Monday, February 19, 2018

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

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.”

Thursday, February 15, 2018

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

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

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

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”

Saturday, February 10, 2018

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


“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”

Wednesday, February 7, 2018

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

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”

Monday, January 29, 2018

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

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”