Parkinson’s disease treatment developed using mPEG-PLGA block copolymer for neuroprotective agent delivery

Parkinson’s disease is a chronic, neural-degenerative which affects motor control and other operations of the nervous system eventually leading to death. Schisantherin A is a recently discovered neuroprotective agent which acts to inhibit damage to neural cells and can be used to slow the progression of Parkinson’s disease (https://www.ncbi.nlm.nih.gov/pubmed/25770828). It has severe limitations, however, as it is poorly soluble in water and quickly cleared from the blood-stream.  Schisantherin A , like many neurological medicines, also faces the severe impediment of the blood-brain-barrier. This barrier which exists between circulating blood and brain tissue is intended to protect the brain from any toxic components that may be in the blood but also serves the unintentional purpose of preventing uptake of medicinal components into the brain tissue.  Recently, researchers at University of North Carolina at Chapel Hill and University of Macau utilized mPEG-PLGA to generate small-sized nanoparticles containing Schisantherin A. They found these nanoparticles to improve serum circulation longevity and uptake across the blood-brain-barrier. This research holds promise for enhanced therapy against this fatal disease. Similar block copolymers can be purchased from PolySciTech division of Akina, Inc. (www.polyscitech.com). Read more about this exciting research here: Chen, Tongkai, Chuwen Li, Ye Li, Xiang Yi, Ruibing Wang, Simon Ming-Yuen Lee, and Ying Zheng. “Small-Sized mPEG–PLGA Nanoparticles of Schisantherin A with Sustained Release for Enhanced Brain Uptake and Anti-Parkinsonian Activity.” ACS Applied Materials & Interfaces (2017). http://pubs.acs.org/doi/abs/10.1021/acsami.7b01171

“Schisantherin A (SA) is a promising anti-Parkinsonism natural product. However, its poor water solubility and rapid serum clearance impose significant barriers to delivery of SA to the brain. This work aimed to develop SA in a nanoparticle formulation that extended SA circulation in the bloodstream and consequently an increased brain uptake and thus to be potentially efficacious for the treatment of Parkinson’s disease (PD). Spherical SA nanoparticles with a mean particle size of 70 nm were prepared by encapsulating SA into methoxy poly(ethylene glycol)-block-poly(d,l)-lactic-co-glycolic acid (mPEG–PLGA) nanoparticles (SA-NPs) with an encapsulation efficiency of ∼91% and drug loading of ∼28%. The in vitro release of the SA-NPs lasted for 48 h with a sustained-release pattern. Using the Madin–Darby canine kidney (MDCK) cell model, the results showed that first intact nanoparticles carrying hydrophobic dyes were internalized into cells, then the dyes were slowly released within the cells, and last both nanoparticles and free dyes were externalized to the basolateral side of the cell monolayer. Fluorescence resonance energy transfer (FRET) imaging in zebrafish suggested that nanoparticles were gradually dissociated in vivo with time, and nanoparticles maintained intact in the intestine and brain at 2 h post-treatment. When SA-NPs were orally administrated to rats, much higher Cmax and AUC0-t were observed in the plasma than those of the SA suspension. Furthermore, brain delivery of SA was much more effective with SA-NPs than with SA suspension. In addition, the SA-NPs exerted strong neuroprotective effects in zebrafish and cell culture models of PD. The protective effect was partially mediated by the activation of the protein kinase B (Akt)/glycogen synthase kinase-3β (Gsk3β) pathway. In summary, this study provides evidence that small-sized mPEG–PLGA nanoparticles may improve cross-barrier transportation, oral bioavailability, brain uptake, and bioactivity of this Biopharmaceutics Classification System (BCS) Class II compound, SA. Keywords: brain delivery; cellular uptake; fluorescence resonance energy transfer (FRET); mPEG−PLGA nanoparticles; oral bioavailability; Schisantherin A”

PLGA from PolySciTech investigated for use as adjuvant in Streptococcus vaccine development

Group A Strep is highly virulent and can be deadly without proper treatment. One means to reduce Strep infections is to apply nanoparticles presenting certain portions of the bacteria’s M-protein marker to elicit an immune response against Strep. Recently, researchers at The University of Queensland and Griffith University (Australia) utilized PolySciTech (www.polyscitech.com) PLGA (PolyVivo AP041) to develop a nanoparticle vaccine against strep. They utilized PLGA as well as poly(lysine) and dextran to make these nanoparticles and found a substantially higher immune response against the PLGA likely due to its negative charge. This research holds promise for the development of an effective vaccine against Strep. Read more:  Marasini, Nirmal, Ashwini Kumar Giddam, Michael R. Batzloff, Michael F. Good, Mariusz Skwarczynski, and Istvan Toth. “Poly-L-lysine-coated nanoparticles are ineffective in inducing mucosal immunity against group a streptococcus.” (2017). http://www.hoajonline.com/journals/pdf/2052-9341-5-1.pdf

“Abstract Background: Group A Streptococcus (GAS) can cause a range of maladies, from simple throat infections to lethal complication, such as rheumatic heart disease. The M-protein, a bacterial cell surface protein, is the major virulence factor of GAS. Several attempts have been made over the past few decades to develop vaccines against GAS that employed peptides derived from the M-protein. One such approach used lipopeptides or lipid core peptide (LCP) systems that incorporated a B-cell epitope derived from the conserved region of the M-protein. Methods: In the present study, we prepared different biodegradable polymer [dextran, poly-(lactic- coglycolic-acid) (PLGA), and poly-L-lysine] nanoparticles (NPs)-based delivery systems for a lipopeptide vaccine candidate (LCP-1).The NPs were characterized by their size, charge, morphology, antigen-presenting cells (APCs) uptake and subsequent APCs maturations efficacy, followed by in vivo nasal immunization in mice. Results: All produced NPs ranged in size from 100-205 nm, and their charge varied depending upon the nature of polymer. A high APCs uptake efficacy for dextran and poly-L-lysine NPswere observed, compared to PLGA NPs. Despite the high uptake by APCs, dextran and poly-L-lysine NPs failed to improve APCs maturation that resulted in low antibody titres. In contrast, while LCP-1 encapsulated into PLGA showed low APCs uptake, it induced significant maturation of DCs and higher antibody titres compared to other NPs. Conclusions: Positively-charged poly-L-lysine NPs were non-immunogenic, while negatively charged PLGA NPs induced similar responses to antigens adjuvanted with cholera toxin B (CTB). Keywords: Mucosal delivery, lipopeptides, nanoparticles, nasal, vaccine, PLGA, Poly-L-lysine”

PLGA-PEG-Maleimide from PolySciTech used in development of macular degeneration treatment

One of the causes of ocular damage which can lead to blindness is choroidal neovascularization, effectively the over-growth of new blood vessels in the back of the eye. This condition is involved in the development of age-related macular degeneration which can lead to blindness. Recently, researchers at Yantai University (China) utilized Mal-PEG-PLGA (PolyVivo AI020) from PolySciTech (www.polyscitech.com) to develop RGD and TAT peptide modified nanoparticles to deliver therapeutics to ocular tissues as part of treatment of macular degeneration. This research holds promise to provide treatment for a disease which causes blindness. Read more: Chu, Yongchao, Ning Chen, Huajun Yu, Hongjie Mu, Bin He, Hongchen Hua, Aiping Wang, and Kaoxiang Sun. “Topical ocular delivery to laser-induced choroidal neovascularization by dual internalizing RGD and TAT peptide-modified nanoparticles.” International Journal of Nanomedicine 12 (2017): 1353. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325139/

“Abstract: A nanoparticle (NP) was developed to target choroidal neovascularization (CNV) via topical ocular administration. The NPs were prepared through conjugation of internalizing arginine-glycine-aspartic acid RGD (iRGD; Ac-CCRGDKGPDC) and transactivated transcription (TAT) (RKKRRQRRRC) peptide to polymerized ethylene glycol and lactic-co-glycolic acid. The iRGD sequence can specifically bind with integrin αvβ3, while TAT facilitates penetration through the ocular barrier. 1H nuclear magnetic resonance and high-performance liquid chromatography demonstrated that up to 80% of iRGD and TAT were conjugated to poly(ethylene glycol)– poly(lactic-co-glycolic acid). The resulting particle size was 67.0±1.7 nm, and the zeta potential of the particles was −6.63±0.43 mV. The corneal permeation of iRGD and TAT NPs increased by 5.50- and 4.56-fold compared to that of bare and iRGD-modified NPs, respectively. Cellular uptake showed that the red fluorescence intensity of iRGD and TAT NPs was highest among primary NPs and iRGD- or TAT-modified NPs. CNV was fully formed 14 days after photocoagulation in Brown Norway (BN) rats as shown by optical coherence tomography and fundus fluorescein angiography analyses. Choroidal flat mounts in BN rats showed that the red fluorescence intensity of NPs followed the order of iRGD and TAT NPs > TAT-modified NPs > iRGD-modified NPs > primary NPs. iRGD and TAT dual-modified NPs thus displayed significant targeting and penetration ability both in vitro and in vivo, indicating that it is a promising drug delivery system for managing CNV via topical ocular administration. Keywords: nanoparticles, ocular drug delivery, choroidal neovascularization, RGD, cell-penetrating peptides. Method for iRGD Conjugation: Briefly, Mal–PEG–PLGA was dissolved in acetone and the organic solvent then evaporated, dispersing the solute evenly on the flask wall. The flask was replenished with 0.01 M phosphate-buffered saline (PBS, pH 7.4) and left overnight to react with iRGD. The iRGD was conjugated to Mal–PEG–PLGA (at 4°C, at a 1:1 molar ratio of peptide to Mal–PEG–PLGA).”

End-of-Grant promo, Gamma sterilization, and Carbonate buffer technical notes

The PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers and other research supplies. March ends the fiscal quarter for several institutions and grants which is why we are having a special end-of-quarter promotion. Orders between $100-250 receive a free drink-coozy, orders $250-500 receive a free string-backpack and orders >$500 receive a free PolySciTech T-shirt. As manager of Akina, I receive technical questions and sometimes I receive the same ones quite often. Often, I receive questions about gamma sterilizing our products. Our experience has been, however, that it is common for ionizing radiation techniques such as this to cause some degradation and cross-linking of polyesters which can change their mechanical properties (tend to become brittle) and their solubility properties (may become insoluble). This is similar to literature reports for the effects of radiation on polymers (http://link.springer.com/article/10.1023/A:1016256903322, http://www.sciencedirect.com/science/article/pii/0032386183901982). One way to reduce this damage is to perform the radiation dosing in an inert gas (argon or nitrogen). We’ve found this reduces some of the reactions which require the participation of atmospheric oxygen, humidity, or other gasses. Alternatively, depending on your application, it may be worthwhile to investigate alternate sterilization techniques such as ethylene oxide exposure. Another issue which has recently come up is the dissolution of thermogelling polymers (PLGA-PEG-PLGA, PLCL-PEG-PLCL) in specific buffers. Thermogel polymers of this category represent a balance between the hydrophilic attractions of the PEG block to water molecules and the hydrophobic attractions of the polyester blocks to each other. Species dissolved in the water which interfere with the water attractions can affect the performance of these thermogels. Although these work well in water, phosphate and several other buffers, they do not work well in carbonate buffers. Likely, this is due to the effects of carbonate species on water’s hydrogen bonding properties (http://pubs.acs.org/doi/abs/10.1021/jp809069g). Poor solubility of these thermogels has been reported in carbonate buffers and avoidance of carbonate buffer is suggested for these materials.

Thermogel PLGA-PEG-PLGA from PolySciTech used in development of minimally invasive liver-cancer microwave ablation therapy

 

Recently, researchers have developed improvements in the localization and effectiveness of Microwave Ablation therapy by combining PolySciTech Division of Akina, Inc. (www.polyscitech.com) thermogelling product (PLGA-PEG-PLGA PolyVivo, Cat# AK088) with non-radioactive Cesium chloride to create an injectable thermal accelerant. This research holds promise for improved ablation treatment of liver cancer.  Read more: Park, William Keun Chan, Aaron Wilhelm Palmer Maxwell, Victoria Elizabeth Frank, Michael Patrick Primmer, Scott Andrew Collins, Grayson Luderman Baird, and Damian Edward Dupuy. “Evaluation of A Novel Thermal Accelerant For Augmentation Of Microwave Energy During Image-guided Tumor Ablation.” Theranostics, in print (2017). http://www.thno.org/v07p1026.pdf

“The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings. Key words: Image-guided thermal ablation, microwave ablation, thermal accelerant, augmentation of microwave energy, non-radioactive cesium chloride, block-co-polymer, PLGA-PEG-PLGA, dipole moment, complex dielectric permittivity, dielectric constant, loss factor.”

New whitepaper on thermogelling PLCL-PEG-PLCL aqueous storage stability as a ready-to-go solution

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polymers. One class of these is thermogelling polymers which can dissolve in cold water and then form into a solid gel once the water is warmed above the LCST. In some situations, one may want to dissolve the polymer in an aqeous solution and then store it in this ready-to-go condition for some time prior to use. As these polymers are hydrolysable, there is a finite span of time that this gel solution can be stored. Recently, accelerated degradation testing was performed using PLCL-PEG-PLCL PolyVivo AK109. The PLCL blocks provide for slower degradation as compared with PLGA blocks and this study was designed to see how long these thermogels can be store. You can see more on this here (http://akinainc.com/pdf/AK109%20storage%20stability.pdf)

mPEG-PLA from PolySciTech used as part of SPION-methicillin loaded nanoparticle development for eradication of drug-resistant bacterial biofilms

There is increasing prevalence of bacterial resistance towards antibiotics due to genetic as well as structural changes. Notably, certain types of bacteria tend to form into tight biofilms which are surrounded by a protective matrix that reduces antibiotic infiltration. These biofilms can be up to 1000 times more resistant towards conventional antibiotics than loose bacteria and account for up to 60% of all infectious diseases in the western world. Recently, researchers at Northeastern University utilized mPEG-PLA (PolyVivo cat# AK021) from PolySciTech division of Akina, Inc. (www.polyscitech.com) to co-encapsulate iron-oxide particles and methicillin inside polymeric nanoparticles. They discovered that these nanoparticles, under a magnetic field, were able to penetrate deep into staph-bacteria biofilms and kill the bacteria, while having no toxicity towards mammalian cells. This research holds promise for providing advanced treatment options of drug-resistant bacteria and infections at medical implant surfaces. Read more: Geilich, Benjamin M., Ilia Gelfat, Srinivas Sridhar, Anne L. van de Ven, and Thomas J. Webster. “Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication.” Biomaterials 119 (2017): 78-85. http://www.sciencedirect.com/science/article/pii/S0142961216307086

“Abstract: The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 μm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 μg/mL SPION and 20 μg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics. Keywords: Biofilm; Polymersome; SPION; Staphylococcus epidermidis; Antibiotic-resistance; Nanomedicine”

Akanocure Press Release

You can obtain commercially available Akanocure products at https://akinainc.com/polyscitech/products/akanocure/index.php read more in a a recent press release regarding Akanocure is available here http://www.purdue.edu/newsroom/releases/2017/Q1/purdue-affiliated-pharmaceutical-company-launches-product-to-produce-rare-disease-fighting-compounds.html

Amine-endcap PLGA from PolySciTech used in development of heart-attack treatment

Heart attack, or myocardial infarction, is the leading cause of death worldwide. One of the causes of tissue damage which occurs during a heart attack is excess calcium influx that occurs once blood-flow is reestablished (reperfusion). This calcium influx leads to cell death and massive tissue damage to the heart muscles rendering them inoperable which can be lethal for the patient. Recently, researchers working jointly at University of Iowa and Mahidol University (Thailand), utilized PLGA-NH2 from PolySciTech division of Akina, Inc. (www.polyscitech.com) (PolyVivo AI063) as a component in developing a targeted nanoparticle preparation which delivered an CaMKII inhibitor peptide to prevent heart-cell death during reperfusion. This research holds promise for the development of a medicine which can be used to prevent tissue damage during a heart-attack potentially aiding in life-saving therapy. Read more here: Wongrakpanich, Amaraporn, Angie S. Morris, Sean M. Geary, A. Joiner Mei-ling, and Aliasger K. Salem. “Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury.” International Journal of Pharmaceutics (2017). http://www.sciencedirect.com/science/article/pii/S0378517317300704

“Abstract: An excess of calcium (Ca2+) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca2+ triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca2+ influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP were taken up by mitochondria and successfully reduced ROS caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP have the potential to be used in protection against ischemia/reperfusion injury.”

PLGA from PolySciTech used as part of optimized doxorubicin nanoparticle study

Nanoparticles references formulations which are submicron in size. A great deal of expertise goes into making nanoparticles with precise properties and this is an exciting field of research for a wide variety of treatments. Recently, researchers utilized PLGA (PolyVivo AP082) from PolySciTech (www.polyscitech.com) for formulation optimization of doxorubicin loaded particles. This research holds promised for improved chemotherapy strategies. Read more: Shaikh, Muhammad Vaseem, Manika Kala, and Manish Nivsarkar. “Formulation and optimization of doxorubicin loaded polymeric nanoparticles using Box-Behnken design: ex-vivo stability and in-vitro activity.” European Journal of Pharmaceutical Sciences (2017). http://www.sciencedirect.com/science/article/pii/S0928098717300507

“Abstract: Biodegradable nanoparticles (NPs) have gained tremendous interest for targeting chemotherapeutic drugs to the tumor environment. Inspite of several advances sufficient encapsulation along with the controlled release and desired size range have remained as considerable challenges. Hence, the present study examines the formulation optimization of doxorubicin loaded PLGA NPs (DOX-PLGA-NPs), prepared by single emulsion method for cancer targeting. Critical process parameters (CPP) were selected by initial screening. Later, Box-Behnken design (BBD) was used for analyzing the effect of the selected CPP on critical quality attributes (CQA) and to generate a design space. The optimized formulation was stabilized by lyophilization and was used for in-vitro drug release and in-vitro activity on A549 cell line. Moreover, colloidal stability of the NPs in the biological milieu was assessed. Amount of PLGA and PVA, oil:water ratio and sonication time were the selected independent factors for BBD. The statistical data showed that a quadratic model was fitted to the data obtained. Additionally, the lack of fit values for the models was not significant. The delivery system showed sustained release behavior over a period of 120 h and was governed by Fickian diffusion. The multipoint analysis at 24, 48 and 72 h showed gradual reduction in IC50 value of DOX-PLGA-NPs (p < 0.05, Fig. 9). DOX-PLGA-NPs were found to be stable in the biological fluids indicating their in-vivo applicability. In conclusion, optimization of the DOX-PLGA-NPs by BBD yielded in a promising drug carrier for doxorubicin that could provide a novel treatment modality for cancer.”