John Garner's Technical Blog
John GarnerJohn Garner, Manager

What's New and on the Manager's Mind

A blog dedicated to answering technical questions in an open format relating to products from PolySciTech, a division of Akina, Inc.


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mPEG-PLGA from PolySciTech used in development of advanced AFM-IR nanoparticle characterization techniques

Wednesday, April 18, 2018, 9:21 PM ET

The best thing about nanotechnology is that it is small. The worst thing about nanotechnology is that it is small… very small… smaller than what a standard light microscope can typically observe. Naturally, obtaining meaningful information about the structure and morphology of nanoparticles is very difficult and requires advanced equipment and analysis techniques. Recently, researchers at University of Sydney (Australia) used mPEG-PLGA (PolyVivo AK037) from PolySciTech (www.polyscitech.com) to generate nanorods and analyzed these using a combination of atomic force microscopy and infrared spectroscopy. These nano-analysis techniques allowed the researchers to measure the various mechanical, structural, and chemical properties of even a single nanoparticle with incredible precision and accuracy. This research holds promise to allow for improved characterization of nanoparticles which will enable better designs and synthesis in the future. Read more: Khanal, Dipesh, Bokai Zhang, Iqbal Ramzan, Curtis Marcott, Quan Li, and Wojciech Chrzanowski. "Probing Chemical and Mechanical Nanodomains in Copolymer Nanorods with Correlative Atomic Force Microscopy—Nanocorrescopy." Particle & Particle Systems Characterization (2018). https://onlinelibrary.wiley.com/doi/abs/10.1002/ppsc.201700409

“Abstract: The interplay between size, shape, mechanical properties, and surface chemistry of nanoparticles orchestrates cellular internalization, toxicity, circulation time, and biodistribution. Therefore, the safety of nanoparticles hinges on our ability to quantify nanoscale physicochemical characteristics. Current characterization tools, due to their limited resolution, are unable to map these properties correlatively at nanoscale. An innovative use of atomic force microscopybased techniques, namely nanocorrescopy, overcomes this limitation and offers multiprobe capability to map mechanical (viscous and elastic) and chemical domains of nanoparticles correlatively. The strengths of this approach are demonstrated using polymer composite nanorods: mPEGPLGA ((mPEG–methoxypoly (ethylene glycol)bpoly (lacticcoglycolic) acid). Precise distribution of PLGA (monomers of lactide and glycolide) and poly(ethylene glycol) (PEG) polymer across nanorods is identified. The hydrophobic lactide component is found predominantly at the apex, while hydrophilic glycolide and PEG assembled at the body of the nanorods and correlate with a gradient of nanomechanical properties. New knowledge of how both nanochemical domains and nanomechanical properties are distributed across the nanorod will allow elucidating the interactions of nanorods with the proteins and biomolecules in the future, which will directly influence the fate of nanorods in vivo and will guide new synthesis methods.”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

PEG-PLA from PolySciTech used in development of ocular-delivery system to treat inflammation

Friday, April 13, 2018, 4:56 PM ET

Inflammatory diseases are typified by an over-reaction of the human immune system against either some trigger or, in some-cases, without a specific trigger. Many diseases are caused by inflammation, however delivery of anti-inflammatory drugs is not always easily accomplished due to location or other disease complications. Recently, researchers at Stony Brook University and Medicon Pharmaceuticals utilized PEG-PLA (Polyvivo AK005) from PolyScitech (www.polyscitech.com) to generate anti-inflammatory nanoparticles for delivery of Phospho-sulindac to the ocular region. Read more: Robert A. Honkanen, Liqun Huang, Gang Xie, Basil Rigas “Phospho-sulindac is efficacious in an improved concanavalin a-based rabbit model of chronic dry eye disease” Translational Research (2018) https://www.sciencedirect.com/science/article/pii/S1931524418300562

“Abstract: Dry eye disease (DED), an inflammatory disease of the ocular surface, affects 15% of humans worldwide. No satisfactory treatment exists for DED partly due to the lack of informative animal models of this disease. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED, using a new rabbit model of chronic DED. In this model, based on the Concanavalin A (Con A) acute DED model, we injected weekly x3 all lacrimal glands with ConA under ultrasound guidance, which prolonged DED to >3 weeks; and used concurrently four parameters of efficacy: tear break up time (TBUT), tear osmolarity, Schirmer's test, and tear lactoferrin levels, making efficacy assessment robust. Rabbits with DED (n=8-10 eyes/group) were treated topically with PS or vehicle 3x/day for 21 days. PS restored to normal TBUT, tear osmolarity and lactoferrin levels (p<0 .0001="" 1="" 6="" 8="" a="" abbreviations:="" account="" acid="" activated="" activation="" activity="" albumin="" amp="" an="" and="" animal="" anti-inflammatory="" apparent="" assay="" b="" beta="" bovine="" break="" bsa="" buffered="" but="" c-jun="" cause="" cells="" completely="" con="" concanavalin="" concentration="" cornea.="" cornea="" corneal="" cyclosporine="" ded.="" ded="" deviation="" diclofenac="" did="" disease="" dodecyl="" drug="" drugs="" dry="" e2="" effect="" effects="" efficacious="" efficacy="" electophoretic="" elisa="" emsa="" enzyme-linked="" eosin="" erk="" error="" establish="" evaluation="" extracellular="" eye="" factor="" for="" further="" gland="" glycol-block-polylactic="" growth="" h="" had="" half="" hematoxylin="" ic50="" il-1="" il-6="" il-8="" ilg="" immunoprecipitation="" immunosorbent="" improve="" in="" indicate="" inferior="" inhibitory="" interleukin="" international="" its="" iu="" jnk="" kappa-light-chain-enhancer="" ketorolac="" kinases="" lacrimal="" levels="" lifitegrast.="" likely="" list="" mapks="" matrix="" maximal="" mean="" melt="" merits="" metalloproteinase="" milliliter="" minute="" mitogen="" ml="" mmp-1="" mmp-9="" mmp="" mmps.="" mmps="" mobility="" model="" more="" much="" n-terminal="" nearly="" new="" nf-="" no="" nonsteroidal="" not="" nsaids="" nuclear="" nzw="" o:p="" ocular="" of="" on="" ophthalmic="" or="" orbital="" oslg="" osmolarity="" our="" palpebral="" pbs="" peg-pla="" per="" pge2="" phosphate="" phosphosulindac="" polyethylene="" portion="" preserved="" progstaglandin="" protein="" ps-treated="" ps="" pslg="" rabbits.="" radio="" regulated="" results="" revolutions="" ripa="" rpm="" s="" safety.="" saline="" schirmer="" sd="" sds="" sem="" serum="" shift="" showed="" side="" signal="" significantly="" slg="" sodium="" standard="" stt="" studies="" suitable="" sulphate="" superior="" suppressed="" tbut="" tear="" tears="" test.="" test="" tgf-="" than="" that="" the="" time="" tosm="" transforming="" two="" ultrasonography="" units="" up="" us="" was="" were="" white="" zealand="">

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

PEG-PLGA from PolySciTech used in development of dual-drug loaded nanoparticles for cisplatin-resistant ovarian cancer treatment

Monday, April 9, 2018, 4:16 PM ET

Despite effective first-line therapies based on platinum-type drugs, ovarian cancer remains one of the deadliest gynecological diseases in the USA. The incidence of relapse is high, as is the development of platinum-resistant ovarian cancer lines that cannot be treated well using cisplatin. Recently, researchers at University of North Carolina at Chapel Hill, Westminster College, Peking Union Medical College and China Medical University (China) used mPEG-PLGA (PolyvivoAK029) and PLGA ( PolyVivo AP087) from PolySciTech (www.polyscitech.com) to develop nanoparticles that deliver both wortmannin and cisplatin. They found this co-delivery system was very effective against ovarian cancer models in which the cancer was resistant to platinum-based drugs, as the wortmannin prevented the cancer from repairing its own DNA. This research holds promise for development of therapies against drug-resistant cancers. Read more: Zhang, Maofan, C. Tilden Hagan, Yuangzeng Min, Hayley Foley, Xi Tian, Feifei Yang, Yu Mi et al. "Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models." Biomaterials (2018). https://www.sciencedirect.com/science/article/pii/S0142961218302333

“Abstract: Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic. Keywords: Nanoparticle; Combination therapy; Platinum resistance; Treatment synergy; Ovarian cancer”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Mal-PEG-PLGA from PolySciTech used in development of oral-exanatide formulation for improved diabetes treatment.

Monday, April 9, 2018, 4:15 PM ET

The incidence of type 2 diabetes has expanded rapidly over the past several decades and is characterized by uncontrolled blood-sugar. Exanatide is a peptide based drug which acts to increase the pancreas response for insulin secretion as a means to control blood sugar. Due to the sensitivity of this peptide to degradation, as well as its poor bioavailability, it is currently only available as an injection. Recently, researchers at Yantai University and Binzhou Medical University (China) used Mal-PEG-PLGA (PolyVivo AI020) and PEG-PLGA (AK037) from PolySciTech (www.polyscitech.com) to develop a transferrin-coated exenatide delivery nanoparticle system that could be ingested and had high bioavailablity. This research holds promise for the development of improved oral diabetes treatment options. Read more: Zhang, Liping, Yanan Shi, Yina Song, Dongyu Duan, Xuemei Zhang, Kaoxiang Sun, and Youxin Li. "Tf ligand-receptor-mediated exenatide-Zn2+ complex oral-delivery system for penetration enhancement of exenatide." Journal of Drug Targeting just-accepted (2018): 1-36. https://www.tandfonline.com/doi/abs/10.1080/1061186X.2018.1455839

“Abstract: Safe and effective oral delivery of peptide is a challenge. Here, we used exenatide and zinc ions (Zn2+) to form a complex to explore a meaningful oral-targeted drug-delivery system. Polyethylene glycol-poly(lactic acid-co-glycolic acid) (PEG-PLGA) was used to prepare nanoparticles (NPs) to escape the degradation caused by gastrointestinal enzymes. Transferrin (Tf) was used as a targeting group. PEG-PLGA-NPs and Tf-modified exenatide-Zn2+-loaded NPs (Tf-PEG-PLGA-NPs) were uniformly sized spheres according to transmission electron microscopy. The results of pharmacodynamic and pharmacokinetic investigations in vivo were consistent with in vitro studies using Caco-2 cells. Tf enhanced NPs transport in cell-uptake and transmembrane-transport experiments. Our results showed that the relative bioavailability of Tf-exenatide-Zn2+-NPs was higher than that of exenatide-Zn2+-NPs. The relative bioavailability of Tf-exenatide-Zn2+-NPs versus subcutaneous injection of exenatide was 6.45%. This was a preliminary exploration of the oral administration of exenatide, that data from which can be used for future investigations. Keywords: transferrin, exenatide-Zn2+, PEG-PLGA, targeted nanoparticles, oral delivery”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

PLGA from PolySciTech used in development of ellipsoid-shaped/lipid-coated particles with controlled cell interaction

Monday, April 9, 2018, 4:14 PM ET

By typical manufacturing techniques, microparticles are simple, spherical, homogenous structures with little feature of interest. This is, effectively, the only configuration possible by conventional emulsion-type manufacturing techniques. There are a great deal of potential applications for developing microparticles which do not obey this simple shape. Recently, researchers at Johns Hopkins University used PLGA (PolyVivo AP087) from PolySciTech (www.polyscitech.com) to develop oblong-shaped microparticles with a carefully controlled coating of a lipid shell bearing various moieties. They investigated the interactions of these particles with cells and proteins and found that ellipsoid particles were resistant to macrophage uptake as well as had several other interesting features. This research holds promise for the development of advanced drug-delivery platforms as well as for other biomedical applications. Read more: Meyer, Randall A., Mohit P. Mathew, Elana Ben-Akiva, Joel C. Sunshine, Ron B. Shmueli, Qiuyin Ren, Kevin J. Yarema, and Jordan J. Green. "Anisotropic Biodegradable Lipid Coated Particles for Spatially Dynamic Protein Presentation." Acta Biomaterialia (2018). https://www.sciencedirect.com/science/article/pii/S1742706118301880

“Abstract: There has been growing interest in the use of particles coated with lipids for applications ranging from drug delivery, gene delivery, and diagnostic imaging to immunoengineering. To date, almost all particles with lipid coatings have been spherical despite emerging evidence that non-spherical shapes can provide important advantages including reduced non-specific elimination and increased target-specific binding. We combine control of core particle geometry with control of particle surface functionality by developing anisotropic, biodegradable ellipsoidal particles with lipid coatings. We demonstrate that these lipid coated ellipsoidal particles maintain advantageous properties of lipid polymer hybrid particles, such as the ability for modular protein conjugation to the particle surface using versatile bioorthogonal ligation reactions. In addition, they exhibit biomimetic membrane fluidity and demonstrate lateral diffusive properties characteristic of natural membrane proteins. These ellipsoidal particles simultaneously provide benefits of non-spherical particles in terms of stability and resistance to non-specific phagocytosis by macrophages as well as enhanced targeted binding. These biomaterials provide a novel and flexible platform for numerous biomedical applications. Statement of Significance: The research reported here documents the ability of non-spherical polymeric particles to be coated with lipids to form anisotropic biomimetic particles. In addition, we demonstrate that these lipid-coated biodegradable polymeric particles can be conjugated to a wide variety of biological molecules in a “click-like” fashion. This is of interest due to the multiple types of cellular mimicry enabled by this biomaterial based technology. These features include mimicry of the highly anisotropic shape exhibited by cells, surface presentation of membrane bound protein mimetics, and lateral diffusivity of membrane bound substrates comparable to that of a plasma membrane. This platform is demonstrated to facilitate targeted cell binding while being resistant to non-specific cellular uptake. Such a platform could allow for investigations into how physical parameters of a particle and its surface affect the interface between biomaterials and cells, as well as provide biomimetic technology platforms for drug delivery and cellular engineering. Keywords: Lipids; Polymers; Membrane fluidity; Particle shape; Biomimetic”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Poly(lactide) from PolySciTech used in generating light-activated shape-changing microparticles

Thursday, April 5, 2018, 4:32 PM ET

Shape memory is an effect in which polymer chains temporarily entangle holding the material in a set shape until the polymer is heated above a specific rubber-glass transition temperature at which point the polymer chains can move and the material naturally forms back into its original shape. Recently, researchers at Johns Hopkins University purchased PLA (PolyVivo AP004) from PolySciTech (www.polyscitech.com) and used it to create a gold nanoparticle loaded microparticle which changes from elongated shapes into spherical shapes when heated gently by exposure to light. This research holds promise to create materials with tunable macrophage uptake for a variety of biomedical applications. Read more: Guo, Qiongyu, Corey J. Bishop, Randall A. Meyer, David R. Wilson, Lauren Olasov, Daphne E. Schlesinger, Patrick T. Mather, James B. Spicer, Jennifer H. Elisseeff, and Jordan J. Green. "Entanglement-Based Thermoplastic Shape Memory Polymeric Particles with Photothermal Actuation for Biomedical Applications." ACS Applied Materials & Interfaces (2018). https://pubs.acs.org/doi/abs/10.1021/acsami.8b01582

“Abstract: Triggering shape memory functionality under clinical hyperthermia temperatures could enable the control and actuation of shape memory systems in clinical practice. For this purpose, we developed light-inducible shape memory microparticles composed of a poly (D,L-lactic acid) (PDLLA) matrix encapsulating gold nanoparticles (Au@PDLLA hybrid microparticles). This shape memory polymeric system for the first time demonstrates the capability of maintaining an anisotropic shape at body temperature with triggered shape memory effect back to a spherical shape at a narrow temperature range above body temperature with a proper shape recovery speed (37 ˚C < T < 45 ˚C). We applied a modified film-stretching processing method with carefully controlled stretching temperature to enable shape memory and anisotropy in these micron-sized particles. Accordingly, we achieved purely entanglement-based shape memory response without chemical crosslinks in the miniaturized shape memory system. Furthermore, these shape memory microparticles exhibited light-induced spatiotemporal control of their shape recovery using a laser to trigger photothermal heating of doped gold nanoparticles. This shape memory system is composed of biocompatible components and exhibits spatiotemporal controllability of its properties, demonstrating potential for various biomedical applications, such as tuning macrophage phagocytosis as demonstrated in this study.”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Malemide-PEG-PLGA and mPEG-PLGA from PolySciTech used in developing ligand-decorated, curcumin-loaded nanoparticles for breast-cancer treatment

Tuesday, April 3, 2018, 4:12 PM ET

There is a greater interface between herbal/traditional medicine and scientific medicine than most know about. Medicine can be derived from many natural sources (e.g. Paclitaxel derived from Pacific Yew tree) and medicinal chemists often focus on discovering new therapeutic agents derived from nature. Tumeric, and more specifically the extracted curcumin, has been of great interest lately due to curcumin’s anti-cancer properties. Simply eating tumeric spice, however, does not yield a significant anticancer effect for the majority of the body as curcumin has very poor absorption across the intestine. However, properly formulated and purified curcumin, can be a very powerful anticancer agent. It has an advantage over other chemotherapeutics in that it has minimal side-effects. Recently, researchers at Yantie University (China) used Maleimide-PEG-PLGA (PolyVivo AI020) and mPEG-PLGA (PolyVivo AK037) from PolySciTech (www.polyscitech.com) to generate curcumin loaded nanoparticles with Fab targeting ligands for treating breast cancer. This research holds promise for effective breast-cancer treatment with minimal chemotherapy side effects. Read more: Duan, Dongyu, Aiping Wang, Ling Ni, Liping Zhang, Xiuju Yan, Ying Jiang, Hongjie Mu, Zimei Wu, Kaoxiang Sun, and Youxin Li. "Trastuzumab-and Fab′ fragment-modified curcumin PEG-PLGA nanoparticles: preparation and evaluation in vitro and in vivo." International Journal of Nanomedicine 13 (2018): 1831. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868600/

“Abstract: Introduction: Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab’ (antigen-binding fragments cut from TMAB)-modified NPs (Fab′-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells. Material and methods: The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab′-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: The release kinetics showed that both Fab′-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab′-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab′-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2−) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab′-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab′-Cur-NPs was higher than that of TMAB-Cur-NPs. Conclusion: Fab′ fragment has greater capacity than the intact antibody to achieve tumor targeting through NP-based delivery. Keywords: trastuzumab-modified curcumin nanoparticles, Fab′-modified curcumin nanoparticles, pharmacokinetics, biodistribution, tumour targeting, breast cancer”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

PLGA from PolySciTech used in development of tannin-inspired antimicrobial bio-adhesives

Thursday, March 22, 2018, 9:37 PM ET

A valuable tool for wound-healing and surgical procedures is tissue adhesives which can bind tissues together and allow them to regrow. Due to the potential for infection, it is desirable for these adhesives to have antibiotic properties. Recently, researchers at Pennsylvania State University, Zhejiang Wanli University, Harbin Engineering University, and Jiangxi Provincial Children’s Hospital used PLGA (PolyVivo AP154) from PolySciTech (www.polyscitech.com) to act as a biocompatibility control for testing the cytotoxicity of their developed systems. This research holds promise to improve would healing and prevent infections. Read more: Guo, Jinshan, Wei Sun, Jimin Peter Kim, Xili Lu, Qiyao Li, Min Lin, Oliver Mrowczynski et al. "Development of tannin-inspired antimicrobial bioadhesives." Acta Biomaterialia (2018). https://www.sciencedirect.com/science/article/pii/S1742706118301284

“Abstract: Tissue adhesives play an important role in surgery to close wounds, seal tissues, and stop bleeding, but existing adhesives are costly, cytotoxic, or bond weakly to tissue. Inspired by the water-resistant adhesion of plant-derived tannins, we herein report a new family of bioadhesives derived from a facile, one-step Michael addition of tannic acid and gelatin under oxidizing conditions and crosslinked by silver nitrate. The oxidized polyphenol groups of tannic acid enable wet tissue adhesion through catecholamine-like chemistry, while both tannic acid and silver nanoparticles reduced from silver nitrate provide antimicrobial sources inherent within the polymeric network. These tannin-inspired gelatin bioadhesives are low-cost and readily scalable and eliminate the concerns of potential neurological effect brought by mussel-inspired strategy due to the inclusion of dopamine; variations in gelatin source (fish, bovine, or porcine) and monomer feeding ratios resulted in tunable gelation times (36 s to 8 min), controllable degradation (up to 100% degradation within a month), considerable wet tissue adhesion strengths (up to 3.7 times to that of fibrin glue), excellent cytocompatibility, as well as antibacterial and antifungal properties. The innate properties of tannic acid as a natural phenolic crosslinker, molecular glue, and antimicrobial agent warrant a unique and significant approach to bioadhesive design. Keywords: tannin; polyphenol; gelatin; bioadhesives; antimicrobial; medical device”


BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Maleimide-PEG-PLGA from PolySciTech used in development of targeted nanoparticle brain-cancer therapy

Thursday, March 22, 2018, 9:35 PM ET

Brain cancer is doubly difficult to treat as most chemotherapeutics are cytotoxic and uptake to the tumor is poor due to the blood-brain-barrier. Recently, researchers at Yantai University (China) used PLGA-PEG-Mal (Polyvivo AI020) from PolySciTech (www.polyscitech.com) to generate targeted nanoparticles for treating glioma. This research holds promise for improved therapy of brain cancer. Read more: Hua, Hongchen, Xuemei Zhang, Hongjie Mu, Qingqing Meng, Ying Jiang, Yiyun Wang, Xiaoyan Lu et al. "RVG29-modified Docetaxel-loaded nanoparticles for brain-targeted glioma therapy." International Journal of Pharmaceutics (2018). https://www.sciencedirect.com/science/article/pii/S0378517318301753

“Abstract: Gliomas are the most common malignant brain tumor, but treatment is limited by the blood–brain barrier (BBB), especially for chemotherapeutic drugs. Although some chemotherapy drugs can pass through the BBB, many of these agents are toxic to normal brain tissue. To maximize therapeutic effects, chemotherapeutic drugs must accumulate at the glioma site. In this study, a specific ligand (the RVG29 peptide) that can combine with acetylcholine receptors was conjugated to polyethylene glycol-modified poly-(D,L-lactide-co-glycolide) (PEG-PLGA) to develop a targeted carrier; preparation of the targeted docetaxel nanoparticles (DTX-NPs) was performed by the nanoprecipitation method. The NPs were approximately 110 nm and had smooth surfaces. Enzyme-linked immunoassay results showed that the amount of receptor on the surface of glioma cells was 2.04-fold higher than that of nonmalignant cells, which may promote accumulation of RVG29-modified NPs at the targeting site. NPs showed targeting properties for glioma cells compared with the non-targeting NPs in an in vitro cellular uptake test. Targeted NPs also showed better BBB penetration in an in vitro model. In vivo tests indicated that RVG29-PEG-PLGA-NPs could selectively accumulate in intracranial glioma tissue. In conclusion, these results indicated that the RVG29-modified NPs have potential efficacy for glioma therapy. Keywords: Brain-targeting; glioma; RVG29; blood–brain barrier; Docetaxel”
BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Fluorescent-PLGA and PLGA-PEG-Mal from PolySciTech used in study on Fab-targeting of nanoparticles

Monday, March 19, 2018, 6:27 PM ET

Targeted nanoparticles have come to the forefront recently for their application towards cancer by allowing the particles to bind to specific sites on tumors. There are many factors, however, which can interfere with this process and not all of them are well understood yet. Recently, researchers at Universidade do Porto (Portugal) and Uppsala University (Sweden) utilized fluorescently-tagged PLGA (PLGA-FKR648, AV015) and PLGA-PEG-Mal (AI110) from PolySciTech (www.polyscitech.com) to create Fab-decorated nanoparticles bearing a fluorescent tracer. These particles were used, along with a series of surfactants, to determine the impact these surfactants had on the targeting capabilities of these nanoparticles. This research holds promise to help in generation of more effective targeted nanoparticle systems by optimizing the surfactant utilized. Read more: Kennedy, Patrick J., Ines Perreira, Daniel Ferreira, Marika Nestor, Carla Oliveira, Pedro L. Granja, and Bruno Sarmento. "Impact of Surfactants on the Target Recognition of Fab-Conjugated PLGA Nanoparticles." European Journal of Pharmaceutics and Biopharmaceutics (2018). https://www.sciencedirect.com/science/article/pii/S0939641118301784

“Abstract: Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed. Keywords: Targeted nanoparticles; PLGA nanoparticles; surfactant; Fab antibody fragment”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

Maleimide-PEG-PLGA from PolySciTech used in fundamental research on thiol-maleimide conjugation for generating targeted nanoparticles

Thursday, March 15, 2018, 9:18 PM ET

A popular method for cancer treatment is to apply chemotherapeutic or other agents through nanoparticles that float through the patient’s bloodstream. Ideally, these particles are preferentially retained within the tumor site where they deliver their medicinal payload. To facilitate this, the nanoparticles are often covered with a specific targeting ligand. This ligand binds to a select site present on the cancer cells which is not found, or is less prevalent in, normal tissue. A popular chemical technique to create such a nanoparticle is to use PLGA-PEG-Maleimide as a precursor component for making nanoparticles covered with maleimide groups. These maleimides react readily with thiols (typically found in proteins as cysteine units) to bind the protein ligand to the outer surface of the nanoparticle. Despite this reaction’s popularity for use in generating targeted nanoparticles, little has been done in terms of understanding and optimizing the exact reaction kinetics involved with this reaction. Recently, researchers at Utrecht University (Netherlands) utilized reactive maleimide-PEG-PLGA (AI020) and inert methoxy-PEG-PLGA (AK037) from PolySciTech (www.polyscitech.com) to investigate the reaction kinetics and optimization parameters of thiol-maleimide conjugation as applied to nanoparticles. Notably, they found that the formed maleimide-coated nanoparticles should be used soon after manufacture as the maleimide unit itself can be affected by a hydrolysis reaction. This valuable research provides critical information for researchers looking to design targeted nanoparticles using this popular and robust chemistry. Read more: Martínez-Jothar, Lucía, Sofia Doulkeridou, Raymond M. Schiffelers, Javier Sastre Torano, Sabrina Oliveira, Cornelus F. van Nostrum, and Wim E. Hennink. "Insights into maleimide–thiol conjugation chemistry: conditions for efficient surface functionalization of nanoparticles for receptor targeting." Journal of Controlled Release (2018). https://www.sciencedirect.com/science/article/pii/S0168365918301238

“Abstract: Maleimide-thiol chemistry is widely used for the design and preparation of ligand-decorated drug delivery systems such as poly(lactide-co-glycolide) (PLGA) based nanoparticles (NPs). While many publications on nanocarriers functionalized exploiting this strategy are available in the literature, the conditions at which this reaction takes place vary among publications. This paper presents a comprehensive study on the conjugation of the peptide cRGDfK and the nanobody 11A4 (both containing a free thiol group) to maleimide functionalized PLGA NPs by means of the maleimide-thiol click reaction. The influence of different parameters, such as the nanoparticles preparation method and storage conditions as well as the molar ratio of maleimide to ligand used for conjugation, on the reaction efficiency has been evaluated. The NPs were prepared by a single or double emulsion method using different types and concentrations of surfactants and stored at 4 or 20 °C before reaction with the targeting moieties. Several maleimide to ligand molar ratios and different reaction times were studied and the conjugation efficiency was determined by quantification of the not-bound ligand by liquid chromatography. The kind of emulsion used to prepare the NPs as well as the type and concentration of surfactant used had no effect on the conjugation efficiency. Reaction between the maleimide groups present in the NPs and cRGDfK was optimal at a maleimide to thiol molar ratio of 2:1, reaching a conjugation efficiency of 84 ± 4% after 30 min at room temperature in 10 mM HEPES pH 7.0. For 11A4 nanobody the optimal reaction efficiency, 58 ± 12%, was achieved after 2 h of incubation at room temperature in PBS pH 7.4 using a 5:1 maleimide to protein molar ratio. Storage of the NPs at 4 °C for 7 days prior to their exposure to the ligands resulted in approximately 10% decrease in the reactivity of maleimide in contrast to storage at 20 °C which led to almost 40% of the maleimide being unreactive after the same storage time. Our findings demonstrate that optimization of this reaction, particularly in terms of reactant ratios, can represent a significant increase in the conjugation efficiency and prevent considerable waste of resources. Keywords: Nanoparticles; PLGA; Maleimide; Targeting; RGD; Nanobody”

BPCR conference (August 29, 2018 9AM - 4PM: Kurz Purdue Technology Center, West Lafayette, IN) is a free, 1-day scientific networking conference hosted by Akina, Inc. which focuses on research companies in the biotechnology, pharmaceutical, medical, and broader life-science fields. See more at BPCRconference.com

PLLA from PolySciTech used in fundamental research project on polymer processing conditions and crystallinity formation

Monday, March 12, 2018, 5:47 PM ET

One of the key parameters controlling polymer mechanical and optical behavior is how the polymer chains arrange or ‘stack’ relative to each other. Chemically, polymers with regular, repeating structures tend to stack more closely into crystalline forms than polymers which have irregular structures where steric hindrance prevent the chains from getting to close to one another. Additionally, the speed and conditions at which the polymers solidify (either from solvent or melt) as well as any mechanical drawing force play a role in crystalline domain formation. The more time the chains have to rearrange, the more they tend to crystallize and, if there is an applied force, they tend to crystallize parallel to the direction of the force. Recently, researchers from Université d’Orléans (France) utilized PLLA (PolyVivo AP006 and PolyVivo AP050) from PolySciTech (www.polyscitech.com) to perform fundamental research on the effect processing conditions have on crystalline PLLA film formation. This research holds promise for the development of mechanically robust or optically clear components for use in biomedical applications. Read more: Vayer, Marylène, Alain Pineau, Fabienne Warmont, Marjorie Roulet, and Christophe Sinturel. "Constrained crystallization of poly (L-lactic acid) in thin films prepared by dip coating." European Polymer Journal (2018)., https://www.sciencedirect.com/science/article/pii/S0014305717322413

“Abstract: Dip coating process used at various withdrawing speeds showed a great ability to control the crystalline structure of thin films of poly(L-lactic acid) which can be of great importance for applications where mechanical or optical properties are involved. Thin films were studied by Atomic Force Microscopy and Grazing Incidence Angle X-ray Diffraction. Withdrawing the silicon substrate in the draining regime (at high speed) led to amorphous films with flat surface whatever the solvent and the molar mass. At low speeds (capillary regime), AFM demonstrated the presence of spherulites or hedrites in the films depending on the solvent and the molar mass. GIXRD showed that spherulites were less crystallized than hedrites. This difference was attributed to solvent evaporation rate. Highlights: PLLA thin films were prepared by dip coating solutions. The thin films were investigated using AFM and GIXRD. Withdrawal at high speed led to amorphous films. Withdrawal at low speed led to partially crystallized films. The nature of solvent and molecular mass influenced the crystalline structure of the films.”

PLGA-PEG-COOH from PolySciTech used in the development of Salinomycin-loaded nanoparticle-based ovarian cancer treatment

Tuesday, March 6, 2018, 9:26 PM ET

Like other tissues, cancer has stem cells as part of its growth. In the case of cancer, these stem cells serve to allow the disease to regrow even if the main tumor is destroyed by traditional therapy. One therapeutic approach is to target the stem-cells thus preventing cancer from re-growing. Recently, researchers at Hubei University of Medicine and Wuhan University (China) used PLGA-PEG-COOH (PolyVivo AI034) from PolySciTech (www.polyscitech.com) to generate CD133 targeted nanoparticles for delivering Salinomycin to ovarian cancer stem cells. This research holds promise for improved therapeutic strategies for this potentially fatal form of cancer. Read more: Mi, Yi, Yuqin Huang, and Jie Deng “The enhanced delivery of salinomycin to CD133+ ovarian cancer stem cells through CD133 antibody conjugation with poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles” Oncology Letters 2018, DOI: 10.3892/ol.2018.8140 https://www.spandidos-publications.com/10.3892/ol.2018.8140

“Abstract: Ovarian cancer is the most lethal gynecologic malignancy, and ovarian cancer stem cells (CSCs) serve a pivotal function in the metastasis and recurrence of ovarian cancer. Multiple previous studies have validated CD133 as a marker of ovarian CSCs. Although salinomycin is a promising therapeutic agent that has been demonstrated to kill CSCs in various types of cancer, poor aqueous solubility hampers its clinical application. The present study used salinomycinloaded poly(lacticcoglycolic acid)poly(ethylene glycol) nanoparticles conjugated with CD133 antibodies (CD133SALNP) to eliminate CD133+ ovarian CSCs. The results revealed that CD133SALNPs were of an appropriate size (149.2 nm) and exhibited sustained drug release. CD133SALNPs efficiently bound to CD133+ ovarian cancer cells, resulting in an increased cytotoxic effect in CD133+ ovarian cancer cells, compared with the untargeted SALNPs and salinomycin. CD133SALNPs reduced the percentage of CD133+ ovarian CSCs in ovarian cells more effectively than treatment with salinomycin or SALNPs, suggesting that CD133SALNP targeted CD133+ ovarian CSCs. In nude mice bearing ovarian cancer xenografts, CD133SALNPs exerted improved therapeutic effects compared with SALNPs and salinomycin. Thus, CD133 was demonstrated to be a promising target for drug delivery to ovarian CSCs, and may be useful as an agent to inhibit the growth of ovarian cancer by targeting CD133+ ovarian CSCs. CD133SALNPs may therefore represent a promising approach for the treatment of ovarian cancer.”

PLA-PEG-PLA from PolySciTech used in development of Photo-thermal platform for use in post-surgical treatment of cancer

Tuesday, March 6, 2018, 9:25 PM ET

There are many different types of ‘light’ beyond the visible spectrum. One example is near-infrared (~700-1000 nm), which is of lower frequency than visible red light. This form of light has the unique capability to penetrate through tissue. This feature is typically applied in tandem with a fluorescent dye for imaging, however it can also be applied with a photothermal agent to cause localized heating in a specific region, such as the tissue immediately surrounding a tumor. Recently, researchers at the Chinese Academy of Sciences and the City University of Hong Kong used PLA-PEG-PLA thermogel (Polyvivo AK100) from PolySciTech (www.polyscitech.com) to generate a near-infrared responsive photothermal therapy gel system. This research holds promise for the development of novel therapeutic options for cancer treatment. Read more: Shao, Jundong, Changshun Ruan, Hanhan Xie, Zhibin Li, Huaiyu Wang, Paul K. Chu, and Xue-Feng Yu “Black-Phosphorus-Incorporated Hydrogel as a Sprayable and Biodegradable Photothermal Platform for Postsurgical Treatment of Cancer” Adv. Sci. 2018, 1700848, 3 March 2018, 10.1002/advs.201700848 http://onlinelibrary.wiley.com/doi/10.1002/advs.201700848/full

“Abstract: Photothermal therapy (PTT) is a fledgling therapeutic strategy for cancer treatment with minimal invasiveness but clinical adoption has been stifled by concerns such as insufficient biodegradability of the PTT agents and lack of an efficient delivery system. Here, black phosphorus (BP) nanosheets are incorporated with a thermosensitive hydrogel [poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL)] to produce a new PTT system for postoperative treatment of cancer. The BP@PLEL hydrogel exhibits excellent near infrared (NIR) photothermal performance and a rapid NIR-induced sol–gel transition as well as good biodegradability and biocompatibility in vitro and in vivo. Based on these merits, an in vivo PTT postoperative treatment strategy is established. Under NIR irradiation, the sprayed BP@PLEL hydrogel enables rapid gelation forming a gelled membrane on wounds and offers high PTT efficacy to eliminate residual tumor tissues after tumor removal surgery. Furthermore, the good photothermal antibacterial performance prevents infection and this efficient and biodegradable PTT system is very promising in postoperative treatment of cancer.”

Akina, Inc. hosting free scientific-networking conference in West Lafayette Purdue Research Park on August 29

Monday, March 5, 2018, 10:09 AM ET

Thanks to the efforts of numerous entrepreneurs, working alongside Purdue Research Foundation, the number of scientific and engineering startup companies in the West Lafayette has exploded over the past decade. In order to encourage collaborations, networking, and visibility in the biotechnology, pharmaceutical, and research-oriented fields, Akina, Inc. (www.akinainc.com) is hosting the BPCR Conference. This is a free, 1-day scientific-networking conference located at the Kurz Purdue Technology Center (KPTC), right in the heart of the Purdue Research Park, and is open to the public. Booth space (10x10’, includes 6’ table and 2 chairs) as well as ‘soap-box’ presentations (30 min. Audio-visual support provided) slots are still available, but will fill up fast so plan to register sooner rather than later. Lunch is provided for registered attendees. Learn more and register online at BPCRconference.com

mPEG-PLA from PolySciTech used in development of novel quisinostat-loaded nanoparticles for brain-cancer therapy

Wednesday, February 28, 2018, 1:51 PM ET

DNA in human cells can be either loose or tightly bound to proteins known as histones. When DNA is bound to histones, it cannot be transcribed (read) and this is a typical method of gene control within a cell as only the relevant portions of the DNA can be transcribed. Unlike normal cells, fast-growing cancers have an excess of an enzyme which binds DNA to the histones very tightly and affects how it is read changing how the cells DNA is interpreted. It has been found that inhibitors of this enzyme, such as quisinostat, can prevent the growth and spread of certain cancers. However, these inhibitors have very poor uptake and delivery. Recently, researchers at Barrow Neurological Institute and Arizona State University utilized mPEG-PLA (polyvivo AK054) from PolySciTech (www.polyscitech.com) to generate nanoparticles loaded with quisinostat. They found these nanoparticles to be effective in slowing the growth of glioblastoma in an animal model. This research holds promise for developing new therapeutic strategies for rapidly growing cancers including brain-cancer. Read more: Householder, Kyle T., Danielle M. DiPerna, Eugene P. Chung, Rosa Luning, Duong Nguyen, Sarah Stabenfeldt, Shwetal Mehta, and Rachael W. Sirianni. "pH Driven Precipitation of Quisinostat onto PLA-PEG Nanoparticles Enables Treatment of Intracranial Glioblastoma." Colloids and Surfaces B: Biointerfaces (2018). https://www.sciencedirect.com/science/article/pii/S0927776518301231

“Highlights: Ionized quisinostat is loaded more efficiently onto PLA-PEG nanoparticles. Quisinostat potency is maintained through nanoparticle processing. Quisinostat-loaded nanoparticles administered IV slow intracranial GL261 glioma tumors. Abstract: Histone deacetylases (HDACs) are known to be key enzymes in cancer development and progression through their modulation of chromatin structure and numerous proteins. Aggressive dedifferentiated tumors, like glioblastoma, frequently overexpress HDACs, while HDAC inhibition can lead to cell cycle arrest, promote cellular differentiation and induce apoptosis. Although multiple HDAC inhibitors, such as quisinostat, are of interest in oncology therapy due to their potent in vitro efficacy, poor delivery has been attributed to their failure in the clinic as monotherapies against solid tumors. Thus, we were motivated to develop quisinostat loaded poly(D,L-lactide)-b-methoxy poly(ethylene glycol) nanoparticles (NPs) to test their ability to enable effective quisinostat delivery to orthotopic glioblastoma. In developing our NP formulation, we identified a novel, pH-driven approach for achieving over 9% (w/w) quisinostat loading. We show quisinostat-loaded NPs maintain drug potency in vitro and effectively slow tumor growth in vivo, leading to a prolonged survival compared to control mice. Keywords: Glioblastoma; nanoparticle; HDAC; quisinostat (JNJ-26481585); PLA-PEG; pH”

PLGA-PEG-NHS and mPEG-PLGA from PolySciTech used in development of peptide-targeting nanoparticle for triple-negative breast cancer therapy

Monday, February 19, 2018, 5:24 PM ET

Targeted medicine is better described as ‘retentive’ or possibly ‘adhesive’ medicine. Any molecule which enters the human blood-stream is rapidly circulated throughout all parts of the entire body. Conventional medicines have a very limited and specific mechanism of action, which is why their effects are only experienced in the disease-state locations. That being said, exceeding the dosage on conventional drugs can cause toxic effects and the most common example of this is acetaminophen, a headache medicine, which in excessive doses can cause toxicity in the liver. Amongst medicinal therapies, chemotherapy is unique in that it is comprised of compounds known to either kill, or prevent the replication of, human cells and it is dosed at a concentration known to be toxic. The ‘theory of action’ is that, since the cancer is growing faster than all other tissues, it will be more affected than other tissues. Unfortunately, all cells are affected, which is why chemotherapy patients lose their hair and have several other side-effects. Although medicine in the blood-stream will flow to all parts of the human body, use of nanoparticles or other delivery systems which have a specific binding ligand will encourage the nanoparticles to be retained at the site of specific cells through ligand binding mechanisms (e.g. the nanoparticles flow everywhere, but they ‘stick’ to the cancer by ligand binding) Recently, researchers from Johns Hopkins University and AsclepiX Therapeutics used AI111 (PLGA-PEG-NHS) and AK037 (mPEG-PLGA) from PolySciTech (www.polyscitech.com) to create peptide-decorated nanoparticles for adhesion to triple-negative breast cancer. This research holds promise for improved treatments for this drug-resistant and highly invasive form of cancer. Read more: Bressler, Eric M., Jayoung Kim, Ron B. Shmueli, Adam C. Mirando, Hojjat Bazzazi, Esak Lee, Aleksander S. Popel, Niranjan B. Pandey, and Jordan J. Green. "Biomimetic peptide display from a polymeric nanoparticle surface for targeting and antitumor activity to human triple‐negative breast cancer cells." Journal of Biomedical Materials Research Part A (2018). http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.36360/full

“Abstract: While poly(lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) can encapsulate drug cargos and prolong circulation times, they show non-specific accumulation in off-target tissues. Targeted delivery of drugs to tumor tissue and tumor vasculature is a promising approach for treating solid tumors while enhancing specificity and reducing systemic toxicity. AXT050, a collagen-IV derived peptide with both antitumor and antiangiogenic properties, is shown to bind to tumor-associated integrins with high affinity, which leads to targeted accumulation in tumor tissue. AXT050 conjugated to PLGA-PEG NPs at precisely controlled surface density functions both as a targeting agent to human tumor cells and demonstrates potential for simultaneous antitumorigenic and antiangiogenic activity. These targeted NPs cause inhibition of adhesion and proliferation in vitro when added to human triple-negative breast cancer cells and microvascular endothelial cells through binding to integrin αVβ3. Furthermore, we find an in vivo biphasic relationship between tumor targeting and surface coating density of NPs coated with AXT050. NPs with an intermediate level of 10% peptide surface coating show approximately two-fold greater accumulation in tumors and lower accumulation in the liver compared to non-targeted PLGA-PEG NPs in a murine biodistribution model. Display of biomimetic peptides from NP surfaces to both target and inhibit cancer cells has the potential to enhance the activity of cancer nanomedicines.”

Mal-PEG-PLGA and mPEG-PLGA from PolySciTech used to develop phototherapy nanoparticles for triple-negative breast cancer treatment

Thursday, February 15, 2018, 4:11 PM ET

Cancer survival rates and prognosis depends on both location and type of cancer. For breast-cancer, one of the most devastating and difficult to treat forms is what is referred to as triple-negative breast cancer. This breast cancer lacks typical markers and factors, such as HER, which normal breast cancers possess. Since these markers are usually targeted in traditional therapy, this makes treating this type of cancer very difficult. Additionally, these types of cancer tend to grow aggressively. Recently, researchers from University of Massachusetts Lowell used Polyvivo mPEG-PLGA (AK037) and PLGA-PEG-Mal (AI020) from PolySciTech (www.polyscitech.com) to develop unique phototriggered nanoparticles to treat breast cancer which respond to near-infrared light to destroy the tumors. This holds promise for improved treatment options for this often lethal and difficult to treat disease. Read more: Jadia, Rahul, Janel Kydd, and Prakash Rai. "Remotely Phototriggered, Transferrin‐Targeted Polymeric Nanoparticles for the Treatment of Breast Cancer." Photochemistry and Photobiology. http://onlinelibrary.wiley.com/doi/10.1111/php.12903/full

“Abstract: Triple Negative Breast Cancer (TNBC) has the worst prognosis amongst all sub-types of breast cancer. Currently no targeted treatment has been approved for TNBC. The goal of this study was to design a remotely triggered, targeted therapy for TNBC using polymeric nanoparticles and light. Active targeting of TNBC was achieved by conjugating the nanoparticles to a peptide (hTf) that binds to the transferrin receptor, which is overexpressed in TNBC. Photodynamic Therapy (PDT) was explored for TNBC treatment by remotely triggering benzoporphyrin derivative monoacid (BPD), a photosensitizer, using near infrared light. In this study, we investigated the use of actively targeting polymeric nanoparticles for PDT against TNBC using in vitro imaging and cytotoxicity studies. Fluorescence imaging confirmed that the BPD loaded nanoparticles showed greater fluorescence in TNBC cells compared to free BPD, but more importantly actively targeted nanoparticles displayed stronger fluorescence compared to passively targeted nanoparticles. Moreover, fluorescence imaging following competition with empty targeted nanoparticles validated the specificity of the targeted nanoparticles for TNBC cells. The PDT killing results were in line with the fluorescence imaging results, where actively targeting nanoparticles exhibited the highest phototriggered cytotoxicity in TNBC cells, making them an attractive nanoplatform for TNBC treatment.”

PLLA from PolySciTech used in developing bioscaffold with dedicated perfusion channel for improved cell-growth

Thursday, February 15, 2018, 4:10 PM ET

Tissue engineering is a new field which holds promise to replace damaged or missing bone, muscle, skin, and even nerve tissue in injured patients. This technology relies on use of cell-scaffolds to provide mechanical support to the growing cells, as well as maintain suitable oxygen perfusion, cell-compatibility, and blood flow. This technology holds amazing potential to prevent amputations or life-time paralysis in the wake of severe trauma. However, the exact structure and nature of the cell-scaffold has to be exactly designed in order for the new-growing tissue to succeed. Recently, researchers at Chonnam National University (Korea) used PLLA (PolyVivo AP007) from PolySciTech (www.polyscitech.com) to develop a novel bone-tissue scaffold with a dedicated perfusion channel to ensure flow of oxygenated blood to the growing cells. This research holds promise to provide for repairing or replacing severely damaged bone tissue without requiring an autograft. Read more: Tan, Shiyi, Jiafei Gu, Seung Chul Han, Dong-Weon Lee, and Kiju Kang. "Design and fabrication of a non-clogging scaffold composed of semi-permeable membrane." Materials & Design 142 (2018): 229-239. https://www.sciencedirect.com/science/article/pii/S0264127518300418

“Highlights: A 3D polymer membrane architecture was proposed as a novel concept of bio scaffold. It had two sub-volumes that were intertwined but separated by a semi-permeable membrane. One sub-volume was used for cell culture, while the other served as a perfusion channel. Mass transfer was implemented through the interfacial semi-permeable membrane. Despite very high porosity, its strength & modulus was appropriate for bones or cartilages. Abstract: In this study, a novel concept of polymer scaffold was proposed based on 3D porous membrane architecture. It had two distinct sub-volumes intertwined with each other but separated by a single continuous smooth semi-permeable membrane. One sub-volume was used for cell culture, while the other served as a perfusion channel. Mass transfer was implemented through the interfacial porous membrane. Consequently, this scaffold was expected to be completely free from clogging problem due to growing tissue. The sample scaffolds of poly l-lactic acid (PLLA) was fabricated based on 3D UV photo-lithography and porogen leaching technique, which provided a P-surface-like architecture composed of porous membrane having smooth and fine texture with considerably high porosity. Despite high overall porosity of approximately 97%, these scaffolds had strengths and Young's moduli appropriate for regeneration of bones or cartilages. Wettability and permeability of polydopamine-coated PLLA porous membrane were sufficiently high. Keywords: 3D membrane architecture; Minimal surface; Scaffold; 3D lithography”

PLGA, PLA, and PCL from PolySciTech used in fundamental research on Penicillin depot delivery

Thursday, February 15, 2018, 4:10 PM ET

There is great value in research for not only publishing results from successes but also from publishing results from lessons learned along the way (so-called ‘Negative results’). PLGA is a widely used polymer but its biodegradation naturally leads to formation of acidic products. These products (lactic/glycolic acid) are biocompatible, as they are common metabolic products already formed during normal cellular metabolism. However, they are still acidic in nature and can lead to a drop in pH within the PLGA carrier (For more on this, check out https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269251/). Penicillin is a widely used antibiotic that is also effective at treating rheumatic heart disease when applied as a series of injections. Recently, Researchers from Monash University, The University of Western Australia, and Princess Margaret Hospital for Children (Australia) used a variety of PLGA’s. PLA’s, and PCL polymers from PolySciTech (www.polyscitech.com) as part of a study on penicillin delivery. This included PolyVivo PLGA’s (AP021, AP043, and AP039) and PolyVivo PLA (AP071) as well as other polymers from PolySciTech to develop an injectable depot formulation for penicillin based on biocompatible NMP solvent. They discovered that the acid-sensitive nature of penicillin, however, prevented it from being used with PLGA as a carrier as the lactic/glycolic acid components degraded the penicillin. Use of PCL fixed this issue, however the total implant mass required an unwieldly 7 grams of material. This research provides critical understanding for others looking to develop long-acting injectable formulations. Read more: Montagnat, Oliver D., Graham R. Webster, Jurgen Bullita, Cornelia Landersdorfer, Rosemary Wyber, Meru Sheel, Jonathan R. Carapetis, and Ben J. Boyd. "Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD)." Drug Delivery and Translational Research (2018): 1-11. https://link.springer.com/article/10.1007/s13346-018-0482-z

“Abstract: The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development. Keywords Rheumatic fever Antibiotic Sustained release Drug delivery PLGA Therapeutic implant”

PLGA from PolySciTech used in the development of a multi-functional, theranostic nanoparticle for cancer therapy

Saturday, February 10, 2018, 10:24 PM ET

“Theranostic” is a term which combines ‘therapy’ and ‘diagnostic’ into a single word. In the realm of cancer research, it is a highly-sought after property for any regimen as cancer is difficult to diagnose, locate, and treat. Nanoparticles which can be targeted towards the cancerous lesions and render them either visible or act as ultrasound/electromagnetic contrast agents have great value in locating and diagnosing the cancer while nanoparticles which deliver chemotherapeutic agents can be useful for treating cancer. Recently, researchers working jointly at Yangzhou University and Soochow University (China) used PLGA (AP040) from PolySciTech (www.polyscitech.com) to develop nanoparticles which were decorated with gold nanoparticles (act as contrast agents as well as photosensitizers) and were loaded with doxorubicin (a chemotherapeutic agent). These particles were tested and found to be effective both at locating cancer as well as treating it. This research holds promise to provide for both improved diagnosis and treatment of cancer. Read more: Xi, Juqun, Wenjuan Wang, Lanyue Da, Jingjing Zhang, Lei Fan, and Lizeng Gao. "Au-PLGA hybrid nanoparticles with catalase-mimicking and near-infrared photothermal activities for photoacoustic imaging-guided cancer therapy." ACS Biomaterials Science & Engineering (2018). http://pubs.acs.org/doi/abs/10.1021/acsbiomaterials.7b00901

“Imaging-guided diagnosis and therapy has been highlighted in the area of nanomedicines. However, integrating multiple functions with high performance in one theranostic (“all-in-one”) still presents considerable challenges. Here, “all-in-one” nanoparticles with drug-loading capacity, catalase-mimetic activity, photoacoustic (PA) imaging ability and photothermal properties were prepared by decorating Au nanoparticles on doxorubicin (DOX) encapsulated poly(lactic-co-glycolic acid) (PLGA) vehicle. The results revealed that the as-prepared Au-PLGA hybrid nanoparticles possessed high photothermal conversion efficiency of up to approximately 69.0%, meanwhile their strong acoustic generation endowed them with efficient PA signal sensing for cancer diagnosis. On an 808 nm laser irradiation, the O2 generation, DOX release profile and reactive oxygen species (ROS) level were all improved, which were beneficial to relieving tumor hypoxia and enhanced the cancer chemo/PTT combined therapy. Overall, the multifunctional Au-PLGA hybrid nanoparticles with these integrated advantages shows promise in PA imaging-guided diagnosis and synergistic tumor ablation. Keywords: Au-PLGA hybrid nanoparticles; catalase-mimicking activity chemo/photothermal therapy; photoacoustic imaging”

Fluorescent PLGA-FKR648 used to track nanoparticles ability to cross the blood-brain-barrier as part of development of HIV treatment

Wednesday, February 7, 2018, 5:34 PM ET

Human immunovirus (HIV) is a wide-spread and incurably lethal disease. The Blood-Brain-Barrier (BBB) separates the brain tissue from the bloodstream and is intended to keep the brain safe from potentially toxic molecules within the bloodstream. One of the more insidious aspects of HIV is the capacity of the virus to ‘hide’ within the brain tissue where most anti-viral medications cannot reach it due to the BBB. This makes treating HIV particularly difficult as the virus can re-infest a patient from surviving copies in the brain tissue, even if the majority of the viral replicates have been destroyed. Recently, researchers at Universidade do Porto (Portugal) and University of Helsinki (Finland) used fluorescent PLGA-FKR648 (PolyVivo AV015) from PolySciTech (www.polyscitech.com) as part of development of BBB crossing nanoparticles to attack HIV virus which hides in the brain. This fluorescently-tagged PLGA was used to develop nanoparticles which could be tracked by microscopy to observe their uptake across the barrier. By visualizing these particles, the researchers were able to validate the success of their particles in crossing the BBB. This research holds promise for improved therapeutic options for HIV. Read more: Martins, Cláudia, Francisca Araújo, Maria João Gomes, Carlos Fernandes, Rute Nunes, Wei Li, Hélder A. Santos, Fernanda Borges, and Bruno Sarmento. "Using microfluidic platforms to develop CNS-targeted polymeric nanoparticles for HIV therapy." European Journal of Pharmaceutics and Biopharmaceutics (2018). https://www.sciencedirect.com/science/article/pii/S0939641117314820

“Abstract: The human immunodeficiency virus (HIV) uses the brain as reservoir, which turns it as a promising target to fight this pathology. Nanoparticles (NPs) of poly(lactic-co-glycolic) acid (PLGA) are potential carriers of anti-HIV drugs to the brain, since most of these antiretrovirals, as efavirenz (EFV), cannot surpass the blood–brain barrier (BBB). Forasmuch as the conventional production methods lack precise control over the final properties of particles, microfluidics emerged as a prospective alternative. This study aimed at developing EFV-loaded PLGA NPs through a conventional and microfluidic method, targeted to the BBB, in order to treat HIV neuropathology. Compared to the conventional method, NPs produced through microfluidics presented reduced size (73 nm versus 133 nm), comparable polydispersity (around 0.090), less negative zeta-potential (−14.1 mV versus −28.0 mV), higher EFV association efficiency (80.7% versus 32.7%) and higher drug loading (10.8% versus 3.2%). The microfluidics-produced NPs also demonstrated a sustained in vitro EFV release (50% released within the first 24 h). NPs functionalization with a transferrin receptor-binding peptide, envisaging BBB targeting, proved to be effective concerning nuclear magnetic resonance analysis (δ = −0.008 ppm; δ = −0.017 ppm). NPs demonstrated to be safe to BBB endothelial and neuron cells (metabolic activity above 70%), as well as non-hemolytic (1–2% of hemolysis, no morphological alterations on erythrocytes). Finally, functionalized nanosystems were able to interact more efficiently with BBB cells, and permeability of EFV associated with NPs through a BBB in vitro model was around 1.3-fold higher than the free drug. Keywords: Nanoparticles; Human immunodeficiency virus; Microfluidic production; Targeting; Blood-brain barrier”

PLGA-PEG-PLGA thermogel from PolySciTech used in development of highly-controlled microwave ablation technique

Monday, January 29, 2018, 2:38 PM ET

Amongst cancer treatments, ablation (the application of heat, cold, or chemicals in a minimally invasive manner directly to the tumor) has gained attention as a method to treat cancer without the systemic damage of chemotherapy or the invasive injuries from standard surgery. One of these techniques, microwave thermal ablation, works by using microwave energy to locally heat the tumor which kills the cancer while minimally affecting surrounding tissues. Recently, Researchers at Brown University/Rhode Island Hospital utilized PolyVivo (AK088) from PolySciTech (www.polyscitech.com) to develop a cesium-salt loaded thermogel which acted to increase the local heating in the vicinity of the tumor improving the effectiveness of thermal ablation. They tested these in an animal model and found the method to be highly effective with minimal side effects. This research holds promise to improve therapeutic options for tumor treatment with minimal side effects. Read more: Park, William Keun Chan, Aaron Wilhelm Palmer Maxwell, Victoria Elizabeth Frank, Michael Patrick Primmer, Jarod Brian Paul, Scott Andrew Collins, Kara Anne Lombardo et al. "The in vivo performance of a novel thermal accelerant agent used for augmentation of microwave energy delivery within biologic tissues during image-guided thermal ablation: a porcine study." International Journal of Hyperthermia 34, no. 1 (2018): 11-18. http://www.tandfonline.com/doi/abs/10.1080/02656736.2017.1317367

“Abstract: Objectives: To investigate the effects of a novel caesium-based thermal accelerant (TA) agent on ablation zone volumes following in vivo microwave ablation of porcine liver and skeletal muscle, and to correlate the effects of TA with target organ perfusion. Materials and methods: This prospective study was performed following institutional animal care and use committee approval. Microwave ablation was performed in liver and resting skeletal muscle in eight Sus scrofa domesticus swine following administration of TA at concentrations of 0 mg/mL (control), 100 mg/mL and 250 mg/mL. Treated tissues were explanted and stained with triphenyltetrazolium chloride (TTC) for quantification of ablation zone volumes, which were compared between TA and control conditions. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. General mixed modelling with a log-normal distribution was used for all quantitative comparisons (p = 0.05). Results: A total of 28 ablations were performed in the liver and 18 in the skeletal muscle. The use of TA significantly increased ablation zone volumes in a dose-dependent manner in both the porcine muscle and liver (p < 0.01). Both the absolute mean ablation zone volume and percentage increase in ablation zone volume were greater in the resting skeletal muscle than in the liver. In one swine, a qualitative mitigation of heat sink effects was observed by TTC and H&E staining. Non-lethal polymorphic ventricular tachycardia was identified in one swine, treated with intravenous amiodarone. Conclusions: The use of a novel TA agent significantly increased mean ablation zone volumes following microwave ablation using a porcine model. The relationship between TA administration and ablation size was dose-dependent and inversely proportional to the degree of target organ perfusion, and a qualitative reduction in heat-sink effects was observed. Keywords: Image-guided thermal ablation, thermal accelerant, augmentation of microwave energy, complete ablation, the heat sink effect”

PLGA-PEG-Mal and PLGA-PEG-methyl from PolySciTech used in development of oral exanatide-nanoparticle based diabetes treatment

Monday, January 22, 2018, 9:28 AM ET

Medicinal technology developments have several goals, depending on the application. In some cases, the goal is to develop a completely new therapy which did not exist before. In other cases, it is to take an existing therapy and reformulate it to improve either efficacy or convenience. Oral formulations are well known to be more convenient for both patient and practitioner as, unlike parental injections, they can be easily self-administered by a patient, are not painful, and do not require handling/safe-disposal of blood-exposed syringes which could potential spread bloodborne pathogens. Diabetes, notably, requires a great deal of injection-based therapy as part of its treatment. One type of this therapy is Exanatide, a glucagen-like peptide 1 receptor which acts to treat type 2 diabetes. Currently Exanatide is only available as an injectable formulation (Bydureon) as oral uptake is very poor. Recently, researchers at Binzhou Medical University, Yantai University, Luye Pharmaceutical Co, and Peking University (China) use PLGA-PEG-Mal (PolyVivo AI020) and mPEG-PLGA (AK037, AK102) from PolySciTech (www.polyscitech.com) to develop Fc decorated nanoparticles capable of crossing the intestinal mucosa for more effective delivery. This research holds promise to provide for a more convenient and effective therapy for diabetes. Read more: Shi, Yanan, Xinfeng Sun, Liping Zhang, Kaoxiang Sun, Keke Li, Youxin Li, and Qiang Zhang. "Fc-modified exenatide-loaded nanoparticles for oral delivery to improve hypoglycemic effects in mice." Scientific Reports 8, no. 1 (2018): 726. https://www.nature.com/articles/s41598-018-19170-y

“Abstract: To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery.”

Mal-PEG-PLGA and mPEG-PLGA from PolySciTech used in development of nanoparticle-based Parkinson’s treatment

Wednesday, January 17, 2018, 9:09 PM ET

Parkinson’s disease is a wide-spread neurodegenerative disorder with over 200,000 USA cases per year. The primary symptoms are loss of control over muscle movements which get progressively worse with time. This disease is caused by damage to dopaminergic neurons which leads to a lack of dopamine in the brain. Although incurable, there are drugs that can delay the progression of Parkinson’s. Because the drug action must occur within the brain, any medicine applied must cross the blood-brain-barrier, a screen that prevents most medicines from reaching the brain. Recently, researchers at Yantai University and Shandong Luye Pharmaceutics utilized mal-PEG-PLGA (Polyvivo AI109) and mPEG-PLGA (PolyVivo AK104) from PolySciTech (www.polyscitech.com) to generate lactoferin-decorated nanoparticles for rotigotine delivery across the blood-brain-barrier as a potential treatment for Parkinson’s disease. This research holds promise to halt the progress of this lethal disease. Read more: Yan X, Xu L, Bi C, Duan D, Chu L, Yu X, Wu Z, Wang A, Sun K “Lactoferrin-modified rotigotine nanoparticles for enhanced nose-to-brain delivery: LESA-MS/MS-based drug biodistribution, pharmacodynamics, and neuroprotective effects” International Journal of Nanomedicine, 9 January 2018 Volume 2018:13 Pages 273—281 https://www.dovepress.com/lactoferrin-modified-rotigotine-nanoparticles-for-enhanced-nose-to-bra-peer-reviewed-fulltext-article-IJN

“Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson’s disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD. Materials and methods: The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs. Results: Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference (P<0 .05="" 6-hydroxydopamine-induced="" alleviated="" and="" between="" biodistribution="" brain="" conclusion:="" contralateral="" deliver="" disease="" dopaminergic="" drug="" effects="" efficacy.="" efficiently="" enhancing="" findings="" for="" furthermore="" have="" in="" keywords:="" lactoferrin-modified="" lf-r-nps="" might="" model="" more="" nanoparticles="" neurodegeneration="" neuroprotective="" nigrostriatal="" nose="" o:p="" of="" our="" parkinson="" pd.="" pharmacodynamics="" potential="" r-nps.="" rat="" rats="" rotations="" rotigotine="" s="" show="" significantly="" that="" the="" therapeutic="" thereby="" therefore="" those="" to="" treated="" treatment="" with="">

These posts are syndicated from John Garner's blog at http://jgakinainc.blogspot.com/ where you can post a question or comment.


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