Monthly Archives: April 2016

PolySciTech mPEG-PLLA used for zinc (II) phthalocyanine delivery as part of photodynamic cancer therapy research

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable block copolymers including mPEG-PLLA. Recently, researchers in Poland used the product PolyVivo AK004 (mPEG-PLLA 2000-5000) to develop a delivery system for zinc(II) phthalocyanine (ZnPc). ZnPc is a photosensitizer which does not have toxicity towards cells unless it is illuminated with a certain wavelength of light (in the range of 600-800nm). Under illumination this one generates unstable singlet oxygen which is a highly cytotoxic agent that kills the cancer cells. The goal with this therapy is that the photosensitizer is applied systemically but only the tumor sites are illuminated by a clinician so that these are selectively targeted. The use of mPEG-PLLA, AK004 reported to have a critical micelle concentration of 2.8 x 10^− 3 mg/mL, led to a greatly increased stability, blood circulation, solubility, and delivery of ZnPc. This exciting research holds promise for cancer therapy. Read more: Lamch, Łukasz, Julita Kulbacka, Jadwiga Pietkiewicz, Joanna Rossowska, Magda Dubińska-Magiera, Anna Choromańska, and Kazimiera A. Wilk. “Preparation and characterization of new zinc (II) phthalocyanine—Containing poly (l-lactide)-b-poly (ethylene glycol) copolymer micelles for photodynamic therapy.” Journal of Photochemistry and Photobiology B: Biology 160 (2016): 185-197. http://www.sciencedirect.com/science/article/pii/S1011134416302603

 

“Abstract: Poly(l-lactide)-b-poly(ethylene oxide) block copolymer (mPEG-b-PLLA) micelles were fabricated and applied as a new biodegradable and biocompatible nanocarrier for solubilization of hydrophobic zinc (II) phthalocyanine (ZnPc). The nanocarrier demonstrated a good colloidal stability and its in vitro sustained cargo release profile was assessed. Photobleaching of ZnPc, both in its native form and encapsulated in the obtained polymeric micelles, was studied by means of spectroscopic measurements. The photodynamic reaction (PDR) protocol for cyto- and photocytotoxicity was performed on metastatic melanoma cells (Me45), normal human keratinocytes (HaCaT) being used for comparison. The intracellular accumulation of free and encapsulated ZnPc was visualized at various time periods (1, 3 and 24 h). The proapoptotic potential of the encapsulated phthalocyanine was evaluated by monitoring DNA double strand break damage fragmentation (TUNEL assay) and caspase 3/7 activity. In addition, in vitro biocompatibility studies were conducted by determining hemolytic activity of Zn-Pc-loaded mPEG-b-PLLA micelles and their lack of cytotoxicity against macrophages (P388/D1) and endothelial cells (HUV-EC-C). Our results suggest that the PDR using Zn-Pc-loaded mPEG-b-PLLA micelles can be effective in inhibiting tumor cell growth and apoptosis induction with higher responses, observed for Me45 cells. Additionally, the ZnPc-loaded micelles appear to be hemato-biocompatible and safe for normal keratinocytes, macrophages and endothelial cells. Highlights: We developed novel ZnPc-loaded mPEG-b-PLLA micelles to improve the therapeutic effect of PDT. Encapsulated ZnPc exhibited much better photostability during irradiation than free photosensitizer. Polymeric micelles efficiently deliver the photosensitizer in metastatic melanoma cells (Me45). Encapsulated ZnPc was found to be safe for normal keratinocytes, macrophages and endothelial cells. Keywords: Nano-photosensitizer; Human melanoma; Phototoxicity; Apoptosis; Biocompatibility”

Image: https://2.bp.blogspot.com/-WnSDlmGBeiU/VyIyyFXdT_I/AAAAAAAACMU/2WrGgUsENVkjoI63_oNCidzxXioJpttwwCLcB/s1600/Lamch%252C%2B2016%2Bphotosensitizer%2BmPEG-PLLA.png

PolySciTech thermogel investigated as part of system for thermally killing drug-resistant bacteria

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of research polymers including thermogels. Recently researchers at the University of Toronto have combined PolyVivo AO031 Poly(N-vinylcaprolactam), a biocompatible thermogel, with gold-nanorods to create a thermogelling system that allows for very precise application of heat by a hand-held laser device which kills both gram positive and negative bacteria. This research holds promise for treating infected wounds to kill bacteria without damaging the underlying tissue. Read more:  Mohamed, Mohamed A. Abdou, Vahid Raeesi, Patricia V. Turner, Anu Rebbapragada, Kate Banks, and Warren CW Chan. “A versatile plasmonic thermogel for disinfection of antimicrobial resistant bacteria.” Biomaterials (2016). http://www.sciencedirect.com/science/article/pii/S0142961216301144

“Abstract: The increasing occurrence of antimicrobial resistance among bacteria is a global problem that requires the development of alternative techniques to eradicate these superbugs. Herein, we used a combination of thermosensitive biocompatible polymer and gold nanorods to specifically deliver, preserve and confine heat to the area of interest. Our data demonstrates that this technique can be used to kill both Gram positive and Gram negative antimicrobial resistant bacteria in vitro. Our approach significantly reduces the antimicrobial resistant bacteria load in experimentally infected wounds by 98% without harming the surrounding tissues. More importantly, this polymer-nanocomposite can be prepared easily and applied to the wounds, can generate heat using a hand-held laser device, is safe for the operator, and does not have any adverse effects on the wound tissue and healing process. Keywords: Photothermal; gold nanorods; Thermogel; wound infections; Antibiotic resistant bacteria”

Poly(lactide) from PolySciTech used as part of plastics enzymatic degradation research.

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of research polymers including poly(lactide) with well controlled properties. Recently, researchers at University of Toronto utilized PLA from polyscitech as a test substrate for developing bacterially derived carboxyl esterases which catalyze the degradation of this polyester. This research holds promise for plastics recycling as a way of sustainable, environmental practices of the future. Read more: Hajighasemi, Mahbod, Boguslaw P. Nocek, Anatoli Tchigvintsev, Greg Brown, Robert Flick, Xiaohui Xu, Hong Cui et al. “Biochemical and structural insights into enzymatic depolymerization of polylactic acid and other polyesters by microbial carboxylesterases.” Biomacromolecules (2016). http://pubs.acs.org/doi/abs/10.1021/acs.biomac.6b00223

“Abstract: Polylactic acid (PLA) is a biodegradable polyester derived from renewable resources, which is a leading candidate for the replacement of traditional petroleum-based polymers. Since the global production of PLA is quickly growing, there is an urgent need for the development of efficient recycling technologies, which will produce lactic acid instead of CO2 as the final product. After screening 90 purified microbial α/β-hydrolases, we identified hydrolytic activity against emulsified PLA in two uncharacterized proteins, ABO2449 from Alcanivorax borkumensis and RPA1511 from Rhodopseudomonas palustris. Both enzymes were also active against emulsified polycaprolactone and other polyesters, as well as against soluble α-naphthyl and p-nitrophenyl monoesters. In addition, both ABO2449 and RPA1511 catalyzed complete or extensive hydrolysis of solid PLA with the production of lactic acid monomers, dimers, and larger oligomers as products. The crystal structure of RPA1511 was determined at 2.2 Å resolution and revealed a classical α/β-hydrolase fold with a wide-open active site containing a molecule of polyethylene glycol bound near the catalytic triad Ser114-His270-Asp242. Site-directed mutagenesis of both proteins demonstrated that the catalytic triad residues are important for the hydrolysis of both monoester and polyester substrates. We also identified several residues in RPA1511 (Gln172, Leu212, Met215, Trp218, and Leu220) and ABO2449 (Phe38 and Leu152), which were not essential for activity against soluble monoesters, but were found to be critical for the hydrolysis of PLA. Our results indicate that microbial carboxyl esterases can efficiently hydrolyze various polyesters making them attractive biocatalysts for plastics depolymerization and recycling.”

PLGA-PEG-PLGA thermogel investigated for use as a surgical aid in elevating tissues during colon cancer treatment

PolySciTech division of Akina Inc. (www.polyscitech.com) provides a wide-array of biodegradable block copolymers including thermogelling PLGA-PEG-PLGA. Recently, PLGA-PEG-PLGA polymers were used experimentally as a surgical aid in endoscopic submucosal dissection (ESD). This is a procedure which holds great promise for surgical removal of certain types of cancer. For this procedure, the outer mucosa needs to be gently elevated away from the lower submucosa, muscularis, and serosa layers. This allows for a lesion to be cut off the external layer without puncturing the delicate inner layers. Read more about this exciting application here: Cao, Luping, Quanlin Li, Chen Zhang, Haocheng Wu, Liqing Yao, Meidong Xu, Lin Yu, and Jiandong Ding. “Safe and efficient colonic endoscopic submucosal dissection using an injectable hydrogel.” ACS Biomaterials Science & Engineering 2, no. 3 (2016): 393-402. http://pubs.acs.org/doi/abs/10.1021/acsbiomaterials.5b00516

“Endoscopic submucosal dissection (ESD) has not yet been widely adopted in the treatment of early colonic cancers due to the greater technical difficulty involved, longer procedure time, and the increased risk of perforation. Adequate mucosal elevation by submucosal injection is crucial for en bloc resection and prevention of perforation during colonic ESD. This study is aimed to evaluate the efficacy of an injectable thermoreversible hydrogel as the colonic submucosal agent for the first time. Triblock copolymer poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA–PEG-PLGA) was synthesized, and its concentrated aqueous solution was injected into the colonic submucosa of living minipig and spontaneously transformed into an in situ hydrogel with adequate mucosal elevation at body temperature. Such a mucosal lifting lasted for a longer time than that created by the control group, glycerol fructose. Colonic ESD was then performed with the administration of hydrogels at various polymer concentrations or glycerol fructose. All colonic lesions were successfully resected en bloc after one single injection of the hydrogel, and repeated injections were not needed. No evidence of major hemorrhage, perforation and tissue damage were observed. Considering the injection pressure, duration of mucosal elevation and efficacy of “autodissection”, the hydrogel containing 15 wt % polymer was the optimized system for colonic ESD. Consequently, the thermoreversible hydrogel is an ideal submucosal fluid that provides a durable mucosal lifting and makes colonic ESD accessible to a large extent. In particular, the efficacy of “autodissection” after one single injection of the hydrogel simplifies significantly the procedures while minimizing the complications. Keywords: endoscopic submucosal dissection (ESD); submucosal injection agent; injectable hydrogel; colonic tumor; autodissection”

PLGA-PEG-Maleimide from PolySciTech used as part of developing hyaluronidase conjugated particle for enhanced tumor penetration and chemotherapy

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of polymers such as PLGA-PEG-Maleimide (PolyVivo AI020). The Maleimide cap on these polymers possesses the capability of conjugating to any thiol-bearing molecule in aqueous solution at near neutral pH with no heating by a simple Michaels-type addition. This process allows for generating nanoparticles which express a desired ligand or targeting moiety on their surface. Recently, researchers at Drexel University utilized PLGA-PEG-Maleimide from PolySciTech for developing a nanoparticle which had recombinant human hyaluronidase PH20 (rHuPH20) labelled on the surface. They found that this conjugation lead to four-times the accumulation of nanoparticles inside a 4T1 syngenic tumor model (advanced breast cancer model) as compared to unlabeled PEG-PLGA nanoparticles. This also led to enhanced performance of model chemotherapeutic doxorubicin against these tumor cells when it was encapsulated in the labeled nanoparticles as compared to conventional delivery of loose drug. Read more: Zhou, Hao, Zhiyuan Fan, Junjie Deng, Pelin K. Lemons, Dimitrios C. Arhontoulis, Wilbur B. Bowne, and Hao Cheng. “Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.” Nano Letters (2016). http://pubs.acs.org/doi/abs/10.1021/acs.nanolett.6b00820

“Abstract: One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systematic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood. Keywords: Extracellular matrix; hyaluronan; appoptosis; heterogeneous; drug release”

PLGA from PolySciTech used as part of biodegradable magnesium-based cardiovascular stent development

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. Recently PLGA from PolySciTech was used by researchers as a control polymer for development of polymer coated resorbable magnesium stents. Read more: Gu, Xinzhu, Zhongwei Mao, Sang-Ho Ye, Youngmi Koo, Yeoheung Yun, Tiasha Tarannum, Vesselin Shanov, and William R. Wagner. “Biodegradable, Elastomeric Coatings with Controlled Anti-proliferative Agent Release for Magnesium-based Cardiovascular Stents.” Colloids and Surfaces B: Biointerfaces (2016). http://www.sciencedirect.com/science/article/pii/S0927776516302570

“Abstract: Vascular stent design continues to evolve to further improve the efficacy and minimize the risks associated with these devices. Drug-eluting coatings have been widely adopted and, more recently, biodegradable stents have been the focus of extensive evaluation. In this report, biodegradable elastomeric polyurethanes were synthesized and applied as drug-eluting coatings for a relatively new class of degradable vascular stents based on Mg. The dynamic degradation behavior, hemocompatibility and drug release were investigated for poly(carbonate urethane) urea (PCUU) and poly(ester urethane) urea (PEUU) coated magnesium alloy (AZ31) stents. Poly(lactic-co-glycolic acid) (PLGA) coated and bare stents were employed as control groups. The PCUU coating effectively slowed the Mg alloy corrosion in dynamic degradation testing compared to PEUU-coated, PLGA-coated and bare Mg alloy stents. This was confirmed by electron microscopy, energy-dispersive x-ray spectroscopy and magnesium ion release experiments. PCUU-coating of AZ31 was also associated with significantly reduced platelet adhesion in acute blood contact testing. Rat vascular smooth muscle cell (rSMC) proliferation was successfully inhibited when paclitaxel was released from pre-loaded PCUU coatings. The corrosion retardation, low thrombogenicity, drug loading capacity, and high elasticity make PCUU an attractive option for drug eluting coating on biodegradable metallic cardiovascular stents. Keywords: Polymer coating; magnesium stents; drug eluting coating”

New Products from PolySciTech

PolySciTech Division of Akina, Inc. (www.polyscitech.com) has added two new products. PolyVivo AI124 Methoxy Poly(ethylene glycol)-b-Poly(caprolactone)-cysteine ethyl ester endcap, mPEG-PCL (2,000:3,000 Da) features a terminal thiol unit for conjugation reactions while PolyVivo AV029 Methoxy-Poly(ethylene glycol)-b-Poly(lactide-co-glycolide)-FKI749 copolymers, mPEG-PLGA (5000-10,000Da, 50:50 LA:GA) features a near-IR fluorescent dye conjugate for nanoparticle tracking applications.

PLGA polymers from PolySciTech used in development of localized resolvin D1 delivery for heart-treatment

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA. One of the strengths of PolySciTech is providing a fairly comprehensive array of PLGA’s with varying lactide:glycolide ratio as well as molecular weight. These parameters affect biodegradation as higher lactide content and higher molecular weight polymers degrade more slowly.  Recently, researchers at University of California Department of Surgery and Cardiovascular Research Institute used a series of PLGA polymers purchased from PolyScitech to develop a localized drug delivery film which had a gradient of lactide content (LA:GA 50:50, 75:25, 85:15) for controlled release of resolvin D1, a lipid mediator which assist in ending inflammation and assisting healing of the vascular wall. One application of this film would be its potential for use in cardiovascular stents. Currently, these are loaded with cytotoxic anti-proliferative agents which prevent in-healing for a time by simply reducing cell growth. The delivery of a mediator which reduced inflammation and aided healing would bring about a more long-lasting solution to the incidence of in-growth. Read more about this exciting research here: Wu, Bian, Giorgio Mottola, Anuran Chatterjee, Kevin D. Lance, Mian Chen, Iris O. Siguenza, Tejal A. Desai, and Michael S. Conte. “Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury.” Journal of Vascular Surgery (2016). http://www.sciencedirect.com/science/article/pii/S0741521416001580

“Abstract: Objective: Lipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury. Methods: Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury. Results: RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and 45%; P < .05) were significantly lower in the RvD1-loaded wrap group compared with both no-wrap and vehicle-wrap controls at 3 days after injury. Conclusions: Local perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.”