Monthly Archives: June 2014

PolySciTech PLGA-PEG-PLGA used for peritoneal ovarian cancer treatment

PolyScitech (www.polyscitech.com) provides several PLGA-PEG-PLGA thermogelling triblock copolymers (AK12, AK19, AK88). Recently PolySciTech triblock thermogel was utilized by University of Wisconsin to deliver paclitaxel, 17-AAG, and rapamycin simultaneously in a controlled manner after injection to form a gel depot.  In mouse model this lead to reduced tumor volume and improved survival times. Read more: Cho, Hyunah, and Glen S. Kwon. “Thermosensitive poly-(d, l-lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly-(d, l-lactide-co-glycolide) hydrogels for multi-drug delivery.” Journal of Drug Targeting 0 (2014): 1-9. http://informahealthcare.com/doi/abs/10.3109/1061186X.2014.931406

“Abstract: A current treatment strategy for peritoneal ovarian cancer is a combination of peritoneal surgery and multi-drug-based chemotherapy that often involves intraperitoneal (IP) injection. A thermosensitive poly-(d,l-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(d,l-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogel platform (thermogels) enabled gel loading of poorly work-soluble paclitaxel (cytotoxic agent), 17-allylamino-17-demethoxygeldanamycin (17-AAG, heat shock protein inhibitor), and rapamycin (mammalian target of rapamycin protein inhibitor). PLGA-b-PEG-b-PLGA thermogels (15%) carrying paclitaxel, 17-AAG, and rapamycin (named Triogel) made a successful transition from a free-flowing solution below ambient temperature to a gel depot at body temperature. Triogel gradually released paclitaxel, 17-AAG, and rapamycin at an equal release rate in response to the physical gel erosion. In an ES-2-luc ovarian cancer xenograft model, a single IP injection of Triogel (60, 60, and 30 mg/kg of paclitaxel, 17-AAG, and rapamycin, respectively) significantly reduced tumor burden and prolonged survival of ES-2-luc-bearing nude mice without notable systemic toxicity relative to those delivered by poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles in solution via IP or intravenous (IV) injection route. These results show a great potential of a biodegradable thermogel platform carrying multi-drugs for IP chemotherapy in peritoneal ovarian cancer. Keywords: 17-AAG, multi-drug delivery, ovarian cancer, paclitaxel, PLGA-b-PEG-b-PLGA, raamycin, regel”

PolySciTech Spinswiper for rapid generation of homogenous microparticles

PolySciTech (www.polyscitech.com) division of Akina provides a wide array of polymer products. However there are other aspects to the research which goes on at Akina and one of the products to come out of this is the spinswiper which is a novel method for scale-up production of microparticles using hydrogel template technology.  This was the focus of a recent Purdue Research Park press release. Read more here: http://purdueresearchpark.com/news/polyscitechs-spinswiper-could-speed-production-controlled-release-microparticles  Also read about some of the recent research using the hydrogel template technology here: Acharya, Ghanashyam, Crystal S. Shin, Matthew McDermott, Himanshu Mishra, Haesun Park, Ick Chan Kwon, and Kinam Park. “The hydrogel template method for fabrication of homogeneous nano/microparticles.” Journal of Controlled Release 141, no. 3 (2010): 314-319. http://www.sciencedirect.com/science/article/pii/S0168365909007019

“Abstract: Nano/microparticles have been used widely in drug delivery applications. The majority of the particles are prepared by the conventional emulsion methods, which tend to result in particles with heterogeneous size distribution with sub-optimal drug loading and release properties. Recently, microfabrication methods have been used to make nano/microparticles with a monodisperse size distribution. The existing methods utilize solid templates for making particles, and the collection of individual particles after preparation has not been easy. The new hydrogel template approach was developed to make the particle preparation process simple and fast. The hydrogel template approach is based on the unique properties of physical gels that can undergo sol–gel phase transition upon changes in environmental conditions. The phase reversible hydrogels, however, are in general mechanically too weak to be treated as a solid material. It was unexpectedly found that gelatin hydrogels could be made to possess various properties necessary for microfabrication of nano/microparticles in large quantities. The size of the particles can be adjusted from 200 nm to > 50 µm, providing flexibility in controlling the size in drug delivery formulations. The simplicity in processing makes the hydrogel template method useful for scale-up manufacturing of particles. The drug loading capacity is 50% or higher, and yet the initial burst release is minimal. The hydrogel template approach presents a new strategy of preparing nano/microparticles of predefined size and shape with homogeneous size distribution for drug delivery applications. Keywords: Hydrogel template; Microfabrication; Microparticle; Homogeneous size; Drug delivery”

New PolySciTech PLGA-PEG-PLGA Thermogel AK88

PolySciTech (www.polyscitech.com) latest product is PolyVivo AK88 (PLGA-PEG-PLGA 1600-1500-1600 3:1 La:Ga) which is a triblock copolymer that optimally thermogels at 37°C as a 20% w/v solution.  Recently similar thermogels were used as a biomaterial to aid endoscopic submucosal dissection as a cushion to reduce perforation and other problems associated with this surgical procedure. Read more: Yu, Lin, Wei Xu, Wenjia Shen, Luping Cao, Yan Liu, Zhaoshen Li, and Jiandong Ding. “Poly (lactic acid-co-glycolic acid)–poly (ethylene glycol)–poly (lactic acid- co-glycolic acid) thermogel as a novel submucosal cushion for endoscopic submucosal dissection.” Acta biomaterialia 10, no. 3 (2014): 1251-1258. http://www.sciencedirect.com/science/article/pii/S174270611300603X

“Abstract: Endoscopic submucosal dissection (ESD) is a clinical therapy for early stage neoplastic lesions in the gastrointestinal tract. It is, however, faced with a crucial problem: the high occurrence of perforation. The formation of a submucosal fluid cushion (SFC) via a fluid injection is the best way to avoid perforation, and thus an appropriate biomaterial is vital for this minimally invasive endoscopic technique. In this study, we introduced an injectable thermogel as a novel submucosal injection substance in ESD. The hydrogel synthesized by us was composed of poly(lactic acid-co-glycolic acid)–poly(ethylene glycol)–poly(lactic acid-co-glycolic acid) (PLGA–PEG–PLGA) triblock copolymers. The polymer/water system was a low-viscosity fluid at room temperature and thus easily injected, and turned into a non-flowing gel at body temperature after injection. The submucosal injection of the thermogel to create SFCs was performed in both resected porcine stomachs and living minipigs. High mucosal elevation with a clear margin was maintained for a long duration. Accurate en bloc resection was achieved with the assistance of the thermogel. The mean procedure time was strikingly reduced. Meanwhile, no obvious bleeding, perforation and tissue damage were observed. The application of the thermogel not only facilitated the ESD procedure, but also increased the efficacy and safety of ESD. Therefore, the PLGA–PEG–PLGA thermogel provides an excellent submucosal injection system, and has great potential to improve the ESD technique significantly. Keywords: Endoscopic submucosal dissection (ESD); Submucosal injection; Biodegradable thermogel; Perforation; Mucosal elevation”

AK88 thermogel

mPEG-P(5BZTMC) as pendant precursor for pro-drug conjugation

PolySciTech (www.polyscitech.com) provides block copolymers of 5-benzyloxy-trimethylene carbonate (e.g. Polyvivo AK78).  This polymer has an inherent benefit of added hydrophobicity from the benzyloxy unit however there is another usage of this material. The Benzyloxy unit acts as a leaving group and can be readily removed by reacting the polymer with hydrogen gas using palladium on carbon catalyst. This leaves a pendant hydroxyl available for a wide array of further conjugation reactions. An example of the usage of this and chemical details for a similar polymer can be seen here: Xie, Zhigang, Huili Guan, Changhai Lü, Xuesi Chen, and Xiabin Jing. “Synthesis and characterization of novel biotinylated biodegradable poly (ethylene glycol)- b-poly (carbonate-lactic acid) copolymers.” Acta biomaterialia 1, no. 6 (2005): 635-641. http://www.sciencedirect.com/science/article/pii/S1742706105001121

“Abstract: Poly(ethylene glycol)-b-poly(5-benzyloxy-trimethylene carbonate-lactic acid) copolymers (PEG-b-P(BTMC-LA)) were synthesized by ring-opening polymerization of lactide and 5-benzyloxy trimethylene carbonate in the presence of mono-hydroxyl poly(ethylene glycol) with diethyl zinc as catalyst. They were further converted into deprotected copolymers with the pendant hydroxyl groups by hydrogenolysis in the presence of Pd(OH)2/C, and finally conjugated with biotin through the free hydroxyl groups. Gel permeation chromatography, Fourier transform infrared, differential scanning calorimetry and 1H nuclear magnetic resonance studies confirmed the copolymer structures and successful attachment of biotin to the copolymer. Keywords: Biotin; Diethyl zinc; Polycarbonate; Polylactide”

mPEG-5BZTMC-biotin usage

PEG-PCL used for dual targeted brain cancer treatment

PolySciTech (www.polyscitech.com) provides a wide array of both standard block copolymers (Polyvivo AK series) as well as those with a reactive functional endcap (Polyvivo AI series).  Recently these types of polymers were used to create a dual targeted nanoparticle for treating glioblastoma multiforme (brain cancer) by functionalizing the particles with interleukin-13 and RGD peptides. Read more: Gao, Huile, Zhi Yang, Shijie Cao, Yang Xiong, Shuang Zhang, Zhiqing Pang, and Xinguo Jiang. “Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment.” Biomaterials 35, no. 7 (2014): 2374-2382. http://www.sciencedirect.com/science/article/pii/S0142961213014427

“Abstract: Glioblastoma multiforme (GBM), one of the most common primary malignant brain tumors, was characterized by angiogenesis and tumor cells proliferation. Antiangiogenesis and antitumor combination treatment gained much attention because of the potency in dual inhibition of both the tumor proliferation and the tumor invasion. In this study, a neovasculature and tumor cell dual targeting delivery system was developed through modification of nanoparticles with interleukin-13 peptide and RGD (IRNPs), in which interleukin-13 peptide was targeting GBM cells and RGD was targeting neovasculature. To evaluate the potency in GBM treatment, docetaxel was loaded into IRNPs. In vitro, interleukin-13 peptide and RGD could enhance the corresponding cells (C6 and human umbilical vein endothelial cells) uptake and cytotoxicity. In combination, IRNPs showed high uptake in both cells and increased the cytotoxicity on both cells. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than mono-modified nanoparticles. Correspondingly, docetaxel-IRNPs displayed best anti-tumor effect with a median survival time of 35 days, which was significantly longer than that of mono-modified and unmodified nanoparticles. Importantly, treatment with docetaxel-IRNPs could avoid the accumulation of HIF1α in GBM site, which was crucial for the tumor invasion. After the treatment, there was no obvious change in normal organs of mice. Keywords: Glioblastoma; Antiangiogenesis; Anti-tumor therapy; Dual targeting delivery”

Mal-PEG-PLGA for crossing Blood-Brain-Barrier as Alzheimer’s treatment

PolySciTech (www.polyscitech.com) provides a variety of PLGA-PEG-Maleimide reactive precursors (PolyVivo AI20, AI53, etc.) for conjugation to peptides and other targeting moieties. Recent research has shown that functionalization of these polymers with lactoferrin allows for transportation of the polymersomes across the blood brain barrier. Read more: Yu, Yuan, Xinguo Jiang, Shuyu Gong, Liang Feng, Yanqiang Zhong, and Zhiqing Pang. “The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood–brain barrier after modification with lactoferrin.” Nanoscale 6, no. 6 (2014): 3250-3258. http://pubs.rsc.org/EN/content/articlehtml/2014/nr/c3nr05196j

Yuan, 2014 BBB

“Abstract: Biotherapeutics such as peptides possess strong potential for the treatment of intractable neurological disorders. However, because of their low stability and the impermeability of the blood–brain barrier (BBB), biotherapeutics are difficult to transport into brain parenchyma via intravenous injection. Herein, we present a novel poly(ethylene glycol)–poly(D,L-lactic-co-glycolic acid) polymersome-based nanomedicine with self-assembled bilayers, which was functionalized with lactoferrin (Lf-POS) to facilitate the transport of a neuroprotective peptide into the brain. The apparent diffusion coefficient (D*) of H+ through the polymersome membrane was 5.659 × 10−26 cm2 s−1, while that of liposomes was 1.017 × 10−24 cm2 s−1. The stability of the polymersome membrane was much higher than that of liposomes. The uptake of polymersomes by mouse brain capillary endothelial cells proved that the optimal density of lactoferrin was 101 molecules per polymersome. Fluorescence imaging indicated that Lf101-POS was effectively transferred into the brain. In pharmacokinetics, compared with transferrin-modified polymersomes and cationic bovine serum albumin-modified polymersomes, Lf-POS obtained the greatest BBB permeability surface area and percentage of injected dose per gram (%ID per g). Furthermore, Lf-POS holding S14G-humanin protected against learning and memory impairment induced by amyloid-β25–35 in rats. Western blotting revealed that the nanomedicine provided neuroprotection against over-expression of apoptotic proteins exhibiting neurofibrillary tangle pathology in neurons. The results indicated that polymersomes can be exploited as a promising non-invasive nanomedicine capable of mediating peptide therapeutic delivery and controlling the release of drugs to the central nervous system.”

Power Outages

Recently Akina’s facility and Polyscitech website (www.polyscitech.com) has suffered from power outages ~4-7PM this past Monday (6/16) and Wednesday (6/18) due to nearby construction work.  If you have been attempting to contact Akina recently it may have been difficult due to loss of power for internet and phone service.  Power has been restored at Akina and so you may contact us at anytime. Apologies for the inconvenience.

New PolySciTech Product mPEG-PEI copolymer for DNA/RNA delivery as cancer therapy

PolySciTech (www.polyscitech.com) has just launched a new product mPEG-PEI (Polyvivo AK86) for use as a delivery vehicle for nucleic acids including DNA, siRNA, mRNA, and miRNA.  Recently this type of polymer was utilized to deliver siRNA to prostate cancer cells as a therapeutic method to knockdown EZH2 gene expression which is responsible for prostate cancer progression. Read more: Wu, Yinxia, Junjie Yu, Yongbiao Liu, Lin Yuan, Hang Yan, Jing Jing, and Guoping Xu. “Delivery of EZH2-shRNA with mPEG-PEI nanoparticles for the treatment of prostate cancer in vitro.” International journal of molecular medicine 33, no. 6 (2014): 1563-1569. http://www.ingentaconnect.com/content/sp/ijmm/2014/00000033/00000006/art00023

“Abstract: Small interfering RNA (siRNA) is a promising therapeutic approach for castration-resistant prostate cancer (PCa). For the clinical application of siRNA, it is vital to find a safe and efficient gene transfer vector. Nanotechnology can provide a crucial advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of new therapeutic delivery vehicles. In this study, we describe a novel nanoparticle (mPEG-PEI) as an efficient non-viral carrier and found that this copolymer displayed enhanced efficiency in the shRNA-mediated knockdown of target genes. The enhancer of zeste homolog 2 (EZH2) is often elevated in castration-resistant PCa and has been implicated in the progression of human PCa. Targeting EZH2 may have therapeutic efficacy for the treatment of metastatic, hormone-refractory PCa. mPEG-PEI binds plasmid DNA yielding nanoparticles and these complexes exhibit low cytotoxicity and high gene transfection efficiency. Taken together, mPEG-PEI may be a promising non-viral gene carrier for the delivery of EZH2 short hairpin (sh)RNA to PC3 cells for advanced PCa therapy.”

PolySciTech AP030 PLGA utilized in thesis dissertation on bone scaffolding

PolySciTech (www.polyscitech.com) provides a wide array of PLGA polymer components. Recently PolyVivo AP030 (PLGA 85:15, Mn-10,000-15,000) was utilized to generate porous PLGA/CaSiO3 composite scaffolds which were tested for their potential applications in use for bone scaffolding.  Read more: Qi, Lin. “Porous PLGA-CaSiO3 (Pseudowollastonite) Composite Scaffolds Optimized for Biocompatibility and Osteoinduction.” PhD diss., University of Akron, 2014. Full-Text available: https://etd.ohiolink.edu/!etd.send_file?accession=akron1397041385&disposition=inline

“ABSTRACT: The goal of this study was to develop an optimal porous composite scaffold, composed of pseudowollastonite (psw; β-CaSiO3), and poly(L,D-lactic-co-glycolic acid) (PLGA). In culture medium, the psw released Ca2+ and soluble silica, which are osteoinductive soluble factors. PLGA was utilized as a structural framework and to maintain pH of the scaffold. Scaffolds were prepared by solvent casting/particle leaching technique to obtain porosity and interconnectivity of pores. The mass of NaCl, psw and PLGA were adjusted to determine the effects of the different components on the scaffold’s biocompatibility and osteoinductive potential, in vitro, on two types of cells, hMSC (human Mesenchymal Stem Cells) and MC3T3 (murine osteoblast precursor cells). An orthogonal study was designed for 9 scaffold compositions. Scanning electron microscopy and micro-computed tomography showed that the scaffold pore structure depended on the amount of NaCl used during fabrication. Variable porosity, and hydrolysis of the psw and PLGA components resulted in pH changes and different released soluble silica concentrations. Total DNA analysis from cell culture in growth medium showed that scaffold compositions which resulted in a small pH shift (± 0.5 on Day 3) and low soluble silica concentration (65±3 ppm) were less cytotoxic than scaffolds for which pH changes were large (±1.2 on Day 3) and soluble silica concentrations were high (87±5 ppm). The viability of hMSCs was lower than that of MC3T3 under the same set of conditions. The hMSCs were incubated on each scaffold surface for 28 days in osteogenic induction medium and alkaline phosphatase staining was used as a preliminary estimate of osteoinductivity of scaffolds. Two scaffold compositions, which showed lower cytotoxicity and higher osteoinductivity than the other compositions, were selected for LIVE/DEAD® staining. Better cell morphology and attachment was observed for the scaffold composed of low NaCl, intermediate psw and intermediate PLGA contents, compared to the scaffold of intermediate NaCl, intermediate psw and high PLGA content. Thus, the optimum psw-PLGA scaffold composition was determined for cell attachment, viability and a preliminary estimate of osteoinduction.”

mPEG-PLGA as a carrier for c-Myc as brain cancer treatment

PolySciTech (www.polyscitech.com) provides a wide array of mPEG-PLGA block copolymers. Recently research has shown these types of polymers have the capacity to form stable nanoparticles loaded with c-Myc SiRNA in order to prevent DNAse degradation and aid delivery of this silencer to treat glioma cells. Read more: Ma, Tao, Jin-Ling Jiang, Ying Liu, Zheng-Bao Ye, and Jun Zhang. “Preparation and evaluation of nanoparticles loading plasmid DNAs inserted with siRNA fragments targeting c-Myc gene.” Pharmaceutical biology 0 (2014): 1-10. http://informahealthcare.com/doi/abs/10.3109/13880209.2014.880489

 

“Abstract: Context: c-Myc plays a key role in glioma cancer stem cell maintenance. A drug delivery system, nanoparticles loading plasmid DNAs inserted with siRNA fragments targeting c-Myc gene (NPs-c-Myc-siRNA-pDNAs), for the treatment of glioma, has not previously been reported. Objective: NPs-c-Myc-siRNA-pDNAs were prepared and evaluated in vitro. Materials and methods: Three kinds of c-Myc-siRNA fragments were separately synthesized and linked with empty siRNA expression vectors in the mole ratio of 3:1 by T4 DNA ligase. The linked products were then separately transfected into Escherichia coli. DH5α followed by extraction with Endofree plasmid Mega kit (Qiagen, Hilden, Germany) obtained c-Myc-siRNA-pDNAs. Finally, the recombinant c-Myc-siRNA3-pDNAs, generating the highest transfection efficiency and the greatest apoptotic ability, were chosen for encapsulation into NPs by the double-emulsion solvent-evaporation procedure, followed by stability, transfection efficiency, as well as qualitative and quantitative apoptosis evaluation. Results: NPs-c-Myc-siRNA3-pDNAs were obtained with spherical shape in uniform size below 150 nm, with the zeta potential about −18 mV, the encapsulation efficiency and loading capacity as 76.3 ± 5.4% and 1.91 ± 0.06%, respectively. The stability results showed that c-Myc-siRNA3-pDNAs remained structurally and functionally stable after encapsulated into NPs, and NPs could prevent the loaded c-Myc-siRNA3-pDNAs from DNase degradation. The transfection efficiency of NPs-c-Myc-siRNA3-pDNAs was proven to be positive. Furthermore, NPs-c-Myc-siRNA3-pDNAs produced significant apoptosis with the apoptotic rate at 24.77 ± 5.39% and early apoptosis cells observed. Discussion and conclusion: Methoxy-poly-(ethylene-glycol)-poly-(lactide-co-glycolide) nanoparticles (MPEG–PLGA-NPs) are potential delivery carriers for c-Myc-siRNA3-pDNAs. Keywords: Apoptosis, double-emulsion solvent-evaporation, flow cytometry, glioma, MPEG–PLGA, transfection”