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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Cancer nanoparticle-based photodynamic therapy developed using mPEG-PLA from PolySciTech

Tuesday, June 20, 2017, 1:36 PM ET

Treating cancer is complicated by several features of the disease including metastasis, drug-resistance, and biological similarity of cancerous cells to healthy ones. Conventional chemotherapy is typically effective at killing cancer cells, however it lacks the capacity to discriminate between cancerous cells and healthy ones. This is where combination therapies can have an advantage. For phototherapy, instead of delivering a toxic molecule (such as cisplatin or paclitaxel) a photosensitizer is delivered. This molecule is inactive, unless it is activated by a very specific frequency of light which activates it killing the cell. The overall method here is to systematically deliver the photosensitizer to a patient and then selectively illuminate the portion where the cancer is located so only the cancer is affected. Recently, researchers working jointly at Northeastern University, George Washington University, and Wenzhou Medical University utilized mPEG-PLA from PolySciTech (www.polyscitech.com) (PolyVivo AK021) to create protoporphyrin IX (a photosensitizer) loaded nanoparticles. They combined these with photodynamic therapy and tested this system as a treatment for melanoma. This research holds promise to improve the treatment of melanoma, especially malignant or drug-resistant forms. Read more: Wang, Mian, Benjamin M. Geilich, Michael Keidar, and Thomas J. Webster. "Killing malignant melanoma cells with protoporphyrin IX-loaded polymersome-mediated photodynamic therapy and cold atmospheric plasma." International Journal of Nanomedicine 12 (2017): 4117. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459981/

“Abstract: Traditional cancer treatments contain several limitations such as incomplete ablation and multidrug resistance. It is known that photodynamic therapy (PDT) is an effective treatment for several tumor types especially melanoma cells. During the PDT process, protoporphyrin IX (PpIX), an effective photosensitizer, can selectively kill cancer cells by activating a special light source. When tumor cells encapsulate a photosensitizer, they can be easily excited into an excited state by a light source. In this study, cold atmospheric plasma (CAP) was used as a novel light source. Results of some studies have showed that cancer cells can be effectively killed by using either a light source or an individual treatment due to the generation of reactive oxygen species and electrons from a wide range of wavelengths, which suggest that CAP can act as a potential light source for anticancer applications compared with UV light sources. Results of the present in vitro study indicated for the first time that PpIX can be successfully loaded into polymersomes. Most importantly, cell viability studies revealed that PpIX-loaded polymersomes had a low toxicity to healthy fibroblasts (20% were killed) at a concentration of 400 µg/mL, but they showed a great potential to selectively kill melanoma cells (almost 50% were killed). With the application of CAP posttreatment, melanoma cell viability significantly decreased (80% were killed) compared to not using a light source (45% were killed) or using a UV light source (65% were killed). In summary, these results indicated for the first time that PpIX-loaded polymersomes together with CAP posttreatment could be a promising tool for skin cancer drug delivery with selective toxicity toward melanoma cells sparing healthy fibroblasts. Keywords: melanoma, polymersomes, protoporphyrin IX, cold atmospheric plasma, photo-dynamic therapy”

PLA from PolySciTech used as precursor for synthesis of environmentally-safe adhesives

Wednesday, June 14, 2017, 2:53 PM ET

Adhesives are used for manufacturing just about everything in our everyday lives. Most of these are petroleum-based materials, which creates an environmental concern due to their chemical off-gassing and lack of degradability. There is an increasing push in polymer science to replace non-degradable synthetics, or petroleum-based materials, with more sustainable alternatives. This becomes increasingly necessary as there is only a limited amount of landfill space available. Poly(lactic acid) (PLA) is a biodegradable polymer which naturally hydrolyzes into non-toxic lactic acid upon contact with water. Lactic acid itself is actually edible (it’s the ingredient that gives Korean kimchi its distinctive tangy-flavor) and can be easily metabolized by a wide variety of organisms back into carbon dioxide and water. For this reason, PLA is a very environmentally safe alternative in comparison to other polymers. However, typical PLA is not considered an adhesive. Recently, researchers at Purdue University utilized several PLAs from PolySciTech (www.polyscitech.com) (PolyVivo Cat# AP035, AP114, and AP138) as precursors to synthesize environmentally-safe poly(lactide)-catechol based adhesives. This research holds promise for the creation of environmentally safe alternatives to petroleum-type adhesives. Read more: Jenkins, Courtney L., Heather M. Siebert, and Jonathan J. Wilker. "Integrating Mussel Chemistry into a Bio-Based Polymer to Create Degradable Adhesives." Macromolecules (2017). http://pubs.acs.org/doi/abs/10.1021/acs.macromol.6b02213

“Adhesives releasing carcinogenic formaldehyde are almost everywhere in our homes and offices. Most of these glues are permanent, preventing disassembly and recycling of the components. New materials are thus needed to bond and debond without releasing reactive pollutants. In order to develop the next generation of advanced adhesives we have turned to biology for inspiration. The bonding chemistry of mussel proteins was combined with preformed poly(lactic acid), a bio-based polymer, by utilizing side reactions of Sn(oct)2, to create catechol-containing copolymers. Structure–function studies revealed that bulk adhesion was comparable to that of several petroleum-based commercial glues. Bonds could then be degraded in a controlled fashion, separating substrates gradually using mild hydrolysis conditions. These results show that biomimetic design principles can bring about the next generation of adhesive materials. Such new copolymers may help replace permanent materials with renewable and degradable adhesives that do not create chronic exposure to toxins.”

PolySciTech PLGA-PEG-PLGA thermogel used in development of equine anti-fungal treatment to prevent blindness both in humans and horses

Thursday, June 8, 2017, 2:16 PM ET

Keratomycosis, is a vision-threatening disease which occurs both in horses and humans. Horses, in particular, tend to be extremely sensitive to fungal diseases such as this and have similar pathology to humans. Voriconazole is commonly applied as an anti-fungal drug, but ocular administration is complicated by poor absorption, tear-excretion, and other factors which make high frequency repeat doses necessary. Unsurprisingly, horses do not typically like to receive eye-drops and administering medicine by this method is not a trivial task. There is a need to generate an extended release formulation for their treatment. Recently, researchers at Auburn University, and University of Queensland (Australia) utilized PLGA-PEG-PLGA thermogels from PolySciTech (www.polyscitech.com) (PolyVivo AK024, and AK019) to generate a Voriconazole loaded thermogel. They tested this gel formulation for delivery kinetics and safety. This research holds promise to provide treatment for this disease which can lead to blindness in both humans and horses. Read more: Cuming, Rosemary S., Eva M. Abarca, Sue Duran, Anne A. Wooldridge, Allison J. Stewart, William Ravis, R. Jayachandra Babu, Yuh-Jing Lin, and Terri Hathcock. "Development of a Sustained-Release Voriconazole-Containing Thermogel for Subconjunctival Injection in Horses Subconjunctival Voriconazole-Thermogel." Investigative Ophthalmology & Visual Science 58, no. 5 (2017): 2746-2754. http://iovs.arvojournals.org/article.aspx?articleid=2629760

“Abstract: Purpose: To determine in vitro release profiles, transcorneal permeation, and ocular injection characteristics of a voriconazole-containing thermogel suitable for injection into the subconjunctival space (SCS). Methods: In vitro release rate of voriconazole (0.3% and 1.5%) from poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) thermogel was determined for 28 days. A Franz cell diffusion chamber was used to evaluate equine transcorneal and transscleral permeation of voriconazole (1.5% topical solution, 0.3% and 1.5% voriconazole-thermogel) for 24 hours. Antifungal activity of voriconazole released from the 1.5% voriconazole-thermogel was determined via the agar disk diffusion method. Ex vivo equine eyes were injected with liquid voriconazole-thermogel (4°C). Distension of the SCS was assessed ultrasonographically and macroscopically. SCS voriconazole-thermogel injections were performed in a horse 1 week and 2 hours before euthanasia and histopathologic analysis of ocular tissues performed. Results: Voriconazole was released from the PLGA-PEG-PLGA thermogel for more than 21 days in all groups. Release followed first-order kinetics. Voriconazole diffused through the cornea and sclera in all groups. Permeation was greater through the sclerae than corneas. Voriconazole released from the 1.5% voriconazole-thermogel showed antifungal activity in vitro. Voriconazole-thermogel was easily able to be injected into the dorsal SCS where it formed a discrete gel deposit. Voriconazole-thermogel was easily injected in vivo and did not induce any adverse reactions. Conclusions: Voriconazole-containing thermogels have potential application in treatment of keratomycosis. Further research is required to evaluate their performance in vivo.”

PolySciTech PLGA-NH2 used in study on nanoparticle biotransport: Nanoparticle transport explained using a kitten and a football game.

Tuesday, June 6, 2017, 11:16 AM ET

Nanoparticles are small… really small. To put it in perspective, a typical human cell ranges in size from 30-100 um in diameter. Nanoparticles range in size from 1 um down to 0.001 um (0.1 um being common) which means that a typical cell is between 300-1000 times the size of a nanoparticle. To put that in perspective, if a nanoparticle was the size of a kitten (~30 cm) then a human cell would close to the size of a football field (~90-100 M). One important question in science is how to get the kitten onto the football field… er… I mean… how to get the nanoparticle into the cell. This is important because nanoparticles can be loaded with medicines that have a variety of therapeutic effects which can be leveraged only if the nano-kitten can make it onto the cellular football field to make the game-winning kick. There’s two basic ways for either to happen. 1. Active targeting: For our metaphor we’ll assume nano-kitty has a game-day ticket which he politely presents at the front gate for entrance. Similarly, nanoparticles can be specifically conjugated to a specific signal molecule that has the right configuration to allow the nanoparticle access through the cellular membrane by accepted channels. (or) 2. Passive-targeting: This simply relies on the really small nano-kitten simply squeezing through a fence and slipping onto the football field ‘unseen’ due to its small size. Similarly, nanoparticles can sometimes enter cells simply because of their small size. A recent study using PST polymers focused on examining the processes at play in passive-targeting. In addition to final-products used directly for research, PolySciTech (www.polyscitech.com) provides a wide array of intermediates which can be used as precursors for making the final materials. For example, amine-endcap activated PLGA-NH2 has the capability to be chemically conjugated to a wide variety of molecules using common laboratory techniques such as carbodiimide-type conjugation between the PLGA-amine and a NHS-activated carboxylic acid on the other molecule. Recently, researchers at Johns Hopkins University utilized PLGA-NH2 (PolyVivo Cat# AI051) as part of an investigation into nanoparticle transport into living cells. They took the PLGA-NH2 and conjugated on a ‘caged’ rhodamine dye that did not fluoresce until it was prepared to do so by exposure to UV-light. This clever technique allowed the researchers to encapsulate the dye completely within the nanoparticles and precisely track and characterize the nanoparticles during cellular uptake studies. This research holds promise to improve nanotherapeutic formulations for treating a wide-variety of diseases. Read more: Schuster, Benjamin S., Daniel B. Allan, Joshua C. Kays, Justin Hanes, and Robert L. Leheny. "Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales." Journal of Controlled Release (2017). http://www.sciencedirect.com/science/article/pii/S0168365917306302

“Abstract: Diffusion through biological gels is crucial for effective drug delivery using nanoparticles. Here, we demonstrate a new method to measure diffusivity over a large range of length scales – from tens of nanometers to tens of micrometers – using photoactivatable fluorescent nanoparticle probes. We have applied this method to investigate the length-scale dependent mobility of nanoparticles in fibrin gels and in sputum from patients with cystic fibrosis (CF). Nanoparticles composed of poly(lactic-co-glycolic acid), with polyethylene glycol coatings to resist bioadhesion, were internally labeled with caged rhodamine to make the particles photoactivatable. We activated particles within a region of sample using brief, targeted exposure to UV light, uncaging the rhodamine and causing the particles in that region to become fluorescent. We imaged the subsequent spatiotemporal evolution in fluorescence intensity and observed the collective particle diffusion over tens of minutes and tens of micrometers. We also performed complementary multiple particle tracking experiments on the same particles, extending significantly the range over which particle motion and its heterogeneity can be observed. In fibrin gels, both methods showed an immobile fraction of particles and a mobile fraction that diffused over all measured length scales. In the CF sputum, particle diffusion was spatially heterogeneous and locally anisotropic but nevertheless typically led to unbounded transport extending tens of micrometers within tens of minutes. These findings provide insight into the mesoscale architecture of these gels and its role in setting their permeability on physiologically relevant length scales, pointing toward strategies for improving nanoparticle drug delivery.Keywords: Photoactivation; Fibrin; Cystic fibrosis; Nanoparticle; Drug delivery; Particle tracking; FRAP; Fluorescence microscopy; Diffusion. (Dye Conjugation protocol): Caged rhodamine-NHS ester and PLGA-NH2 were conjugated through formation of an amide bond. (Conjugating the dye to polymer in this way, rather than encapsulating the dye in the particles, reduces the likelihood of free dye being released.) Briefly, 90 mg of PLGA-NH2 was added to 5 mg of caged rhodamine-NHS ester, leading to a slight molar excess of dye compared to PLGA, 1.23:1, and put under vacuum for 1 h. The mixture was then flushed with nitrogen gas, dissolved in 500 μl of anhydrous dichloromethane (DCM), and reacted for 12 h at room temperature under nitrogen gas. Additional DCM was added as needed to facilitate transfer into 10 ml of − 20 °C diethyl ether to precipitate the product. The PLGA, now conjugated with the caged rhodamine, was washed twice in cold ether by centrifugation. Excess ether was decanted off and the final product, the purified PLGA-caged rhodamine, was placed in a lyophilizer (FreeZone 4.5 Plus; Labconco) for 12 h. The dried product was stored at − 20 °C in a shielded container to prevent exposure to incident UV light. It is important to note that the amide bond is formed between the amine end-cap of the PLGA and the succinimidyl (NHS) ester on the rhodamine; that is, the dye itself and not the ortho-nitroveratryloxycarbonyl (NVOC) cage is directly conjugated to PLGA. Thus, when the photolytic reaction occurs upon exposure to UV light, only the caging group is cleaved, and free dye is not released”

Recent Patent features use of Aquagel for Weight-control application

Thursday, June 1, 2017, 3:19 PM ET

Recently published patent details the use of Aquagel from PolySciTech (www.polyscitech.com) for use as a weight-control device to prevent over-eating. Read more: Mintchev M, Yadid-Pecht O, Fattouche M, inventors; Eat Little Inc., assignee. Ingestible implement for weight control. United States patent US 9,579,227. 2017 Feb 28. https://www.google.com/patents/US9579227

“ABSTRACT: An orally administrable implement for expanding in a stomach of an animal, including a mammal, to fill a space in the stomach, is provided for weight control. The implement includes: a fluid-permeable expandable container having a first dimension and a second dimension; and a plurality of clusters comprising a swellable material contained within the container and capable of swelling when contacted with a fluid; whereby when the implement is ingested, the fluid in the stomach enters the container causing the clusters therein to swell and the container to expand from the first dimension to the second dimension.”

PLA from PolySciTech used in fundamental study on polymer solubility

Thursday, June 1, 2017, 3:18 PM ET

Hansen solubility parameters have been used for decades to determine polymer solubility. In most cases, these parameters, based on the various solvent-polymer attraction forces, do provide for prediction of polymer solubility in a given solvent. However, there are instances where the polymers do not interact with solvents in a way predicted by these parameters and understanding the cause of these differences requires more fundamental research. Recently, researchers at The National Center for Scientific Research (France) Used PolySciTech (www.polyscitech.com) poly(lactides) of two different molecular weights (PolyVivo AP086 and AP114) along with PMMA and PS and a wide variety of solvents to perform an in-depth study on solvent-polymer interaction looking at both solubility and swelling. This research holds promise for a more fundamental understanding of polymers and solvents which can be applied to a wide range of applications both medical and industrial. Read more: Vayer, Marylène, Alexane Vital, and Christophe Sinturel. "New insights into polymer-solvent affinity in thin films." European Polymer Journal (2017). http://www.sciencedirect.com/science/article/pii/S0014305716316512

“Abstract: Polymer-solvent affinity, estimated from the Hansen solubility parameters (HSP), was compared to experimental results of dissolution and swelling of polymer prepared in the specific form of thin film. This was carried out for 3 common polymers (PS, PLA, PMMA) and a series of 16 polar and non-polar solvents. The affinity properties predicted from the calculation of the relative energy distance (RED) values of most of the studied solvent/polymer pairs were in relative good agreement with the dissolution tests performed on the film. In contrast, no clear correlation between the RED and the swelling behavior was found. The observed deviations were attributed to the inability of the HSP theory derived from data acquired in polymer solutions to be extrapolated to the particular case of swollen polymer film. Highlights: Polymer/solvent affinity was estimated using Hansen solubility parameters. Polymer-solvent affinity was evaluated using swelling of polymer thin films. Three polymers PS, PLA and PMMA and 16 solvents were tested. Discrepancies between estimation and experimental results were highlighted. Keywords: polymer thin film; Hansen solubility parameters; swelling; polymer-solvent affinity.”

Fundamental nanoparticle-biological interaction research performed using PLGA-PEG-PLGA from PolySciTech

Thursday, June 1, 2017, 3:16 PM ET

Although there have been several papers focusing on polymer nanoparticles for drug-delivery applications, there still remains much to be learned about the biological fate of these delivery systems in a fundamental sense aside from specific formulations. Recently, researchers working jointly at University of Ss Cyril and Methodius (Macedonia), CIC biomaGUNE (Spain), Wroclaw University of Science and Technology (Poland), University College Dublin (Ireland), Royal College of Surgeons in Ireland, and Alkaloid AD (Macedonia) utilized PolySciTech (www.polyscitech.com) PLGA-PEG-PLGA block polymers of different sizes (PolyVivo AK017 and PolyVivo AK032) to generate nanoparticles and then assay them for bio-transport and cellular uptake. This fundamental research holds promise to improve nanoparticle delivery systems in general by improving the understanding of their biological interactions. Read more: Dimchevska, Simona, Nikola Geskovski, Rozafa Koliqi, Nadica Matevska-Geskovska, Vanessa Gomez Vallejo, Boguslaw Szczupak, Eneko San Sebastian et al. "Efficacy assessment of self-assembled PLGA-PEG-PLGA nanoparticles: correlation of nano-bio interface interactions, biodistribution, internalization and gene expression studies." International Journal of Pharmaceutics (2017). http://www.sciencedirect.com/science/article/pii/S0378517317304660

“Abstract: The aim of our study was to develop and compare the biological performance of two types of biodegradable SN-38 loaded nanoparticles (NPs) with various surface properties, composed of low and high Mw triblock PLGA-PEG-PLGA copolymers, applying rational quality and safety by design approach. Therefore, along with the optimization of crucial physico-chemical properties and in order to evaluate the therapeutical potential and biocompatibility of prepared polymeric nanoparticles, analysis of nano-bio interactions, cell internalization, gene expression and biodistribution studies were performed. The optimized formulations, one of low Mw and one composed of high Mw PLGA-PEG-PLGA copolymer, exhibited different characteristics in terms of surface properties, particle size, zeta potential, drug loading, protein adsorption and biodistribution, which may be attributed to the variations in nano-bio interface interactions due to different NP building blocks length and Mw. On the contrary to protein adsorption and biodistribution studies, both types of NPs exhibited similar results during cell internalization and gene expression studies performed in cell culture medium containing serum proteins. This pool of useful data for internalization and efficacy as well as the notable advance in the circulation time of low Mw NPs may be further employed for shaping the potential of the designed nanocarriers. Keywords: polymeric nanoparticles; 7-ethyl-10-hydroxycamptotecin (SN-38); PLGA-PEG-PLGA/PEO-PPO-PEO; nanoprecipitation; nano-bio interface interactions; gene expression”

PolySciTech Thermogelling PLGA-PEG-PLGA used in development of cataract therapy to prevent blindness

Wednesday, May 31, 2017, 4:11 PM ET

Cataract surgery is typically successful in returning sight to people who have suffered from loss of sight due to cloudiness of the eye’s lense. One complication from the surgery, however, is the formation of Posterior capsule opacity, which once again removes vision by making it impossible to see through the affected portions of the eye. Recently, researchers at The Ohio State University utilized PLGA-PEG-PLGA from PolySciTech (www.polyscitech.com) (PolyVivo AK024) to develop a thermogel-based delivery system for cyclosporine A to prevent PCO. This research holds promise to restore sight to people affected by this condition. Read more: Gervais, Kristen J. "Evaluation of a biodegradable thermogel polymer for intraocular delivery of cyclosporine A to prevent posterior capsule opacification." PhD diss., The Ohio State University, 2017. (https://etd.ohiolink.edu/pg_10?0::NO:10:P10_ACCESSION_NUM:osu1492101014927609, https://etd.ohiolink.edu/!etd.send_file?accession=osu1492101014927609&disposition=inline)

“Abstract: Purpose: To utilize a thermosensitive hydrogel (thermogel) polymer to achieve sustained release of cyclosporine A (CsA) for targeted destruction of lens epithelial cells (LEC) and reduction of posterior capsule opacification (PCO) after cataract surgery. Part I of the study evaluated the drug delivery system in an ex vivo canine model of PCO, while Part II evaluated intraocular delivery in an in vivo rabbit model. Methods. A PLGA-PEG-PLGA thermogel polymer was formulated to release CsA ([300µg/mL]) or vehicle (ethanol). PART I: Extracapsular cataract extraction and intraocular lens (IOL) placement were performed in 24 canine cadaver globes. Lens capsule explants with residual LEC were treated with 200µL of CsA-eluting (n=12) or vehicle-eluting (n=12) thermogel and maintained in culture. Posterior capsule coverage by LEC was graded following 7 (n=8), 14 (n=6), or 28 (n=10) days of treatment. Following histology, LEC were manually quantified via light microscopy from capsules treated for 28-days. CsA concentration in culture media was quantified by tandem liquid chromatography-mass spectrometry (LC-MS/MS) at each time point. Differences in percent posterior capsule coverage and LEC counts were analyzed by the student’s t-test with Welch’s correction. PART II: Phacoemulsification cataract surgery and IOL placement were performed in 10 adult rabbits (20 eyes). Ten left eyes served as negative controls and were treated with viscoelastic material only. Five right eyes were treated with 200µL CsA-eluting thermogel polymer, and five right eyes were treated with vehicle-eluting thermogel polymer. Clinical ophthalmic examination parameters and PCO grading were performed daily for 6 days post-operatively, and then weekly until the termination of the study at 49 days. Aqueous humor samples were analyzed for CsA concentration at day 6 post-operatively. Following euthanasia, globes were collected and analyzed histologically for degree of PCO formation and any evidence of ocular toxicity. Clinical examination parameters were compared between treatment groups using the Wilcoxon signed rank or Wilcoxon rank sum test. Results. PART I: Posterior capsule coverage by LEC was significantly reduced in CsA-thermogel treated capsules compared to vehicle-treated capsules. Histologic LEC counts were significantly lower in CsA-thermogel treated capsules. Cumulative CsA release from the thermogel was greater than 10µg/mL over a minimum of 7 days. PART II: No significant differences in clinical PCO scores were identified when comparing treatment with CsA-eluting thermogel to vehicle-eluting thermogel. The rate of onset and severity of PCO formation were significantly decreased in thermogel-treated eyes (CsA- and thermogel-treated data combined) compared to non-thermogel-treated eyes up to 4 weeks post-operatively. At the conclusion of the study, no significant differences in PCO formation were found clinically or histologically between treatment groups. The mean aqueous humor CsA level at day 6 post-operatively was 3.2pg/mL. No direct toxic effects of the thermogel polymer or CsA were documented in any eyes. Conclusions. Use of a CsA-eluting thermogel polymer may be a viable pharmacologic method for inducing targeted LEC death and reducing PCO formation. Intraocular administration of the drug delivery system is feasible and does not result in ocular toxicity.”

PolySciTech PS-PLA and PLA used in development of protein-loaded nanoparticles to study polymer-protein interactions

Friday, May 26, 2017, 1:43 PM ET

Proteins are a class of biopolymers which serve a multitude of critical functions within living organisms. Some proteins, such as collagen and keratin, provide mechanical support while others act as enzymes performing critical processes such as cellular metabolism, signaling, membrane transport. Because of their many biochemical interactions, protein-based medicines hold great promise for treating a wide range of diseases. Proteins are long biopolymers that are folded into a specific 3D orientation by a series of intramolecular forces, some of which are more delicate than others. The exact shape of the fold is critical to how the protein functions and if the protein is unfolded it, typically, can never be folded back into the same shape it was again. A simple, everyday example of this is cooking an egg. As an egg is heated, the proteins in the egg transition from folded into linear forms and link onto one another aggregating into insoluble crosslinked gels. In this way, the proteins transition from the clear, viscous fluid of a freshly cracked egg into the white solid gel associated with a well cooked egg. Similarly, many industrial and laboratory practices such as processing with organic solvents, high temperatures, etc. can cause denaturation rendering the protein useless. This, in addition to the high water-solubility of proteins, makes generating controlled-delivery systems for them particularly challenging. Recently, researchers from University of Washington utilized PolySciTech (www.polyscitech.com) PS-PLA (PolyVivo AK042) and Polylactide to make nanoparticles loaded with albumin to study the interaction between polymers and proteins for drug-delivery applications. This research holds promise for enabling the development of a wide array of controlled-delivery systems of protein-based drugs. Read more: Smith, Josh, Kayla G. Sprenger, Rick Liao, Andrea Joseph, Elizabeth Nance, and Jim Pfaendtner. "Determining dominant driving forces affecting controlled protein release from polymeric nanoparticles." Biointerphases 12, no. 2 (2017): 02D412. http://avs.scitation.org/doi/abs/10.1116/1.4983154

“ABSTRACT: Enzymes play a critical role in many applications in biology and medicine as potential therapeutics. One specific area of interest is enzyme encapsulation in polymer nanostructures, which have applications in drug delivery and catalysis. A detailed understanding of the mechanisms governing protein/polymer interactions is crucial for optimizing the performance of these complex systems for different applications. Using a combined computational and experimental approach, this study aims to quantify the relative importance of molecular and mesoscale driving forces to protein release from polymeric nanoparticles. Classical molecular dynamics (MD) simulations have been performed on bovine serum albumin (BSA) in aqueous solutions with oligomeric surrogates of poly(lactic-co-glycolic acid) copolymer, poly(styrene)-poly(lactic acid) copolymer, and poly(lactic acid). The simulated strength and location of polymer surrogate binding to the surface of BSA have been compared to experimental BSA release rates from nanoparticles formulated with these same polymers. Results indicate that the self-interaction tendencies of the polymer surrogates and other macroscale properties may play governing roles in protein release. Additional MD simulations of BSA in solution with poly(styrene)-acrylate copolymer reveal the possibility of enhanced control over the enzyme encapsulation process by tuning polymer self-interaction. Last, the authors find consistent protein surface binding preferences across simulations performed with polymer surrogates of varying lengths, demonstrating that protein/polymer interactions can be understood in part by studying the interactions and affinity of proteins with small polymer surrogates in solution.”

PolySciTech polyesters used in development of neuroprotective controlled-delivery system for glaucoma treatment

Friday, May 26, 2017, 11:33 AM ET

Glaucoma, a disease in which damage to the optic nerve leads to eventual blindness, involves oxidative stress that leads to extensive optic nerve injury. Preventing oxidative stress (e.g. reducing reactive oxygen species formation with the cells) is an effective means to prevent cellular death and delay nerve damage. It has been found that reducing agents (such as phenylphosphine-borane complexes) can act to prevent the over-formation of reactive oxygen species and reduce nerve damage from Glaucoma. Administering these medicines over the course of this chronic disease, however, requires repeat injections in the same ocular location, which is inconvenient to both patient and provider. A better strategy is to deliver a single injection every few months which delivers the neuroprotective agent in a controlled manner. Recently, researchers working at University of Wisconsin and McGill University (Canada) utilized many degradable polyesters (PLGA, PLA, PLCL, PDOCL) from PolySciTech (www.polyscitech.com) (PolyVivo cat# AP001, AP002, AP003, AP004, AP006, AP007, AP008, AP010, AP011, AP013, AP014, AP016, AP017, AP018, AP020, AP021, AP023, AP024, AP030, AP031, AP032, and AP034) to develop such a controlled delivery system. This research holds promise for improved glaucoma therapy to delay the progression of this disease. Read more: Janus, David A., Christopher J. Lieven, Megan E. Crowe, and Leonard A. Levin. "Polyester-Based Microdisc Systems for Sustained Release of Neuroprotective Phosphine-Borane Complexes." Pharmaceutical Development and Technology just-accepted (2017): 1-32. http://www.tandfonline.com/doi/abs/10.1080/10837450.2017.1333516

“Abstract: Phosphine-borane complexes are recently developed redox-active drugs that are neuroprotective in models of optic nerve injury and radioprotective in endothelial cells. However, a single dose of these compounds is short-lived, necessitating development of sustained-release formulations of these novel molecules. We screened a library of biodegradable co- and non-block polyester polymer systems for release of incorporated phosphine-borane complexes to evaluate them as drug delivery systems for use in chronic disease. Bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) was combined with biodegradable polymers based on poly(D,L-lactide) (PDLLA), poly(L-lactide) (PLLA), poly(caprolactone) (PCL), poly(lactide-co-glycide) (PLGA), or poly(dioxanone-co-caprolactone) (PDOCL) to make polymer microdiscs, and release over time quantified. Of 22 polymer-PB1 formulations tested, 17 formed rigid polymers. Rates of release differed significantly based on the chemical structure of the polymer. PB1 released from PLGA microdiscs released most slowly, with the most linear release in polymers of 60:40 LA:GA, acid endcap, Mn 15,000-25,000 and 75:25 LA:GA, acid endcap, Mn 45,000-55,000. Biodegradable polymer systems can therefore be used to produce sustained-release formulations for redox-active phosphine-borane complexes, with PLGA-based systems most suitable for very slow release. Sustained release could enable translation to a clinical neuroprotective strategy for chronic diseases such as glaucoma. Keywords: Phosphine-Borane, Sustained Release, Polymer, Polyester, Neuroprotection”

Nanoparticles for oral delivery of insulin developed using PolySciTech mPEG-PLGA

Wednesday, May 24, 2017, 1:02 PM ET

Insulin injections are an effective treatment for diabetes, but are painful and difficult to sustain on a constant basis. Insulin cannot, under normal conditions, be ingested for example as a tablet because the protein is very delicate and will be destroyed by stomach enzymes. Loading of proteins into nanoparticles is not a trivial task as many of the solvents used to process nanoparticles would damage proteins causing them to unfold and denature irreversibly. Recently, researchers working jointly at Massachuesettes Institute of Technology (MIT), CHU de Quebec Research Center (Canada), Harvard Medical School, King Abdulaziz University (Saudi Arabia), and Soonchunhyang University (Korea) utilized mPEG-PLGA from PolySciTech (www.polyscitech.com) (PolyVivo Cat# AK010) to generate insulin loaded nanoparticles by a zinc precipitation technique. This research holds promise not only to provide for improved insulin therapy with greater patient convenience but also to allow for the loading of other proteins into nanoparticles for therapeutic applications. This work was featured both in a research publication and in a PhD Dissertation. Read more: Chopra, Sunandini, Nicolas Bertrand, Jong-Min Lim, Amy Wang, Omid C. Farokhzad, and Rohit Karnik. "Design of Insulin-Loaded Nanoparticles Enabled by Multistep Control of Nanoprecipitation and Zinc Chelation." ACS Applied Materials & Interfaces 9, no. 13 (2017): 11440-11450. http://pubs.acs.org/doi/abs/10.1021/acsami.6b16854, Dissertation: Chopra, Sunandini. "Development of nanoparticles for oral delivery of insulin." PhD diss., Massachusetts Institute of Technology, 2017. https://dspace.mit.edu/bitstream/handle/1721.1/108946/986242657-MIT.pdf?sequence=1

“Abstract: Nanoparticle (NP) carriers provide new opportunities for controlled delivery of drugs, and have potential to address challenges such as effective oral delivery of insulin. However, due to the difficulty of efficiently loading insulin and other proteins inside polymeric NPs, their use has been mostly restricted to the encapsulation of small molecules. To better understand the processes involved in encapsulation of proteins in NPs, we study how buffer conditions, ionic chelation, and preparation methods influence insulin loading in poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA–PEG) NPs. We report that, although insulin is weakly bound and easily released from the NPs in the presence of buffer ions, insulin loading can be increased by over 10-fold with the use of chelating zinc ions and by the optimization of the pH during nanoprecipitation. We further provide ways of changing synthesis parameters to control NP size while maintaining high insulin loading. These results provide a simple method to enhance insulin loading of PLGA–PEG NPs and provide insights that may extend to other protein drug delivery systems that are subject to limited loading. Keywords: biologics; diabetes; insulin; nanomedicine; oral drug delivery; PLGA−PEG nanoparticles; zinc”

Movie for using polymer micelles to assist drug dissolution

Wednesday, May 24, 2017, 1:02 PM ET

PolySciTech (www.polyscitech.com) Polymer University: Micelles 103 Movie now posted. Fun and educational look at solubility problems in medicine as well as how block polymers assist with delivery of poorly soluble drugs. Introduces hydrophobicity, hydrophilicity, interfacial tension, and micelle formation in a light-hearted and easy to follow format.

PLGA from PolySciTech used in development of veterinary peptide/nanoparticle-based vaccine against bovine paratuberculosis

Tuesday, May 23, 2017, 3:14 PM ET

In addition to human medical applications, there are also a wide range of veterinary applications for biodegradable polymers. Paratuberculosis is a costly disease of the bovine small intestine which occurs with high prevalence in US dairy herds. Currently available vaccines do not provide complete protection from infection due to poor immune activation. Attenuated virus vaccines against Paratuberculosis can only be used in sheep as they cause cross-reactivity in cattle. For this reason, dairy farmers have relatively little recourse against this disease to protect their herds. Recently, researchers working jointly at Washington State University, the US department of agriculture, and Alexandria University (Egypt) used PLGA from PolySciTech (www.polyscitech.com) (PolyVivo AP054) to create peptide-based vaccine (rather than killed or attenuated-virus) loaded nanoparticles for improved effectiveness. This research holds promise to improve dairy cattle disease resistance which will ensure a more sustainable food supply. Read more: Souza, Cleverson D., John P. Bannantine, Wendy C. Brown, M. Grant Norton, William C. Davis, Julianne K. Hwang, Parissa Ziaei et al. "A nano particle vector comprised of poly lacticcoglycolic acid and monophosphoryl lipid A and recombinant Mycobacterium avium subsp paratuberculosis peptides stimulate a proimmune profile in bovine macrophages." Journal of Applied Microbiology (2017). http://onlinelibrary.wiley.com/doi/10.1111/jam.13491/full

“Abstract: Aims: We evaluated the potential of a nanoparticle (NP) delivery system to improve methods of delivery of candidate peptide based vaccines for Paratuberculosis in cattle. Methods and Results: Peptides derived from Mycobacterium avium subsp paratuberculosis (Map), and the proinflammatory monophosphoryl lipid A (MPLA) were incorporated in polymeric NPs based on poly (D, L-lactide-co-glycolide) (PLGA). The PLGA/MPLA NPs carriers were incubated with macrophages to examine their effects on survival and function. PLGA/MPLA NPs, with and without Map antigens, are efficiently phagocytized by macrophages with no evidence of toxicity. PLGA/MPLA NP formulations did not alter the level of expression of MHC I or II molecules. Expression of TNFα and IL12p40 was increased in Map loaded NPs. T cell proliferation studies using a model peptide from Anaplasma marginale demonstrated that a CD4 T cell recall response could be elicited with macrophages pulsed with the peptide encapsulated in the PLGA/MPLA NP. Conclusions: These findings indicate PLGA/MPLA NPs can be used as a vehicle for delivery and testing of candidate peptide based vaccines. Keywords: PLGA ; monophosphoryl lipid A; Mycobacterium avium subsp. paratuberculosis; Anaplasma marginale ; peptide vaccine”

Biodegradable polyesters (PLGA, PLA, PCL) from PolySciTech investigated for controlling Mg-based cardiovascular stent degradation

Tuesday, May 23, 2017, 2:19 PM ET

One treatment for cardiovascular disease is balloon angioplasty, in which a stent is emplaced at the site of arterial blockage in the heart. Initial work with bare-metal stents had reasonably successful results in keeping the artery open by providing structural support but, over time, the tissue of the vessel would grow back over the stent and into the interior portion of it reclosing the artery by a process known as restenosis. A variety of strategies have been applied to solving this issue. One strategy is to utilize a temporary, biodegradable stent comprised primarily of magnesium, which slowly corrodes back into biocompatible magnesium ions leaving no foreign surface for the arterial cells to grow over. However, the speed of Mg breakdown, on its own, is too rapid for stent application. Recently, researchers working at University of California at Riverside and Norco College utilized PLGA, PLLA, and PCL from PolySciTech (www.polyscitech.com) PLLA (No. AP007), PLGA (90:10) (No. AP049), PLGA (50:50) (No. AP089), and PCL (No. AP009) to develop a series of biodegradable coatings to cover over magnesium-type stents. These coatings were used to delay Mg degradation and to improve the stent-surface interaction with arterial cells. This research holds promise for improved cardiovascular treatment by using biodegradable stents which do not suffer from late-stage restenosis. Read more: Jiang, Wensen, Qiaomu Tian, Tiffany Vuong, Matthew Shashaty, Chris Gopez, Tian Sanders, and Huinan Liu. "Comparison Study on Four Biodegradable Polymer Coatings for Controlling Magnesium Degradation and Human Endothelial Cell Adhesion and Spreading." ACS Biomaterials Science & Engineering (2017). http://pubs.acs.org/doi/abs/10.1021/acsbiomaterials.7b00215

“Magnesium (Mg)-based bioresorbable cardiovascular scaffold (BCS) is a promising alternative to conventional permanent cardiovascular stents, but it faces the challenges of rapid degradation and poor endothelium recovery after device degradation. To address these challenges, we investigated poly(l-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA) (90:10), PLGA (50:50), and polycaprolactone (PCL) coatings on Mg, respectively, and evaluated their surface and biological properties. Intact polymer coatings with complete coverage on Mg substrate were achieved. The biological performance of the materials was evaluated by culturing with human umbilical vein endothelial cells (HUVECs) in vitro using the direct culture method. The pH of the culture media and Mg2+ and Ca2+ ion concentrations in the media were measured after culture to characterize the degradation rate of the materials in vitro. The results showed that the PLGA (50:50) coating improved the adhesion and spreading of HUVECs the most among the four polymer coatings. Moreover, we found three possible factors that promoted HUVECs directly attached on the surface of PLGA (50:50)-coated Mg: (1) the higher concentration of Mg2+ ions released into culture media with a concentration range of 9–15 mM; (2) the lower Ca2+ ion concentration in culture media at 1.3–1.6 mM; and (3) the favorable surface conditions of PLGA (50:50), when compared with the other sample groups. This in vitro study provided the first evidence that the PLGA (50:50) is a promising coating material for Mg-based biodegradable metals toward potential cardiovascular or neurovascular applications. Keywords: bioresorbable cardiovascular scaffold; bioresorbable magnesium implants; human umbilical vein endothelial cells; in vitro direct culture method; polymer coatings”

PLGA-PEG-amine from PolySciTech used to generate brain-penetrating nanoparticles for treatment of neural diseases

Monday, May 22, 2017, 3:02 PM ET

A significant problem in treating disease which affect the brain is that getting medicine into the brain tissue is very difficult. This is due to the ‘blood-brain-barrier’ which prevents medicines in the bloodstream from crossing over into the brain tissue. This is a unique feature of the brain, as other organs (kidneys, liver, lungs, etc.) readily absorb medicines from the blood stream. A simple method to overcome this barrier is to simply dose the medicine so high that even if a small portion of the drug crosses into the brain it is effective. However, this strategy does not work with medicines that have side-effects at high doses. Another method of dealing with this problem is to generate medicine-loaded nanoparticles which are specifically modified in such a way as to allow them to penetrate across the blood-brain barrier so they can deliver medicine into the brain for treatment of neural diseases. Recently, researchers working jointly at University of Southern Denmark (Denmark) and Instituto de Investigacao e Inovacao em Saude (Portugal) utilized PLGA-PEG-NH2 from PolySciTech (www.polyscitech.com) (PolyVivo AI058) to generate transferrin decorated nanoparticles for blood-brain-barrier penetration. This research holds promise for improved delivery of medicine to brain tissue for improved treatment of cancer or neural disease such as alzeheimers. Read more: Gomes, Maria Joao, Patrick J. Kennedy, Susana Martins, and Bruno Sarmento. "Delivery of siRNA silencing P-gp in peptide-functionalized nanoparticles causes efflux modulation at the blood–brain barrier." Nanomedicine 0 (2017). http://www.futuremedicine.com/doi/abs/10.2217/nnm-2017-0023

“Aim: Explore the use of transferrin-receptor peptide-functionalized nanoparticles (NPs) targeting blood–brain barrier (BBB) as siRNA carriers to silence P-glycoprotein (P-gp). Materials & methods: Permeability experiments were assessed through a developed BBB cell-based model; P-gp mRNA expression was evaluated in vitro; rhodamine 123 permeability was assessed after cell monolayer treatment with siRNA NPs. Results: Beyond their ability to improve siRNA permeability through the BBB by twofold, 96-h post-transfection, functionalized polymeric NPs successfully reduced P-gp mRNA expression up to 52%, compared with nonfunctionalized systems. Subsequently, the permeability of rhodamine 123 through the human BBB model increased up to 27%. Conclusion: Developed BBB-targeted NPs induced P-gp downregulation and consequent increase on P-gp substrate permeability, revealing their ability to modulate drug efflux at the BBB.”

PLGA from PolySciTech used as part of development of pH responsive nanoparticles for cancer treatment

Tuesday, May 16, 2017, 4:48 PM ET

One of the fundamental problems with treatment of cancer is that the disease itself is still “part” of the human body. Cancer is simply a portion of the tissue and cells which are growing/proliferating at the wrong rate or in a manner which is damaging other tissues. For most diseases caused by an external pathogen, designing a medicinal treatment is simply a matter of finding an agent which affects the pathogen and not the patient. For example, the antibiotic penicillin prevents synthesis of cell-walls, which are key components of bacteria but not found in human cells. For this reason, penicillin can be easily administered to patients at high systemic doses with minimal concern for side effects. Unfortunately, for cancer, the situation is not so simple. Most agents which act to kill or prevent growth of cancer cells also have similar action on healthy cells, due to the fact both that the disease and the patient are of the same cell-type. For this reason, the few differences between cancer cells and normal cells that do exist are ideal targets to improve the action of therapeutics against cancer while maintaining minimal activity against normal cells. One difference between normal tissues and cancer is that, due differences in tumor metabolism, the tumor tissues become acidic with pH ~6.5-7 (typical cellular pH is 7.4). This has led to rumors that acidity causes the tumor to grow and that cancer can be prevented, or even cured, simply by consuming pH basic (or so-called “alkaline”) foods. If this was truly the case, then cancer could be cured by simply eating Rolaids or TUMS, which is not the case. It is the growing cancer generates the acidic environment, not the other way around. This pH variability is one difference between normal tissue and cancerous tissues which can be used for optimizing targeted drug strategies. Recently, researchers working jointly at Purdue University, Fudan University (China), Shenyang Pharmaceutical University (China), and Eli Lilly, utilized PLGA from PolySciTech (www.polyscitech.com) (PolyVivo AP081) to create drug-loaded nanoparticles. These were surface modified to render them pH sensitive for preferential release at low pH. Although they worked well during in-vitro testing, there were problems with components of blood interacting with the coating and altering it preventing the pH effect from being fully utilized during in-vivo research. This is an important aspect of real science is that often, during development, there are setbacks to overcome which are discovered over the course of the research. This research holds promise for development of improved chemotherapeutics. Read more: Han, Ning, Jun Xu, Liang Pang, Hyesun Hyun, Jinho Park, and Yoon Yeo. "Development of surface-variable polymeric nanoparticles for drug delivery to tumors." Molecular Pharmaceutics (2017). http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.7b00050

“Abstract: To develop nanoparticle drug carriers that interact with cells specifically in the mildly acidic tumor microenvironment, we produced polymeric nanoparticles modified with amidated TAT peptide via a simple surface modification method. Two types of core poly(lactic-co-glycolic acid) nanoparticles (NL and NP) were prepared with a phospholipid shell as an optional feature and covered with polydopamine that enabled the conjugation of TAT peptide on the surface. Subsequent treatment with acid anhydrides such as cis-aconitic anhydride (CA) and succinic anhydride (SA) converted amines of lysine residues in TAT peptide to β-carboxylic amides, introducing carboxylic groups that undergo pH-dependent protonation and deprotonation. The nanoparticles modified with amidated TAT peptide (NLpT-CA and NPpT-CA) avoided interactions with LS174T colon cancer cells and J774A.1 macrophages at pH 7.4 but restored the ability to interact with LS174T cells at pH 6.5, delivering paclitaxel efficiently to the cells following a brief contact time. In LS174T tumor-bearing nude mice, NPpT-CA showed less accumulation in the lung than NPpT, reflecting the shielding effect of amidation, but tumor accumulation of NPpT and NPpT-CA was equally minimal. Comparison of particle stability and protein corona formation in media containing sera from different species suggests that NPpT-CA has been activated and opsonized in mouse blood to a greater extent than those in bovine serum-containing medium, thus losing the benefits of pH-sensitivity expected from in vitro experiments. Keywords: acid anhydrides; drug delivery; pH sensitive; PLGA nanoparticles; TAT peptide”

PLGA from PolySciTech used as rapamycin eluting coating on magnesium alloy stents for restenosis prevention as part of heart-disease research

Monday, May 15, 2017, 1:26 PM ET

A popular treatment for cardiac blockage is angioplasty. Under this treatment, a thin catheter is run up to the affection portion of the heart and then a balloon is expanded near the tip to remove the blockage. A drawback to this technique is that, over time, the affected blood vessel re-narrows unless something is left in place, such as a stent. Over a longer period of time, the tissues of the blood vessel will regrow over the stent and re-block the vessel by a process called restenosis. A wide variety of technologies have been applied to dealing with this issue so as to provide a long-term and effective angioplasty treatment for treating coronary artery diseases which can lead to heart-attacks if the vessel. Recently, Researchers working jointly at Purdue University, Shanghai Jiao Tong University (China), and Microport Endovascular Co. utilized PLGA from PolySciTech (www.polyscitech.com) (PolyVivo AP122) to generate a drug-loaded coating on the stent which released anti-proliferative rapamycin to prevent restenosis. They tested this coating both on conventional stainless steel surfaces as well as novel magnesium alloys. They analyzed these samples for drug release, polymer degradation, cellular response, and other parameters. They found drug release was accelerated by the magnesium alloy underlayment and that these materials showed superior anti-proliferative capacity relative to stainless steel. This research holds promise to effectively treat coronary artery disease and prevent heart-attacks by maintaining good blood flow through the blood vessels of the heart. Read more: Shi, Yongjuan, Jia Pei, Lei Zhang, Byung Kook Lee, Yeonhee Yun, Jian Zhang, Zhonghua Li, Song Gu, Kinam Park, and Guangyin Yuan. "Understanding the effect of magnesium degradation on drug release and anti-proliferation on smooth muscle cells for magnesium-based drug eluting stents." Corrosion Science (2017). http://www.sciencedirect.com/science/article/pii/S0010938X16314433

“Abstract: To understand the possible influence of substrate degradation on the drug-loading system of magnesium alloy-based drug-eluting stents, a rapamycin drug-loading poly(lactic-co-glycolic acid) coating was prepared on Mg-Nd-Zn-Zr stents for a systematic investigation in a phosphate buffer system. Mg degradation accelerated the drug release kinetics prominently, which was mainly attributed to H2 evolution in the diffusion-controlled phase while thereafter to PLGA erosion. Although physiochemical stability of the released rapamycin was partially deteriorated by magnesium degradation, the drug-loading system on magnesium substrates exhibited a more potent long-term inhibition on smooth muscle cell proliferation in vitro as compared to drug-loaded stainless steel. Highlights: We firstly reported that the degradation of magnesium substrate would improve the in vitro rapamycin release from drug-loading PLGA/RAPA system on a Mg-Nd-Zn-Zr alloy. We quantitatively analyzed the factors enhancing the in vitro drug release kinetics from Mg-based drug-eluting system, distinguishing that it was mainly caused by H2 evolution, while pH only played a trivial role. We reported for the first time that the Mg-based PLGA/RAPA drug-loading system exhibited more pronounced long-term inhibition for the proliferation of smooth muscle cells, under conditions that PLGA with low degradation rate was used as the drug carrier. Keywords Magnesium; Organic coatings; Polymer; Erosion; Interfaces; Kinetic parameters.”

PLGA from PolySciTech used for generating dopamine-Mn coated theranostic nanoparticles for use in cancer treatment

Tuesday, May 9, 2017, 12:02 PM ET

Chemotherapy is the primary means of treating cancer however the currently available regimens suffer from significant side-effects and related toxicity due to the non-specific nature of this approach which damages both tumors as well as normal tissues. Combination therapies have been developed as a means for dealing with this by providing for a more targeted approach to cancer treatment in which the tumor is affected by the medicine to a greater degree than healthy tissues. Recently, PLGA from PolySciTech (www.polyscitech.com) (PolyVivo cat# AP040) was utilized to generate a doxorubicin loaded nanoparticle coated with dopamine and manganese. These particles serve both as magnetic resonance contrast agent and as a photothermal-triggered delivery system. This research holds promise for improved treatment of a wide array of cancers. Read more: Xi, Juqun, Lanyue Da, Changshui Yang, Rui Chen, Lizeng Gao, Lei Fan, and Jie Han. "Mn2+-coordinated PDa@ DOX/Plga nanoparticles as a smart theranostic agent for synergistic chemo-photothermal tumor therapy." International Journal of Nanomedicine 12 (2017): 3331. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411169/

“Abstract: Nanoparticle drug delivery carriers, which can implement high performances of multi-functions, are of great interest, especially for improving cancer therapy. Herein, we reported a new approach to construct Mn2+-coordinated doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a platform for synergistic chemo-photothermal tumor therapy. DOX-loaded PLGA (DOX/PLGA) nanoparticles were first synthesized through a double emulsion-solvent evaporation method, and then modified with polydopamine (PDA) through self-polymerization of dopamine, leading to the formation of PDA@DOX/PLGA nanoparticles. Mn2+ ions were then coordinated on the surfaces of PDA@DOX/PLGA to obtain Mn2+-PDA@DOX/PLGA nanoparticles. In our system, Mn2+-PDA@DOX/PLGA nanoparticles could destroy tumors in a mouse model directly, by thermal energy deposition, and could also simulate the chemotherapy by thermal-responsive delivery of DOX to enhance tumor therapy. Furthermore, the coordination of Mn2+ could afford the high magnetic resonance (MR) imaging capability with sensitivity to temperature and pH. The results demonstrated that Mn2+-PDA@ DOX/PLGA nanoparticles had a great potential as a smart theranostic agent due to their imaging and tumor-growth-inhibition properties. Keywords: PLGA nanoparticles, polydopamine, chemo-photothermal therapy, smart theranostic agent”

Amine-endcap PLGA from PolySciTech used in the development of nanoparticle based asthma treatment

Monday, May 8, 2017, 10:47 AM ET

Asthma is a very common disease affecting over 300 million people across the globe and is typified by severe inflammation of respiratory passages. Recently, overexpression of a Ca2+/calmodulin-dependent protein kinase (CaMKII) has been identified as one of the pathways which leads to this inflammation in asthma patients. A peptide which acts to inhibit CaMKII has been identified however delivering high doses of this peptide specifically to the lung-tissue requires a unique delivery system. Recently, Researchers working jointly at University of Iowa, Johns Hopkins University, and Mahidol University (Thailand) utilized amine-end capped PLGA from PolySciTech (www.polyscitech.com) (PolyVivo Cat# AI063) along with chitosan to develop inhalable cationic nanoparticle to deliver this peptide to the lung-tissue. They found this particle to be effective at cell penetration and to provide for asthma treatment with minimal side-effects in a mouse model. This research holds promise for improved asthma therapy. Read more: Morris, Angie S., Sara C. Sebag, John D. Paschke, Amaraporn Wongrakpanich, Kareem Ebeid, Mark E. Anderson, Isabella M. Grumbach, and Aliasger K. Salem. "Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma." Molecular Pharmaceutics (2017). http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.7b00114

“Abstract: Asthma is a common lung disease affecting over 300 million people worldwide and is associated with increased reactive oxygen species (ROS), eosinophilic airway inflammation, bronchoconstriction and mucus production. Targeting of novel therapeutic agents to the lungs of patients with asthma may improve efficacy of treatments and minimize side effects. We previously demonstrated that Ca2+/calmodulin-dependent protein kinase (CaMKII) is expressed and activated in the bronchial epithelium of asthmatic patients. CaMKII inhibition in murine models of allergic asthma reduces key disease phenotypes, providing the rationale for targeted CaMKII inhibition as a potential therapeutic approach for asthma. Herein we developed a novel cationic nanoparticle (NP)-based system for delivery of the potent and specific CaMKII inhibitor peptide, CaMKIIN, to airways. CaMKIIN-loaded NPs abrogated the severity of allergic asthma in a murine model. These findings provide the basis for development of innovative, site-specific drug delivery therapies, particularly for treatment of pulmonary diseases such as asthma. Keywords: Polylactide-co-glycolide, PLGA, Nanoparticle, Chitosan, Asthma, CaMKIIN”

Polymers 102 "Biodegradation"

Friday, May 5, 2017, 11:40 AM ET

New Polymers University Video: Polymers 102 "Biodegradation" introduces hydrolysis of polyesters https://akinainc.com/polyscitech/products/polyvivo/polyU.php#102

mPEG-PLGA from PolySciTech utilized in optimization and fine-tuning of microfluidic nanoparticle formation techniques

Tuesday, May 2, 2017, 2:12 PM ET

Polymeric nanoparticles are widely used to improve solubility of poorly soluble medicines and blood-circulation times of rapidly cleared medicines. In this way, these are often utilized to improve the efficacy of medicines by ensuring more of the medication actually reaches the location of usage rather than be cleared out of the blood-stream. There are a wide variety of ways to make nanoparticles, most of which are based around mixing the polymer from a solvent that dissolves the polymer well in with a solvent that doesn’t dissolve it at all. This is typically done in the presence of a surfactant so that the polymer solidifies into tiny spheres. The easiest of these techniques is a simple emulsion. Anyone could do this, even in a kitchen. Simply dissolve a Styrofoam cup in a small amount of acetone (paint thinner), load a household blender with soapy water and slowly drip the polystyrene cup solution into the blender full of sudsy water while it is stirring at maximum speed. After a few minutes of stirring, pass the white slurry through a coffee filter to remove any big particles and you now have a milky-looking slurry of polystyrene nanoparticles. I do not actually suggest doing this because: 1) acetone is flammable, 2) there is no practical application for generating nanoparticles in your kitchen, 3) the next time you go to make milk-shakes, they may taste terrible, and 4) it will certainly void the warranty on your house-hold blender (just because you can, doesn’t mean you should try this at home). Nanoparticles made by this type of emulsion technique come out in a wide range of different sizes, because the processes which drive their formation are random. However, microfluidics is a newer technique in which the mixing is precisely controlled so that all the nanoparticles are generated at the same size and in a highly controlled manner. Defining exactly how the blending of the polymer solution with the non-solvent occurs is a process which requires a great deal of experimentation and fluid mechanics to elucidate the precise parameters (concentrations, mixing speeds, etc.) that allow for predetermined sizes of polymer nanoparticles to be made. Recently, Researchers at The University of Queensland (Australia) utilized mPEG-PLGA from PolySciTech (www.polyscitech.com) of two different block sizes (PolyVivo AK026 (5k-55K) and AK037 (5K-20K)) to investigate microfluidic mechanisms for producing monodisperse nanoparticles with extremely well controlled sizes. For this, they dissolved the polymers into acetonitrile and then processed them through an advanced microfluidics system to generate precisely sized nanoparticles. This research holds promise for the generation of well-controlled nanoparticles to encapsulate medicines and improve their efficacy. Read more: Baby, Thejus, Yun Liu, Anton PJ Middelberg, and Chun-Xia Zhao. "Fundamental studies on throughput capacities of hydrodynamic flow-focusing microfluidics for producing monodisperse polymer nanoparticles." Chemical Engineering Science (2017). http://www.sciencedirect.com/science/article/pii/S0009250917302993

“Abstract: Microfluidics enables the manipulation of liquids at the picoliter (or less) scale and proves to be superior over conventional bulk methods for mixing and reaction. The ability of microfluidic systems to rapidly mix reagents to provide homogeneous reaction environments, to vary the reaction conditions continuously, and to even allow reagent addition during the progress of a reaction, makes it attractive for nanoparticle synthesis. However, the low production rate limits its practical applications. Different approaches have been developed to achieve higher yield but most of them rely on the design of complex devices. Herein, we investigated fundamentally the throughput capacities of hydrodynamic flow-focusing microfluidics for producing poly (lactide-co-glycolide)-b-polyethylene glycol (PLGA-PEG) nanoparticles with uniform size ranging from 50-150 nm. The effects of different factors of microfluidic design, including channel width, channel depth, channel structure and flow rate ratios, on particle size, size distribution, and production throughput were studied and compared. In contrast to the widely used microfluidic device which has a production rate of 1.8 mg/h, our simple approach is capable of increasing the production rate of nanoparticles by more than two orders of magnitude up to 288 mg/h using a single simple device. This study demonstrated the potentials of using simple 2D microfluidic devices for a large scale production of polymeric nanoparticles that could eliminate the need for designing and fabricating complex microfluidic devices. Keywords: Microfluidics; 2D hydrodynamic flow focusing; PLGA-PEG NPs; mixing; nanoprecipitation. Highlights: A single hydrodynamic flow focusing (HFF) microfluidic device for production of polymeric nanoparticles at hundred milligram per hour scale. Tunable properties of the synthesized nanoparticles. Precise control over the size and size distribution of the synthesized nanoparticles. A library of polymer nanoparticles with systematically varied size.”

Polymers 101: What is a polymer?

Thursday, April 27, 2017, 2:10 PM ET

Akina's first polymer educational video is live. Polymers 101: What is a polymer?

mPEG-PCL, mPEG-PLA, and mPEG-PLGA from PolySciTech used in design of theranostic stealth nanocarriers as part of drug-delivery research

Tuesday, April 25, 2017, 4:59 PM ET

One promising area of research in cancer therapy is the development of theranostics. This area of research focuses on simultaneous application of both a therapeutic agent (typically a chemotherapeutic agent such as paclitaxel) and a diagnostic agent (typically a contrast agent or fluorescent dye which renders the tumor ‘visible’). This research requires highly advanced delivery systems which can ensure that the tumor receives a suitable quantity of both agents such that it becomes visible to a surgeon as well as receives an effective dose of the therapeutic agent. In a fundamental sense, this requires well-designed nanocarriers with high loading efficiency (large doses of each agent) and which are highly stable in the bloodstream. Recently, researchers at Wroclaw University (Poland) utilized a series of PolySciTech (www.polyscitech.com) polymers including mPEG-PCL (PolyVivo Cat# AK128), mPEG-PLA (PolyVivo Cat# AK056), and mPEG-PLGA (PolyVivo Cat# AK037) to systematically generate a series of test-loaded nanoparticles containing model DNA and fluorescent dye Thiazole Orange. The researchers systematically investigated all steps involved in nanoparticle formation and tested the particles for their stability, loading capacity, and other parameters relevant to their clinical usage. This research holds promise for the development of highly advanced nanocarriers to assist in theranostic treatments of a wide variety of cancers. Read more: Bazylińska, Urszula. "Rationally designed double emulsion process for co-encapsulation of hybrid cargo in stealth nanocarriers." Colloids and Surfaces A: Physicochemical and Engineering Aspects (2017). http://www.sciencedirect.com/science/article/pii/S092777571730359X
“Abstract: Double emulsion process has become highly promising for development of PEG-ylated nanocarriers (NCs) with co-encapsulated hybrid model agents, i.e, hydrophilic deoxyribonucleic acid (DNA) and hydrophobic Thiazole Orange (TO) dye, in the double compartment structure to protect them from the environmental conditions and to investigate different parameters affecting the size, charge and morphology as well as colloidal and biological stability of the final theranostic nanosystems. Different stabilizing agents including surfactants: Cremophor A25, Cremophor RH 40, Poloxamer 407, di-C12DMAB as well as polymers: PEG-PDLLA, PEG-PLGA, PEG-PCL, were screened to choose suitable ones for this approach. The average size of the synthesized NCs measured by dynamic light scattering (DLS) remained < 200 nm. The encapsulation efficiency of the hybrid cargo was confirmed by UV-Vis spectroscopy. Morphology and shape of the loaded nanocontainers were investigated by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Time-depended colloidal stability studies with DLS and ζ-potential followed by turbidimetric technique allow to select only the long-term nanosystems to final investigation the “stealth” properties of the fabricated PEGylated NCs. Highlights: Double emulsion process has become easy-scalable synthetic approach to develop “stealth” nanocarriers (NCs) successful in DNA and TO co-encapsulation. PEG-PDLLA, PEG-PLGA, PEG-PCL acted as pre-approved biocompatible components of the NCs polymer shell.The optimized encapsulation process resulted in NCs with diameter < 200 nm, narrow size distribution and nearly neutral surface. DLS, ζ-potential and backscattering studies confirmed a long-term NCs stability, indicating their potential as theranostic biocompatible agents. The biological stability exposed the PEG-ylated NCs ability to overcome various specific barriers to efficient drug and gene delivery. Keywords: w/o/w emulsions; PEG-ylated polyesters; DNA; Thiazole Orange; colloidal stability. Fabrication method: Polymeric nanocarriers stabilized by PEG-PLGA, PEG-PCL, PEG-PDLLA and non-ionic or cationic surfactants for co-encapsulation of therapeutic (model DNA in the initial concentration of 0.1 mg/ml) and diagnostic agent (TO in the initial concentration of 0.2 mg/ml) were prepared by modified double emulsion (w/o/w) evaporation process without any pH adjustment [8]. Generally, aqueous internal phase (with DNA) was emulsified for 5 min in dichloromethane (containing TO, PEG-ylated polymer in concentration of 5 mg/ml and di-C12DMAB) in the ratio 1:4 using a homogenizer with 25,000 rpm. This primary nanoemulsion was poured into 1% hydrophilic surfactant solution (Cremophor A25, Cremophor RH 40 or Poloxamer 407) aqueous solution stirring in a homogenizer for 10 min (25,000 rpm) and immersed in an ice water bath to create the water-in-oil-in-water (w/o/w) emulsion. The organic solvent was then evaporated under reduced pressure in a rotary evaporator (Ika RV 10 digital) and polymeric nanocarriers loaded by the hybrid cargo were collected overnight.”

mPEG-PLA from PolySciTech used by Yale University in development of a novel blood-circulation assay method

Tuesday, April 18, 2017, 10:41 AM ET

A fundamental difficulty with medicinal applications to humans is that the circulatory systems of most living organisms are designed specifically to screen out any perceived toxins or ‘non-self’ components. Typically, the kidneys and the liver work together along with macrophages (white blood cells) to remove any chemicals or particulates from the bloodstream. Although this system provides protection to the human body from toxic ingestion, it creates great difficulty for applying medicines as it greatly reduces the blood circulation time of medicinal molecules. For general medicinal applications, the loss of drug from the bloodstream is calculated as the circulation half-life and dosing schedules are calculated to match. One method to improve blood-circulation is to encapsulate the drug molecule inside of PEG-PLA so-called ‘stealth’ nanoparticles. For these particles, the PEG external coating prevents attacks by macrophages while the size alone reduces uptake and clearance by kidneys or liver. These particles enhance the blood circulation time of medicines, but a key question is by exactly how much is the blood circulation time enhanced and what is the new circulation half-life. This question critical for practical applications as it would define the dosing schedule of the encapsulated drug as it must be dosed often enough to maintain effect but not too often so as to potentially have toxic side-effects. Recently, researchers at Yale University utilized mPEG-PLA from PolySciTech (www.polyscitech.com) (PolyVivo Cat# AK054) to generate stealth-nanoparticles as test substrates for their novel fluorescence microscopy-based technique for determining half-life of particles using as little as 2 uL of blood. This research holds promise for rapid and routine determination of half-life using very small samples of blood. Read more: Tietjen, Gregory T., Jenna DiRito, Jordan S. Pober, and W. Mark Saltzman. "Quantitative microscopy-based measurements of circulating nanoparticle concentration using microliter blood volumes." Nanomedicine: Nanotechnology, Biology and Medicine (2017). http://www.sciencedirect.com/science/article/pii/S1549963417300643

“Abstract: Nanoparticles (NPs) are potential drug delivery vehicles for treatment of a broad range of diseases. Intravenous (IV) administration, the most common form of delivery, is relatively non-invasive and provides (in theory) access throughout the circulatory system. However, in practice, many IV injected NPs are quickly eliminated by specialized phagocytes in the liver and spleen. Consequently, new materials have been developed with the capacity to significantly extend the circulating half-life of IV administered NPs. Unfortunately, current procedures for measuring circulation half-lives are often expensive, time consuming, and can require large blood volumes that are not compatible with mouse models of disease. Here we describe a simple and reliable procedure for measuring circulation half-life utilizing quantitative microscopy. This method requires only 2 μL of blood and minimal sample preparation, yet provides robust quantitative results. Graphical Abstract: Quantitative microscopy can be used to measure circulating concentrations of nanoparticles with as little as 2 μL of blood. However, when using such small volumes, the path length within and between samples can vary significantly as the high viscosity of blood can yield differences in think layer thickness as the blood spreads following application of a coverslip. This yields variability in the measured mean fluorescence intensity. Addition of a reference nanoparticle of a different color can correct the mean fluorescence intensity variance. Thus, quantitative microscopy can serve as a robust method for measuring nanoparticle half-life using μL volumes of blood. NP formulation: NP were prepared by a standard nanoprecipitation procedure. PLA–PEG (PolyVivo AK054) was dissolved at an initial concentration of 100 mg/mL in DMSO and then diluted to the desired concentration for NP formulation (typically ~55 mg/mL for the ~165 nm NPs used in this study) along with addition of either DiI or DiO dye also dissolved in DMSO. NPs were loaded with DiI or DiO dye at a final wt dye/wt polymer ratio of 0.5%. The dye/polymer solution in DMSO was added drop wise to vigorously stirring sterile diH2O in batches of 200 μL polymer/dye solution added to 1.3 mL of diH2O with identical repetitions performed to generate a full NP batch. NP were subsequently filtered through a 1.2 μm cellulose acetate membrane (GE Healthcare Life Sciences - Whatman) filter to remove any free dye or polymer aggregates and then pooled. Typically, 8 small batches of ~11 mg polymer each were combined for a total pooled batch size of ~88 mg initial polymer weight. The pooled NP solutions were then transferred to a 12 mL volume 10,000 MWCO dialysis cassettes (Thermo Scientific - Slide-A-Lyzer) and dialyzed against 2× exchanges of ~2.2 L of diH2O at room temperature to remove excess DMSO. Following dialysis NPs were aliquoted and snap frozen in liquid N2. One aliquot from each NP batch was lyophilized in a pre-weighed tube in order to determine the NP concentration. Standard NP concentration was typically ~5 mg/mL. NP batches were diluted to ~0.1 mg/mL and analyzed via dynamic light scattering (DLS) to confirm NP size and homogeneity.”

PhD Research Thesis from The University of Milan utilizes PLGA from PolySciTech as radical chain transfer agent

Wednesday, April 12, 2017, 3:49 PM ET

Sometimes research holds surprising results. Radical chain transfer is a process which allows for controlling the molecular weight and end-cap properties of poly(vinyl) type polymers. Conventionally, radical chain transfer agents comprise of molecules custom designed for that exact purpose, such as thiol compounds in which the sulfur atom actively participates in the free radical interaction. Conventionally, PLGA is not typically applied to free radical chain transfer however researchers at The University of Milan were able to use PLGA from PolySciTech (www.polyscitech.com) (PolyVivo cat# AP059) in this fashion to create PLGA-g-PVP. This research holds promise for the development of novel polymer compounds for a wide array of applications. Read more: Capuano, G. "Amphiphilic, Biodegradable and Biocompatible Polymers for Industrial Applications." (2017). Universita Degli Studi Di Milano Facolta Di Scienze E Tecnologie PhD School in Industrial Chemistry XXIX Cycle PhD Student Capuano Giovanna Thesis. https://air.unimi.it/bitstream/2434/477898/2/phd_unimi_R10587.pdf

“The aim of this PhD work was to establish the synthetic procedures for new families of biocompatible and biodegradable and/or bioeliminable biomaterials that can be differently processed to obtain nanoparticles, core-shell nanof ibres and hydrogel slabs or conduits, respectively. Depending on composition, size and morphology, these biomaterials may be intended for applications as drug delivery systems and/or tissue regeneration. Specifically, the research project has been developed along two main lines: Synthesis of poly(lactic-glycolic acid)-g-poly(1-vinylpyrrolidin-2-one) (PLGA-g-PVP) copolymers whose architecture consisted of a long PLGA backbone with oligomeric PVP pendants. These were obtained by the radical polymerisation of 1-vinylpyrrolidin-2-one in molten PLGA 50:50, acting as chain transfer agent. Synthesis of a new classes of poly(saccharide)-poly(aminoamine)s 3D-network intended as scaffolds for the regeneration of liver. (Synthesis of PLGA-g-PVP): PLGA (2.012 g, PolyVivo AP059) and VP (0.203 g, 1.83 mol) were added to dichloromethane (30 mL) in a two-necked 100 mL flask equipped with a stir bar. The resultant solution was purged 5 min with nitrogen and AIBN (2.1 mg, 0.013 mmol) was added. Dichloromethane was then eliminated at room temperature and 0.2 tor. After three nitrogen-vacuum cycles, the reaction mixture was heated to 100 °C, maintained at this temperature under nitrogen for 2.5 h, cooled to room temperature and dissolved in dichloromethane (100 mL). The solution was poured drop-wise in diethyl ether (1 L) under vigorous stirring and the resultant slurry stirred for further 2 h. The precipitated product was finally retrieved by filtration, washed with fresh ether (200 mL) and dried under vacuum.”

These posts are syndicated from John Garner's blog at http://jgakinainc.blogspot.com/.

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