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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PLGA-PEG-Mal from PolySciTech used in development of immunosuppressant releasing tissue scaffold

Monday, January 1, 2018, 9:28 PM ET

One of the major challenges in stem-cell and tissue engineering is rejection of the new cells by the body through the immune system. Since systemic delivery of immunosuppressant medicines has severe side-effects, a better solution is localized delivery of immunosuppressants to prevent the cells in the scaffold from being attacked by immune cells. Recently, researchers from Fudan University, Tianjin Medical University (China), and Ewha Women’s University (Korea) used PLGA-PEG-Mal (PolyVivo AI136) from PolySciTech (www.polyscitech.com) to create tacrolimus loaded PLGA-PEG- RADA16 self-attractive nanoparticles. These were loaded into stem-cell hydrogels and remained within the hydrogel by electrostatic attraction. This resulted in a consistent and controlled release of immunosuppressant from the scaffold to prevent immune response against the loaded stem cells. This research holds promise to improve results for a wide array of tissue engineering applications. Read more: Li, Ruixiang, Jianming Liang, Yuwei He, Jing Qin, Huining He, Seungjin Lee, Zhiqing Pang, and Jianxin Wang. "Sustained Release of Immunosuppressant by Nanoparticle-anchoring Hydrogel Scaffold Improved the Survival of Transplanted Stem Cells and Tissue Regeneration." Theranostics 2018; 8(4): 878-893. doi: 10.7150/thno.22072 http://www.thno.org/v08p0878.pdf

“The outcome of scaffold-based stem cell transplantation remains unsatisfied due to the poor survival of transplanted cells. One of the major hurdles associated with the stem cell survival is the immune rejection, which can be effectively reduced by the use of immunosuppressant. However, ideal localized and sustained release of immunosuppressant is difficult to be realized, because it is arduous to hold the drug delivery system within scaffold for a long period of time. In the present study, the sustained release of immunosuppressant for the purpose of improving the survival of stem cells was successfully realized by a nanoparticle-anchoring hydrogel scaffold we developed. Methods: Poly (lactic-co-glycolic acid) (PLGA) nanoparticles were modified with RADA16 (RNPs), a self-assembling peptide, and then anchored to a RADA16 hydrogel (RNPs + Gel). The immobilization of RNPs in hydrogel was measured in vitro and in vivo, including the Brownian motion and cumulative leakage of RNPs and the in vivo retention of injected RNPs with hydrogel. Tacrolimus, as a typical immunosuppressant, was encapsulated in RNPs (T-RNPs) that were anchored to the hydrogel and its release behavior were studied. Endothelial progenitor cells (EPCs), as model stem cells, were cultured in the T-RNPs-anchoring hydrogel to test the immune-suppressing effect. The cytotoxicity of the scaffold against EPCs was also measured compared with free tacrolimus-loaded hydrogel. The therapeutic efficacy of the scaffold laden with EPCs on the hind limb ischemia was further evaluated in mice. Results: The Brownian motion and cumulative leakage of RNPs were significantly decreased compared with the un-modified nanoparticles (NPs). The in vivo retention of injected RNPs with hydrogel was obviously longer than that of NPs with hydrogel. The release of tacrolimus from T-RNPs + Gel could be sustained for 28 days. Compared with free tacrolimus-loaded hydrogel, the immune responses were significantly reduced and the survival of EPCs was greatly improved both in vitro and in vivo. The results of histological evaluation, including accumulation of immune cells and deposition of anti-graft antibodies, further revealed significantly lessened immune rejection in T-RNPs-anchoring hydrogel group compared with other groups. In pharmacodynamics study, the scaffold laden with EPCs was applied to treat hind limb ischemia in mice and significantly promoted the blood perfusion (~91 % versus ~36 % in control group). Conclusion: The nanoparticle-anchoring hydrogel scaffold is promising for localized immunosuppressant release, thereby can enhance the survival of transplanted cells and finally lead to successful tissue regeneration. Key words: stem cell; immune suppression; tacrolimus; nanoparticles; endothelial progenitor cells; RADA16 hydrogel.”

Searchable publication listings by product and application available on Akina website

Friday, December 22, 2017, 3:42 PM ET

The number of peer-reviewed journal publications using PST products per year has been steadily increasing over the past several years. This has led to a berth of valuable data regarding the polymer applications and uses. Since this is useful technical data for these products, as much as possible, we try to keep our website up to date with all publications using our products to provide our customers with this valuable resource. If you are interested in PST products for your research and want to get some ideas about how they have been used by others, make sure to visit https://akinainc.com/polyscitech/products/polyvivo/referenced_by.phpfor a full listing of publications. We also have metadata uploaded with keywords and abstracts, so keyword searching can give more details regarding specific applications. Alternatively, if you have used PST materials in a publication and you don’t see it listed, contact jg@akinainc.com with the citation to get it added.

As a side note, this is the last blog posting before Akina closes for 2017. Please note: Akina, Inc. will be closed December 25th through January 2nd for the Christmas and New Year's holidays. Orders placed during this time will be processed when we re-open on Wednesday, January 3rd. Happy Holidays to all.

mPEG-PLA from PolySciTech used in development of nanoparticle treatment to protect brain tissue from inflammation damage

Thursday, December 21, 2017, 4:49 PM ET

One of the major contributing factors to morbidity and death from brain cancer and other neurodegenerative disorders is the inflammation brought on within the brain tissue itself. This leads to swelling, oxidation, and potentially death. Typically treating any ailment that affects the brain is difficult as relatively few medicinal compounds cross from the blood stream into the brain tissue (the blood-brain-barrier). Nanotechnology can be used to improve this however. Recently, researchers at Kent State University and Northeast Ohio Medical University used mPEG-P(DL)La (PolyVivo AK021) from PolySciTech (www.polyscitech.com) to generate a delivery system for simvastatin to protect against neuroinflammation. This research holds promise to reduce damage caused by brain-tumors as well as other diseases implicated with inflammation of neural tissue. Read more: Manickavasagam, Dharani, Kimberly Novak, and Moses O. Oyewumi. "Therapeutic Delivery of Simvastatin Loaded in PLA-PEG Polymersomes Resulted in Amplification of Anti-inflammatory Effects in Activated Microglia." The AAPS Journal 20, no. 1 (2018): 18. https://link.springer.com/article/10.1208/s12248-017-0176-3

“Abstract: Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood–brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(d,l) lactic acid) diblock co-polymers. Studies in BV2 microglia indicated that Sim-Ps was superior to Sim alone in suppressing nitric oxide (NO) and proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretion against LPS activation. The effectiveness of Sim-Ps as compared with Sim alone, in attenuating NO and cytokine production by activated BV2 cells can be attributed to (a) colloidal stability of the delivery platform, (b) protracted release of biologically active Sim, and (c) particulate internalization coupled with enhanced Sim exposure to BV2 cells. Intranasal delivery in BALB/c mice demonstrated enhanced brain distribution with increasing time after administration. Overall data demonstrated suitability of PEG-PdLLA polymersomes in Sim delivery for potential application in treating neuroinflammation. Key Words: inflammation, microglia, neuroprotection, polymersomes, simvastatin”

mPEG-PLA from PolySciTech investigated for use as an ultrasound contrast-agent

Thursday, December 21, 2017, 4:48 PM ET

Ultrasound imaging is widely used as a diagnostic tool in medicine, but suffers from the drawback of relatively poor contrast. For this reason, this technique is often used after injection of a specific contrast agent, such as microbubbles or liposomes containing mannitol, to provide for improved imaging of features within the tissue. Recently, researchers from The George Washington University and North Dakota State University utilized mPEG-PLLA (Polyvivo AK004) from PolySciTech (www.polyscitech.com) to generate acoustic polymersomes as a contrast agent and investigated their acoustic properties. This research holds promise for improving the diagnostic capabilities of ultrasound. Read more: Xia, Lang, Fataneh Karandish, Krishna Nandan Kumar, James Froberg, Prajakta Kulkarni, Kara N. Gange, Yongki Choi, Sanku Mallik, and Kausik Sarkar. "Acoustic Characterization of Echogenic Polymersomes Prepared From Amphiphilic Block Copolymers." Ultrasound in medicine & biology (2017). https://www.sciencedirect.com/science/article/pii/S0301562917324092

“Abstract: Polymersomes are a class of artificial vesicles prepared from amphiphilic polymers. Like lipid vesicles (liposomes), they too can encapsulate hydrophilic and hydrophobic drug molecules in the aqueous core and the hydrophobic bilayer respectively, but are more stable than liposomes. Although echogenic liposomes have been widely investigated for simultaneous ultrasound imaging and controlled drug delivery, the potential of the polymersomes remains unexplored. We prepared two different echogenic polymersomes from the amphiphilic copolymers polyethylene glycol–poly-DL-lactic acid (PEG-PLA) and polyethylene glycol–poly-L-lactic acid (PEG-PLLA), incorporating multiple freeze-dry cycles in the synthesis protocol to ensure their echogenicity. We investigated acoustic behavior with potential applications in biomedical imaging. We characterized the polymeric vesicles acoustically with three different excitation frequencies of 2.25, 5 and 10 MHz at 500 kPa. The polymersomes exhibited strong echogenicity at all three excitation frequencies (about 50- and 25-dB enhancements in fundamental and subharmonic, respectively, at 5-MHz excitation from 20 µg/mL polymers in solution). Unlike echogenic liposomes, they emitted strong subharmonic responses. The scattering results indicated their potential as contrast agents, which was also confirmed by clinical ultrasound imaging. Key Words: Ultrasound imaging; Contrast agent; Microbubble; Polymersomes; Echogenic; Drug delivery”

mPEG-PLGA from PolySciTech used in development of microparticle-based delivery system for regulatory T-cell induction factors as an anti-inflammatory therapy

Tuesday, December 19, 2017, 8:59 AM ET

Several diseases and conditions are associated with an excessive immune response which leads to inflammation that can damage tissue. There are medicines available which can reduce the immune response (e.g. anti-histamines, steroidal anti-inflammatories) however, these all have side-effects due to their relatively non-specific nature in globally preventing immune response. The immune system itself has a built-in regulatory mechanism which acts through regulatory T-cells that act to reduce immune response and improve the recognition of antigens as ‘self.’ A more effective and therapeutic strategy is to provide factors which promote the formation and recruitment of regulatory t-cells to a site of inflammation. Recently, researchers at The University of Pittsburgh used mPEG-PLGA (PolyVivo AK037) from PolySciTech (www.polyscitech.com) to create a microparticle designed to release pro-regulatory-t-cell factors into the eye as a means to reduce localized inflammation by promoting the body’s own feedback system to control the immune response. This research holds promise not only to treat ocular diseases, but to be applied to other disease in which excessive immune response is implicated. Read more: Ratay, Michelle L., Stephen C. Balmert, Abhinav P. Acharya, Ashlee C. Greene, Thiagarajan Meyyappan, and Steven R. Little. "TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model." Scientific Reports 7, no. 1 (2017): 17527. https://www.nature.com/articles/s41598-017-17869-y

“Abstract: Dry eye disease (DED) is a highly prevalent, ocular disorder characterized by an abnormal tear film and ocular surface. Recent experimental data has suggested that the underlying pathology of DED involves inflammation of the lacrimal functional unit (LFU), comprising the cornea, conjunctiva, lacrimal gland and interconnecting innervation. This inflammation of the LFU ultimately results in tissue deterioration and the symptoms of DED. Moreover, an increase of pathogenic lymphocyte infiltration and the secretion of pro-inflammatory cytokines are involved in the propagation of DED-associated inflammation. Studies have demonstrated that the adoptive transfer of regulatory T cells (Tregs) can mediate the inflammation caused by pathogenic lymphocytes. Thus, as an approach to treating the inflammation associated with DED, we hypothesized that it was possible to enrich the body’s own endogenous Tregs by locally delivering a specific combination of Treg inducing factors through degradable polymer microspheres (TRI microspheres; TGF-β1, Rapamycin (Rapa), and IL-2). This local controlled release system is capable of shifting the balance of Treg/T effectors and, in turn, preventing key signs of dry eye disease such as aqueous tear secretion, conjunctival goblet cells, epithelial corneal integrity, and reduce the pro-inflammatory cytokine milieu in the tissue.”

PLA-Fluorescein from PolySciTech used in PhD thesis work on development of theranostic nanoparticles for treatment of heart-disease

Monday, December 18, 2017, 2:14 PM ET

A critical yet often overlooked factor in atherosclerosis (heart-disease) is inflammation, as swelling contributes to the constriction of the blood vessels and damage to the tissue. This also presents a potential therapeutic target as preventing inflammation can assist with reducing the incidence of morbidity and mortality with this disease. Recently, researchers at Massachusetts Institute of Technology used P(DL)La and P(DL)La-Fluorescein (PolyVivo AV016) from PolySciTech (www.polyscitech.com) to develop nanoparticles to deliver simvastatin to affected tissue. The use of fluorescein conjugated PLA allowed for easy tracking of the nanoparticles by visual techniques. This research holds promise to treat inflammatory diseases. Read more: Chung, Bomy Lee. "Theranostic nanoparticles for the management of inflammatory diseases and conditions." PhD diss., Massachusetts Institute of Technology, 2017. https://dspace.mit.edu/handle/1721.1/112504

“Abstract: Atherosclerosis, the gradual buildup of plaques within arteries, is the main cause of cardiovascular diseases (CVDs). The World Health Organization reports that CVDs are the number one cause of death in the world. In the United States alone, around 85 million people suffer from CVDs; this is associated with a cost of over $316 billion per year and responsible for about a third of all deaths in the US. Recent findings have shown that inflammation plays a pivotal role in atherosclerosis. Although statins have traditionally been prescribed for their lipid-lowering benefits, studies have indicated that they can have other effects as well (so-called "pleiotropic effects"), including anti-inflammatory, anti-oxidant, and anti-thrombotic benefits. This thesis presents a novel theranostic (therapeutic + diagnostic) nanoparticle platform for the treatment and diagnosis of atherosclerosis. Given the anti-inflammatory effects of statins when cells are directly treated, the aim of this nanoparticle platform was to target macrophages within plaques given their central role in plaque development and progression. First, simvastatin-loaded nanoparticles were designed and optimized. The particles consisted of a biodegradable polymer core and a lipid shell. Using bulk nanoprecipitation methods, as well as microfluidic devices, the physical characteristics of the particles could be controlled and fine-tuned to meet the desired specifications: 100 to 200 nm in size, -15 to -20 mV in zeta potential, and 70%+ simvastatin loading efficiency. Imaging agents, such as iron oxide nanocrystals used for magnetic resonance imaging (MRI), were successfully incorporated into the nanoparticles and can offer diagnostic capabilities to the nanoparticles. Next, various nanoparticle formulations were shown to be therapeutically effective in cell and mice models of atherosclerosis. For instance, in vitro treatment of macrophages led to decreases in the expression of TNF-a and MCP-1 by roughly 20% and 50%, respectively. This pattern has also been observed in murine models, with researchers showing that simvastatin-loaded particles can halt plaque development (and even decrease plaque area) while reducing the expression of pro-inflammatory genes (e.g., of TNF-a, IL- IP) by an order of magnitude. Overall, this thesis presents a new and innovative nanoparticle platform that has the potential for the simultaneous treatment and diagnosis of atherosclerosis. Given their anti-inflammatory benefits, these nanoparticles have the potential to impact the treatment of not only atherosclerosis but also various other inflammatory conditions and diseases as well.”

PLGA from PolySciTech used in developing Bioadhesive hydrogels for tissue-engineering applications

Monday, December 18, 2017, 2:13 PM ET

As a general rule, it is very difficult to have a material which adheres well to biological tissues. Biological tissues are warm, wet, and typically covered with a coating of proteins which tend to reduce adhesion. This makes designing adhesives for them very difficult. For tissue engineering applications it is critical that whatever scaffold or patch is applied, remains well-adhered to the tissue for it to work. The adhesive must also be biocompatible. Interestingly, a solution for bioadhesion has presented itself in nature from barnacles/mussels, which secrete an incredibly adhesive biopolymer to hold onto rocks. Recently, researchers at University of Texas at Arlington, used PLGA (PolyVivo AP154) from PolySciTech (www.polyscitech.com) to create nanoparticles to improve the bioadhesion of barnacle/mussel-inspired alginate-dopa hydrogels. This research holds promise for improved tissue engineering patches and scaffolds to treat wounds and defects. Read more: Pandey, Nikhil, Amirhossein Hakamivala, Cancan Xu, Prashant Hariharan, Boris Radionov, Zhong Huang, Jun Liao et al. "Biodegradable Nanoparticles Enhanced Adhesiveness of MusselLike Hydrogels at Tissue Interface." Advanced healthcare materials (2017). http://onlinelibrary.wiley.com/doi/10.1002/adhm.201701069/full

“Abstract: Popular bioadhesives, such as fibrin, cyanoacrylate, and albumin–glutaraldehyde based materials, have been applied for clinical applications in wound healing, drug delivery, and bone and soft tissue engineering; however, their performances are limited by weak adhesion strength and rapid degradation. In this study a mussel-inspired, nanocomposite-based, biodegradable tissue adhesive is developed by blending poly(lactic-co-glycolic acid) (PLGA) or N-hydroxysuccinimide modified PLGA nanoparticles (PLGA-NHS) with mussel-inspired alginate–dopamine polymer (Alg-Dopa). Adhesive strength measurement of the nanocomposites on porcine skin–muscle constructs reveals that the incorporation of nanoparticles in Alg-Dopa significantly enhances the tissue adhesive strength compared to the mussel-inspired adhesive alone. The nanocomposite formed by PLGA-NHS nanoparticles shows higher lap shear strength of 33 ± 3 kPa, compared to that of Alg-Dopa hydrogel alone (14 ± 2 kPa). In addition, these nanocomposites are degradable and cytocompatible in vitro, and elicit in vivo minimal inflammatory responses in a rat model, suggesting clinical potential of these nanocomposites as bioadhesives.”

mPEG-PLGA from PolySciTech used in development of combination chemotherapy nanoparticles for treatment of lung cancer

Monday, December 18, 2017, 2:10 PM ET

Lung cancer is a prevalent and deadly disease contributing to about 222,500 new cases and 155,870 deaths per year in America alone. Lung cancer propagates itself through cancer stem-cells, cells within cancer which can differentiate into multiple cell types. Treating the cancer requires both eliminating the mature cancer cells and the stem-cells, so that the cancer cannot grow back. Recently, researchers at Xiangyang Central Hospital and Second Military Medical University (China) used mPEG-PLGA (PolyVivo AK101) from PolySciTech (www.polyscitech.com) to generate salinomycin and gefitinib loaded nanoparticles for lung cancer treatment. This research holds promise to develop more effective treatment strategies for this disease by eliminating both cancer cells and cancer stem cells. Read more: Zhang, Yu, Qi Zhang, Jing Sun, Huijie Liu, and Qingfeng Li. "The combination therapy of salinomycin and gefitinib using poly (D, L-lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles for targeting both lung cancer stem cells and cancer cells." OncoTargets and therapy 10 (2017): 5653. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709995/

“Abstract: Purpose: Lung cancer (LC) is the leading cause of cancer death worldwide. Evidences suggest that both LC cancer stem cells (CSCs) and cancer cells are supposed to be eliminated to achieve superior treatment effect against LC. Salinomycin could eradiate CSCs in various types of cancers, and gefitinib is a first-line therapy in LC. The purpose of the present study was to develop salinomycin-loaded nanoparticles (salinomycin-NPs) combined with gefitinib-loaded nanoparticles (gefitinib-NPs) to eradicate both LC CSCs and cancer cells. Methods: Salinomycin and gefitinib were encapsulated separately by poly(d,l-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles by the emulsion/solvent evaporation approach. The anti-LC activity of salinomycin-NPs and gefitinib-NPs was investigated. Results: Salinomycin-NPs and gefitinib-NPs are of ~140 nm in size, high drug encapsulation efficacy and sustained release of drugs. CD133+ LC CSCs showed the characteristics of CSCs, including significantly enhanced stem cell gene expression, tumorsphere formation ability, and tumorigenicity in mice. Both salinomycin and salinomycin-NPs are capable of selectively inhibiting LC CSCs, as reflected by their enhanced cytotoxic effects toward CD133+ LC CSCs and ability to reduce tumorsphere formation in LC cell lines, whereas gefitinib and gefitinib-NPs could significantly inhibit LC cells. Salinomycin-NPs and salinomycin could reduce the population of LC CSCs in the tumors in vivo. It is noteworthy that salinomycin-NPs combined with gefitinib-NPs inhibited the growth of tumors more efficiently compared with salinomycin combined with gefitinib or single salinomycin-NPs or gefitinib-NPs. Conclusion: Salinomycin-NPs combined with gefitinib-NPs represent a potential approach for LC by inhibiting both LC CSCs and cancer cells. Keywords: cancer stem cells, lung cancer, nanoparticles, salinomycin, gefitinib”

PLGA and PLGA-PEG-Mal from PolySciTech used in development of cancer immunotherapy

Friday, December 15, 2017, 10:09 PM ET

One of the more insidious facets of cancer is that, for a variety of biochemical reasons, most cancers do not elicit an immune response from the body. The human body’s immune system is well adept at thwarting foreign cells and pathogens and is very capable of destroying many cancer cells once activated. For this reason, there has been a great deal of research in ‘immunotherapy’ which is effectively a process of vaccinating the human body against cancer so that it recognizes and destroys cancer cells as though they were pathogens. This provides for a much more selective therapy overall as compared to conventional cytotoxic chemotherapies. Recently, researchers at Dana Faber, Harvard Medical School, MIT, Howard Hughes Medical Institute, and Koch Institute for Integrative Cancer Research utilized Mal-PEG-PLGA (Cat# AI053) and PLGA (Cat # AP041) from PolySciTech (www.polyscitech.com) to generate nanoparticles with reactive exteriors. These nanoparticles were conjugated to targeting ligands via Michael’s reaction between the maleimide units and thiol-bearing antibody fragments. The formed nanoparticles were found to target immune cells and deliver immunotherapy agents to them. This research holds promise for enhanced cancer therapy. Read more: Cartwright, A.N., Hartl, C.A., Park, C.G., Schmid, D., Irvine, D.J., Freeman, G.J., Maiarana, J., Wucherpfennig, K.W., Goldberg, M.S., Subedi, N. and Puerto, R.B., 2017. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nature communications, 8, p.1747. https://www.nature.com/articles/s41467-017-01830-8

“Abstract: Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively into tumors. We describe antibody-targeted nanoparticles that bind to CD8+ T cells in the blood, lymphoid tissues, and tumors of mice. PD-1+ T cells are successfully targeted in the circulation and tumor. The delivery of an inhibitor of TGFβ signaling to PD-1-expressing cells extends the survival of tumor-bearing mice, whereas free drugs have no effect at such doses. This modular platform also enables PD-1-targeted delivery of a TLR7/8 agonist to the tumor microenvironment, increasing the proportion of tumor-infiltrating CD8+ T cells and sensitizing tumors to subsequent anti-PD-1. Targeted delivery of immunotherapy to defined subsets of endogenous leukocytes may be superior to administration of free drugs.”

PLGA-PEG-PLGA from PolySciTech used in development of infantile hemangioma treatment

Monday, December 11, 2017, 10:40 AM ET

Infantile hemangioma is a non-cancerous tumor in which an excess of blood vessels grow in a particular area with excessive cell proliferation. Small, skin hemangioma’s manifest as benign birthmarks and do not typically require treatment. However, large hemangioma’s or hemangioma’s that affect organs (especially the liver) can be fatal and require treatment. Since these affect primarily infants, treatment must be performed carefully as side-effects and other complications can be readily encountered due to size and metabolic features in very small children. Recently, researchers from Henan Provincial People’s Hospital and Second Military Medical University utilized PLGA-PEG-PLGA (Polyvivo#: AK016) from PolySciTech (www.polyscitech.com) to formulate urea-loaded microspheres as a delivery system to treat hemangioma. This research holds promise for treating this potentially life-threatening infantile disease. Read more: Zhu, Xiaoshuang, Xiaonan Guo, Dakan Liu, Yubin Gong, Jin Sun, and Changxian Dong. "Significant inhibition of infantile hemangioma growth by sustained delivery of urea from liposomes-in-microspheres." Oncology Reports 39, no. 1 (2018): 109-118. https://www.spandidos-publications.com/or/39/1/109

“Abstract: Infantile hemangioma (IH) is a benign pediatric tumor, and rapid growth of IH can result in serious morbidity and even mortality. Only one drug Hemangeol™ (propranolol hydrochloride oral solution) has been approved for the treatment of IH, whereas patients suffer from its adverse effects and high frequency of administration. We have used urea, an organic compound and a normal body metabolite, in the treatment of IH for 20 years, and demonstrated that urea is an effective and well-tolerated treatment for IH. To reduce the daily administration of urea, we firstly utilized urea-loaded liposomes-in-microspheres (ULIM) as a novel topical controlled release system to realize the sustained release of urea. ULIM were fabricated from the encapsulation of urea-loaded liposomes in poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) microspheres. The characteristics, activity and mechanism against IH of ULIM were examined in vitro and in vivo. ULIM were of a desired particle size (~62.4 µm), drug encapsulation efficiency (~51.5%) and sustained drug release for 40 days. ULIM inhibited the proliferation of hemangioma endothelia cells (HemECs) and expression of vascular endothelial growth factor-A in HemECs. The therapeutic effect of ULIM in IH was better than propranolol, urea, urea-loaded liposomes and urea-loaded microspheres in vivo, as reflected by markedly decreased hemangioma weight, volume and microvessel density. None of the treated mice showed behavioral changes, severe sideeffects and weight loss. Our results suggest that use of ULIM is a potential and safe approach with which to locally and efficiently deliver urea to hemangioma, and is a promising alternative to propranolol in the treatment of IH.”

PEG-PLGA from PolySciTech used in development of gastric cancer treatment

Friday, December 8, 2017, 10:19 PM ET

Gastric cancer is a very common and deadly form of cancer which kills about 11,000 people per year in America. Eliminating cancer stem cells is a key step to treating this form of cancer. Recently, researchers working at Sichuan University, Guizhuo Provincial People’s Hospital, and Second Military Medical University (China) utilized PEG-PLGA From PolySciTech (www.polyscitech.com) to develop nanoparticles loaded with salinomycin, which kills cancer stem-cells, and docetaxel, a standard chemotherapy agent, for treatment of gastric cancer. They found this combination in nanoparticles suppressed tumor growth more effectively than alone or without the nanoparticles. This research holds promise for treating this common and lethal form of cancer. Read more: Li, Lan, Dejun Cui, Limin Ye, Yu Li, Liyi Zhu, Lanqun Yang, Banjun Bai, Zhao Nie, Jie Gao, and Yu Cao. "Codelivery of salinomycin and docetaxel using poly (D, L-lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles to target both gastric cancer cells and cancer stem cells." Anti-Cancer Drugs 28, no. 9 (2017): 989-1001. http://journals.lww.com/anti-cancerdrugs/Fulltext/2017/10000/Codelivery_of_salinomycin_and_docetaxel_using.6.aspx

“Cancer stem cells (CSCs) in gastric cancer (GC) have been established recently as key therapeutic targets for the successful treatment of GC. Emerging evidence suggests that both CSCs and cancer cells should be eradicated to achieve optimal therapeutic efficacy. In the present study, salinomycin, which has been reported to kill CSCs, was used in combination with docetaxel, a chemotherapeutic drug that is used as first-line therapy in GC, to eradicate both GC stem cells (SCs) and cancer cells. Salinomycin and docetaxel were loaded separately into poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles of 140 nm with a narrow size distribution, high drug loading, and sustained drug release. GC SCs were isolated by magnetic-activated cell sorting on the basis of CD44 expression as the CSC phenotype. CD44+ GC SCs showed the characteristics of CSCs, including increased SC gene expression, tumorsphere formation capacity, and tumorigenicity in nude mice. We found that both salinomycin and salinomycin-loaded nanoparticles (salinomycin-NPs) could selectively eradicate GC SCs, as reflected by reduced tumorsphere formation capacity and the frequency of CD44+ GC cells, whereas docetaxel and docetaxel-loaded nanoparticles (docetaxel-NPs) could significantly eradicate GC cells. In nude mice bearing GC xenografts, salinomycin-NPs and salinomycin significantly decreased the intratumor population of GC SCs. Notably, salinomycin-NPs combined with docetaxel-NPs suppressed tumor growth more effectively than did salinomycin combined with docetaxel, single salinomycin-NPs, or docetaxel-NPs. Therefore, salinomycin-NPs combined with docetaxel-NPs represent a promising strategy for the treatment of GC by eradicating both GC SCs and cancer cells.”

Maleimide-PEG-PLGA from PolySciTech used in development of nanoparticle system for treatment of arthritis

Friday, December 8, 2017, 10:18 PM ET

Arthritis is a debilitating inflammatory disease of the joints which can damage cartilage and create a considerable amount of pain as well as loss of function for the patient. Targeted therapy offers hope for relief to patients from this chronic disease. One means of generating targeted nanoparticles is to utilize thiol-maleimide reaction to connect peptides to the exterior of Maleimide-reacting nanoparticles made using Mal-PEG-PLGA. Recently, Researchers at University of Connecticut and University of Harford utilized mPEG-PLGA (PolyVivo #AK037) and Maleimide-PEG-PLGA (Polyvivo #AI020) from PolySciTech (www.polyscitech.com) to generate a nanoparticle system for treatment of arthritis. This research holds promise for treating this debilitating disease. Read more: Jiang, Tao, Ho-Man Kan, Komal Rajpura, Erica J. Carbone, Yingcui Li, and Kevin W-H. Lo. "Development of Targeted Nanoscale Drug Delivery System for Osteoarthritic Cartilage Tissue." Journal of Nanoscience and Nanotechnology 18, no. 4 (2018): 2310-2317. http://www.ingentaconnect.com/contentone/asp/jnn/2018/00000018/00000004/art00006

Osteoarthritis is a severe and debilitating joint disease, which is characterized as results from damage and degeneration of the articular cartilage of the joint surfaces. The incidence of osteoarthritis is growing increasingly high while current treatment methods remain suboptimal. The major issue for current osteoarthritic medications is that patients frequently experience adverse, nonspecific side effects that are not a direct result of the specific pharmacological action of the drug. The treatment processes could be made more effective, safe, and comfortable if it were possible to deliver the drugs specifically to cartilage tissue. Therefore, developing site-specific and controlled drug release delivery systems is needed for overcoming the aforementioned issues. We have developed a poly(lactic-co-glycolic acid) (PLGA)-based nanoscale drug delivery system based on a short cartilage-targeting peptide sequence: WYRGRL. Nanoparticles (NPs) made of methoxy-poly(ethylene glycol) (PEG)-PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged WYRGRL peptide was then linked to the surface of the nanoparticles through the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the C═C double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged WYRGRL peptide to PLGA NPs was confirmed by NMR technique. We further demonstrated that the novel delivery system binds very specifically to cartilage tissue in vitro and ex vivo. Given that biodegradable PLGA-based NPs have shown promise for drug delivery, they could be used for a positive advancement for treatments of osteoarthritic patients by creating a more effective treatment process that achieves healing results faster and with fewer deleterious side effects. Taken together, these promising results indicated that this nanoscale targeting drug delivery system was able to bind to cartilage tissue and might have a great potential for treating osteoarthritis. Keywords: Musculoskeletal Tissue; Nanomedicine; Osteoarthritis; Targeted Drug Delivery; Targeting Ligands

PEG-PLGA from PolySciTech used in development of nanoparticle-based Leukemia treatment

Friday, December 8, 2017, 10:17 PM ET

Leukemia is a cancer which affects how blood cells are produced in bone marrow and contributes to about 24,500 deaths each year in US. T cell acute lymphoblastic leukemia (T-ALL), in particular is a form of leukemia which has poor survival prognosis in adult (<50 a="" affected="" and="" be="" bone-marrow="" both="" by="" can="" chemotherapeutics.="" effect.="" effectiveness="" for="" from="" have="" href="http://www.polyscitech.com/" huazhong="" improved="" inhibitors="" into="" its="" jiao="" kinase="" maximum="" nanoparticles="" of="" other="" peg-plga="" polyscitech="" preferentially="" purchased="" recently="" regions="" requires="" researchers="" science="" shanghai="" technology="" the="" these="" tissue="" to="" tong="" traditional="" treatment="" treatments="" university="" uptake="" using="">www.polyscitech.com
) to make nanoparticles co-loaded with both IRAK (kinase inhibitor) and ABT-737 (microtubule-targeting chemotherapeutic) for leukemia therapy. This research holds promise to improve therapeutic and survival outcomes for this difficult to treat disease. Read more: Wu, Xiaoyan, Lin Wang, Yining Qiu, Bingyu Zhang, Zhenhua Hu, and Runming Jin. "Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia." International Journal of Nanomedicine 12 (2017): 8025. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673049/

“Abstract: T cell acute lymphoblastic leukemia (T-ALL) is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid) nanoparticles (IRAK/ABT-NP) to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC50 of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution. Keywords: T cell acute lymphoblastic leukemia, IRAK1/4 inhibitor, ABT-737, Box-Behnken design and response surface methodology, PEG-PLGA”

PEG-PLA from PolySciTech utilized in development of nanoparticles to protect kidneys during transplant procedures.

Tuesday, December 5, 2017, 8:12 PM ET

Kidney transplantation is a life-saving practice in which a donor kidney is transplanted into a recipient. During kidney transplantation, damage to the organ can occur when the flow of blood through it stops (upon removal from the donor) and suddenly restarts again once placed in the recipient. This incidence of ‘reperfusion injury’ can damage the delicate lining of the organ and potentially lead to a loss of function. Recently, researchers from Yale University and University of Cambridge utilized mPEG-PLA (PolyVivo AK054) from PolySciTech (www.polyscitech.com) to develop nanoparticles that coat and protect the interior of kidneys so that they are less affected by reperfusion injury. This research holds promise both to protect organs for transplant, as well as to treat any problems with the organ during the time between removal and placement. Read more: Tietjen, Gregory T., Sarah A. Hosgood, Jenna DiRito, Jiajia Cui, Deeksha Deep, Eric Song, Jan R. Kraehling et al. "Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys." Science Translational Medicine 9, no. 418 (2017): eaam6764. http://stm.sciencemag.org/content/9/418/eaam6764.abstract

“Abstract: Particle perfusion for organ transplant: Ischemia-reperfusion injury, which occurs when a tissue or organ is temporarily cut off from blood flow, is a major issue limiting organ viability for transplantation. Tietjan et al. devised a way to target the injury-sensitive endothelium of organs during ex vivo perfusion. Using nanoparticles conjugated to an antibody targeting a protein expressed on endothelial cells, the authors demonstrated that they could perfuse human kidneys and that nanoparticles accumulated in kidney endothelial cells. In addition to expanding the pool of viable organs for transplant, this approach could potentially be used to deliver targeted therapies to organs during ex vivo perfusion rather than treating the transplant recipient systemically. Ex vivo normothermic machine perfusion (NMP) is a new clinical strategy to assess and resuscitate organs likely to be declined for transplantation, thereby increasing the number of viable organs available. Short periods of NMP provide a window of opportunity to deliver therapeutics directly to the organ and, in particular, to the vascular endothelial cells (ECs) that constitute the first point of contact with the recipient’s immune system. ECs are the primary targets of both ischemia-reperfusion injury and damage from preformed antidonor antibodies, and reduction of perioperative EC injury could have long-term benefits by reducing the intensity of the host’s alloimmune response. Using NMP to administer therapeutics directly to the graft avoids many of the limitations associated with systemic drug delivery. We have previously shown that polymeric nanoparticles (NPs) can serve as depots for long-term drug release, but ensuring robust NP accumulation within a target cell type (graft ECs in this case) remains a fundamental challenge of nanomedicine. We show that surface conjugation of an anti-CD31 antibody enhances targeting of NPs to graft ECs of human kidneys undergoing NMP. Using a two-color quantitative microscopy approach, we demonstrate that targeting can enhance EC accumulation by about 5- to 10-fold or higher in discrete regions of the renal vasculature. In addition, our studies reveal that NPs can also nonspecifically accumulate within obstructed regions of the vasculature that are poorly perfused. These quantitative preclinical human studies demonstrate the therapeutic potential for targeted nanomedicines delivered during ex vivo NMP.”

Cell-scaffold interaction quantitatively investigated using fluorescently labeled PLGA from PolySciTech

Tuesday, December 5, 2017, 8:06 PM ET

A powerful technique commonly applied in tissue engineering is cell-scaffolding in which a highly-porous, biocompatible material is implanted into a patient. This mesh allows for cells to grow inside of its structure to repair damaged or lost tissue. There still remains a great deal to learn about exactly how cells interact with the substrate they are growing on, as the structure and chemistry of the mesh is critical to how the cells grow. One common problem with growing roughly translucent microscopic cells on an opaque microfiber mesh is visualizing what is going on with the cells. This is where fluorescent imaging comes in to play. In this method, each component is bound to a specific dye that emits light when excited by a specific wavelength of light. This allows researchers to image each component of the system, separately. Recently, researchers from National institute of Standards and Technology (NIST) and National Institute of Health (NIH) utilized fluorescently conjugated PLGA-FKR648 (PolyVivo AV015) from PolySciTech (www.polyscitech.com) to make a series of cell-scaffolds and test their interactions with cells. The fluorescent nature of this polymer allowed for direct imaging of the mesh by fluorescence techniques, so they could investigate cell-interactions in fine detail. This research provides a valuable tool for tissue-engineering researchers looking to optimize their mesh designs. Read more: Bajcsy, Peter, Soweon Yoon, Stephen J. Florczyk, Nathan A. Hotaling, Mylene Simon, Piotr M. Szczypinski, Nicholas J. Schaub, Carl G. Simon, Mary Brady, and Ram D. Sriram. "Modeling, validation and verification of three-dimensional cell-scaffold contacts from terabyte-sized images." BMC Bioinformatics 18, no. 1 (2017): 526. https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-017-1928-x

“Background: Cell-scaffold contact measurements are derived from pairs of co-registered volumetric fluorescent confocal laser scanning microscopy (CLSM) images (z-stacks) of stained cells and three types of scaffolds (i.e., spun coat, large microfiber, and medium microfiber). Our analysis of the acquired terabyte-sized collection is motivated by the need to understand the nature of the shape dimensionality (1D vs 2D vs 3D) of cell-scaffold interactions relevant to tissue engineers that grow cells on biomaterial scaffolds. Results: We designed five statistical and three geometrical contact models, and then down-selected them to one from each category using a validation approach based on physically orthogonal measurements to CLSM. The two selected models were applied to 414 z-stacks with three scaffold types and all contact results were visually verified. A planar geometrical model for the spun coat scaffold type was validated from atomic force microscopy images by computing surface roughness of 52.35 nm ±31.76 nm which was 2 to 8 times smaller than the CLSM resolution. A cylindrical model for fiber scaffolds was validated from multi-view 2D scanning electron microscopy (SEM) images. The fiber scaffold segmentation error was assessed by comparing fiber diameters from SEM and CLSM to be between 0.46% to 3.8% of the SEM reference values. For contact verification, we constructed a web-based visual verification system with 414 pairs of images with cells and their segmentation results, and with 4968 movies with animated cell, scaffold, and contact overlays. Based on visual verification by three experts, we report the accuracy of cell segmentation to be 96.4% with 94.3% precision, and the accuracy of cell-scaffold contact for a statistical model to be 62.6% with 76.7% precision and for a geometrical model to be 93.5% with 87.6% precision. Conclusions: The novelty of our approach lies in (1) representing cell-scaffold contact sites with statistical intensity and geometrical shape models, (2) designing a methodology for validating 3D geometrical contact models and (3) devising a mechanism for visual verification of hundreds of 3D measurements. The raw and processed data are publicly available from https://isg.nist.gov/deepzoomweb/data/ together with the web -based verification system. Keywords: Co-localization Cellular measurements Cell-scaffold contact Segmentation models Contact evaluation Web-based verification Large-volume 3D image processing”

PLGA melting temperature

Tuesday, December 5, 2017, 8:26 AM ET

Image shows DSC determined melting temperature of a series of PolyVivo PLGA's as well as LA:GA ratio and MW. For very low MW PLGA's, the melting temperature can even be at room temperature or below.

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


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