduction in tumor volume in A549 xenograft model which was significantly higher than individual treatments alone. Conclusion Targeting PFKFB3 through shRNA based RNAi is a promising approach for potentiating activity of DTX in NSCLC.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2244-x
      Issue No: Vol. 34, No. 11 (2017)
  • Development of Halofluorochromic Polymer Nanoassemblies for the Potential
           Detection of Liver Metastatic Colorectal Cancer Tumors Using Experimental
           and Computational Approaches
    • Authors: Derek Reichel; Louis T. Curtis; Elizabeth Ehlman; B. Mark Evers; Piotr Rychahou; Hermann B. Frieboes; Younsoo Bae
      Pages: 2385 - 2402
      Abstract: Purpose To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes. Methods We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm. Results Dye-conjugated PNAs showed no aggregation under opsonizing conditions for 24 h and displayed low tissue diffusion and cellular uptake. Both hfPNAs and n-hfPNAs accumulated in primary and liver metastatic CRC tumors within 12 h post intravenous injection. In comparison to n-hfPNAs, hfPNAs fluoresced strongly only in the acidic tumor microenvironment (pH < 7.0) and distinguished small metastatic CRC tumors from healthy liver stroma. Computational simulations revealed that PNAs would steadily accumulate mainly in acidic (hypoxic) interstitium of metastatic tumors, independently of the vascularization degree of the tissue surrounding the lesions. Conclusion The combined experimental and computational data confirms that hfPNAs detecting acidic tumor tissue can be used to identify small liver metastatic CRC tumors with improved accuracy.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2245-9
      Issue No: Vol. 34, No. 11 (2017)
  • Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic
           Profiles After Dermal Drug Application
    • Authors: Syunsuke Yamamoto; Masatoshi Karashima; Noriyasu Sano; Chiharu Fukushi; Kimio Tohyama; Yuta Arai; Hideki Hirabayashi; Nobuyuki Amano
      Pages: 2415 - 2424
      Abstract: Purpose Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs. Methods First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed. Results The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction. Conclusions Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2247-7
      Issue No: Vol. 34, No. 11 (2017)
  • Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin
    • Authors: Hanah Mesallati; Lidia Tajber
      Pages: 2425 - 2439
      Abstract: Purpose To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs). Methods ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined. Results The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug. Conclusions The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.
      PubDate: 2017-11-01
      DOI: 10.1007/s11095-017-2250-z
      Issue No: Vol. 34, No. 11 (2017)
  • Administration of a Sol-Gel Formulation of Phenylephrine Using
           Low-Temperature Hollow Microneedle for Treatment of Intermittent Fecal
    • Authors: Hyunji Lee; Jung-Hwan Park; Jung Ho Park
      Abstract: Purpose A low temperature hollow microneedle system was devised to deliver sol-gel transition formulation near the surface of the skin for extended release and local delivery of drug by a non-invasive method. This new system can improve treatment of intermittent fecal incontinence. Method The low-temperature system was integrated with a hollow microneedle to maintain the low temperature of the sol formulation. Various sol-gel formulations using Pluronic F-127 (PF-127) and Hydroxy-propyl-methyl-cellulose (HPMC) were prepared, and their gelation temperature, flow property, and diffusion retardation were observed. Resting anal sphincter pressure in response to a phenylephrine (PE) sol-gel formulation was measured using an air-charged catheter. The biocompatibility of the sol-gel PE formulation was evaluated by observing the immunological response. Results When the PF-127 25%, HPMC 1% and PE formulation (PF25-HPMC1-PE) was injected through the peri-anal skin of the rat in vivo, the highest pressure on the anal sphincter muscle occurred at 6–8 h and anal pressure increased and lasted twice as long as with the phosphate-buffered saline (PBS)-PE formulation. There was no significant difference in the number of mast cells after administration into the rat in vivo between the PF25-HPMC1-PE formulation and the PBS-PE formulation. Conclusion The combination of a low-pain hollow microneedle system and an injectable sol-gel formulation improved the efficacy of treatment of intermittent fecal incontinence. A low-temperature hollow microneedle system using a sol-gel formulation has many applications in medical treatments that require depot effect, local targeting, and pain control.
      PubDate: 2017-11-27
      DOI: 10.1007/s11095-017-2261-9
  • miR-542-3p Appended Sorafenib/All- trans Retinoic Acid (ATRA)-Loaded Lipid
           Nanoparticles to Enhance the Anticancer Efficacy in Gastric Cancers
    • Authors: Tong Li; Yu Zhang; Yuan-Pu Meng; Li-Shan Bo; Wen-Bo Ke
      Abstract: Purpose In this study, miR-542-3p appended SRF/ATRA-loaded solid lipid nanoparticle was successfully prepared and demonstrated for its therapeutic efficacy against gastric cancers. Methods The particles were nanosized and typically spherical in shape. In vitro release study showed that release of ATRA was significantly slower compared to that of SRF from the NPs. Results MTT assay showed that miR-542-3p have a strong inhibitory effect on the proliferation of MGC-803 cancer cells in a typical dose dependent manner. Nanocarrier encapsulation of SRF + ATRA induced a significantly higher cytotoxic effect compared to either individual drug or cocktail combinations indicating that the cellular uptake of different formulations was rate limiting factor in the therapeutic efficacy. Importantly, miR-542-3p-based miSRNP exhibited an extremely significant toxic effect compared to any other treated group. Importantly, miSRNP induced a significantly higher early (~55%) and late (~15%) apoptotic effect in gastric cancer cells. In vivo anticancer analysis results clearly suggest that nanoparticle encapsulation of combination of SRF and miRNA (with miRNA) will have greater antitumor efficacy in tumor mice. Conclusion Overall, unique combination of miRNA coupled with SRF + ATRA in a lipid nanocarrier could be a promising therapeutic approach in gastric cancer treatment.
      PubDate: 2017-11-27
      DOI: 10.1007/s11095-017-2202-7
  • Model-Based Methods in the Biopharmaceutical Process Lifecycle
    • Authors: Paul Kroll; Alexandra Hofer; Sophia Ulonska; Julian Kager; Christoph Herwig
      Abstract: Model-based methods are increasingly used in all areas of biopharmaceutical process technology. They can be applied in the field of experimental design, process characterization, process design, monitoring and control. Benefits of these methods are lower experimental effort, process transparency, clear rationality behind decisions and increased process robustness. The possibility of applying methods adopted from different scientific domains accelerates this trend further. In addition, model-based methods can help to implement regulatory requirements as suggested by recent Quality by Design and validation initiatives. The aim of this review is to give an overview of the state of the art of model-based methods, their applications, further challenges and possible solutions in the biopharmaceutical process life cycle. Today, despite these advantages, the potential of model-based methods is still not fully exhausted in bioprocess technology. This is due to a lack of (i) acceptance of the users, (ii) user-friendly tools provided by existing methods, (iii) implementation in existing process control systems and (iv) clear workflows to set up specific process models. We propose that model-based methods be applied throughout the lifecycle of a biopharmaceutical process, starting with the set-up of a process model, which is used for monitoring and control of process parameters, and ending with continuous and iterative process improvement via data mining techniques.
      PubDate: 2017-11-22
      DOI: 10.1007/s11095-017-2308-y
  • Inhalation Biopharmaceutics: Progress Towards Comprehending the Fate of
           Inhaled Medicines
    • Authors: Carsten Ehrhardt
      PubDate: 2017-11-16
      DOI: 10.1007/s11095-017-2304-2
  • Folate Conjugated Hybrid Nanocarrier for Targeted Letrozole Delivery in
           Breast Cancer Treatment
    • Authors: Abbas Hemati Azandaryani; Soheila Kashanian; Katayoun Derakhshandeh
      Abstract: Purpose Letrozole as a steroidal anticancer drug with hydrophobic nature is usually administrated by oral route for patient treatment and the injectable formulation for this drug has not still been reported. In this study, a new letrozole incorporated folate-conjugated polymer – lipid hybrid nanoparticles – is introduced for cancer treatment. Methods Nanoparticles were fabricated via modified oil in water ionic gelation method using optimization parameters and then were coupled to folic acid using carbodiimide activation. The physicochemical characterization in vitro drug release, cytotoxicity, and then ex vivo study of obtained carrier was investigated. Results Both thermal and crystallography studies proved the amorphous loading of drug in the nanocarrier. The cytotoxicity investigation with an average IC50 value of 79 ± 2.40 nM proved the efficiency of the coupled folic acid carrier for the intracellular uptake of letrozole on the breast cancer line. Ex vivo, the study proved the positive effect of the letrozole entrapment on the drug bioavailability. Conclusions The obtained targeted nanocarrier could overcome the limitations associated with the LTZ as a potent non-steroidal drug. Both the entrapment and therapeutic efficiency of letrozole in the amphiphilic carrier were increased using the lipid nanoparticles and the surface modification, respectively.
      PubDate: 2017-11-06
      DOI: 10.1007/s11095-017-2260-x
  • Chemical and Biophysical Characteristics of Monoclonal Antibody Solutions
           Containing Aggregates Formed during Metal Catalyzed Oxidation
    • Authors: Linda O. Narhi; Quanzhou Luo; Jette Wypych; Riccardo Torosantucci; Andrea Hawe; Kiyoshi Fujimori; Yasser Nashed-Samuel; Vibha Jawa; Marisa K. Joubert; Wim Jiskoot
      Abstract: Purpose To physicochemically characterize and compare monoclonal antibody (mAb) solutions containing aggregates generated via metal catalyzed oxidation (MCO). Methods Two monoclonal IgG2s (mAb1 and mAb2) and one monoclonal IgG1 (rituximab) were exposed to MCO with the copper/ascorbic acid oxidative system, by using several different methods. The products obtained were characterized by complementary techniques for aggregate and particle analysis (from oligomers to micron sized species), and mass spectrometry methods to determine the residual copper content and chemical modifications of the proteins. Results The particle size distribution and the morphology of the protein aggregates generated were similar for all mAbs, independent of the MCO method used. There were differences in both residual copper content and in chemical modification of specific residues, which appear to be dependent on both the protein sequence and the protocol used. All products showed a significant increase in the levels of oxidized His, Trp, and Met residues, with differences in extent of modification and specific amino acid residues modified. Conclusion The extent of total oxidation and the amino acid residues with the greatest oxidation rate depend on a combination of the MCO method used and the protein sequence.
      PubDate: 2017-11-06
      DOI: 10.1007/s11095-017-2262-8
  • EphA2 Targeted Doxorubicin-Nanoliposomes for Osteosarcoma Treatment
    • Authors: Fateme Haghiralsadat; Ghasem Amoabediny; Samira Naderinezhad; Kamran Nazmi; Jantine Posthuma De Boer; Behrouz Zandieh-Doulabi; Tymour Forouzanfar; Marco N. Helder
      Abstract: ABSTRACT Purpose To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against Saos-2 osteosarcoma cells. Methods PEGylated liposomes were prepared by thin film method using Dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearylphosphatidylethanolamine-polyethyleneglycol conjugate (DSPE-mPEG) in 67.9:29.1:3 M ratios, and loaded with DOX (L-DOX) by pH-gradient method. Targeted liposomes (YSA-L-DOX), were prepared by conjugating YSA-peptide to DSPE-mPEG. Liposomes were physicochemically characterized and tested in cellular toxicity assays. Results YSA conjugation efficiency was >98%. Size and polydispersity index of both L-DOX and YSA-L-DOX were around 88 nm and 0.188, respectively. Both had similar zeta potential, and 85% DOX loading efficiencies. DOX release kinetics followed the Korsmeyer-Peppa model, and showed comparable release for both formulations from 1–8 h, and a plateau of 29% after 48 h. Both formulations could be stably stored for ≥6 months at 4°C in the dark. Toxicity assays showed a significant 1.91-fold higher cytotoxicity compared to free DOX in the Saos-2 cells, and 2-fold lesser toxicity in primary bone cells compared to the Saos-2 cells. Cellular uptake studies showed higher and more nuclear uptake in YSA-L-DOX compared to L-DOX treated cells. Conclusions YSA-L-DOX vesicles might be effective for targeted treatment of osteosarcoma.
      PubDate: 2017-11-06
      DOI: 10.1007/s11095-017-2272-6
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