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 from PolySciTech used in development of acetazolamide-eluting pancreatic bile stent to treat postoperative pancreatic fistula

Wednesday, June 16, 2021, 3:45 PM ET

Postoperative pancreatic fistula (POPF) remains the major cause of morbidity after pancreatic resection, affecting up to 41% of cases. It occurs due to pancreatic juices leaking from the surgically exfoliated surfaces or from the cut sections of an anastomosis (where intestinal and pancreas tubes join together). This can lead to sever abscess infections and a potentially lethal internal hemorrhage. Recently, researchers at Asan Medical Center, University of Ulsan College of Medicine, Inha University (Korea) and College of Medicine, UT Health Science Center at San Antonio (USA) used PLGA (AP132) from PolySciTech (www.polyscitech.com) to create a biodegradable tubular stent which releases acetazolamide that prevents damage from pancreatic juices. This research holds promise to improve outcomes from this common surgical complication. Read more: Park, Jung-Hoon, Jieun Park, Yejong Park, Jeon Min Kang, Dea Sung Ryu, Jeongsu Kyung, Jong Kun Jang et al. "Acetazolamide-eluting biodegradable tubular stent prevents pancreaticojejunal anastomotic leakage." Journal of Controlled Release (2021). https://www.sciencedirect.com/science/article/pii/S0168365921002972

“Highlights: AZ-BTS effectively suppresses self-digestion caused by pancreatic juice leakage. BTS with or without AZ has inhibitory effect of anastomotic stricture formation. AZ-BTS was fabricated by a multiple dip-coating technique with reliable release. The releases AZ, targets carbonic anhydrase, protects tisssues from pancreatic juice. Animal model induced a reproducible incidence of anastomotic leakage and symptoms. Abstract: Postoperative pancreatic fistula at the early stage can lead to auto-digestion, which may delay the recovery of the pancreaticojejunal (PJ) anastomosis. The efficacy and safety of an acetazolamide-eluting biodegradable tubular stent (AZ-BTS) for the prevention of self-digestion and intra-abdominal inflammatory diseases caused by pancreatic juice leakage after PJ anastomosis in a porcine model were investigated. The AZ-BTS was successfully fabricated using a multiple dip-coating process. Then, the drug amount and release profile were analyzed. The therapeutic effects of AZ were examined in vitro using two kinds of pancreatic cancer cell lines, AsPC-1 and PANC-1. The efficacy of AZ-BTS was assessed in a porcine PJ leakage model, with animals were each assigned to a leakage group, a BTS group and an AZ-BTS group. The overall mortality rates in these three groups were 44.4%, 16.6%, and 0%, respectively. Mean α-amylase concentrations were significantly higher in the leakage and BTS groups than in the AZ-BTS group on day 2–5 (p < 0.05 each all). The luminal diameters and areas of the pancreatic duct were significantly larger in the leakage group than in the BTS and AZ-BTS groups (p < 0.05 each all). These findings indicate that AZ-BTS can significantly suppress intra-abdominal inflammatory diseases caused by pancreatic juice leakage and also prevent late stricture formation at the PJ anastomotic site in a porcine model.”

PLGA-NHS and PLGA-amine from PolySciTech used in development of theranostic nanoparticle for treatment of brain cancer

Wednesday, June 16, 2021, 3:44 PM ET

Brain cancer, especially glioblastoma, remains difficult to treat due to the sensitivity of the region of the body that it affects and difficulty with delivering medicinal molecules into the brain. Recently, researchers at Indiana University School of Medicine used PLGA-NH2 (AI062) and PLGA-NHS (AI116) from PolySciTech (www.polyscitech.com) to create CD133 targeted nanoparticles loaded both with chemotherapeutic agents (temozolomide and idasanutlin) along Zirconium radio-tracer to enable both treatment of and imaging of brain cancer. This research holds promise to improve therapies against this disease in the future. Read more: Smiley, Shelby B., Yeonhee Yun, Pranav Ayyagari, Harlan E. Shannon, Karen E. Pollok, Michael W. Vannier, Sudip K. Das, and Michael C. Veronesi. "Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma-In Vitro Evaluation in Glioblastoma Stem Cells." Pharmaceutical Research (2021): 1-13. https://link.springer.com/article/10.1007/s11095-021-03050-8

“Abstract: Purpose: Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging. Methods: Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed by a double emulsion technique loading TMZ and/or RG7388. The NPs were covalently bound to a 15-nucleotide base-pair CD133 aptamer to target the CD133 antigen expressed on the surfaces of GBM CSCs. For diagnostic functionality, the NPs were labelled with radiotracer Zirconium-89 (89Zr). Results: NPs maintained size range less than 100 nm, a low negative charge and exhibited the ability to target and kill the CSC subpopulation when TMZ and RG7388 were used in combination. The targeting function of CD133 aptamer promoted killing in GBM CSCs providing impetus for further development of targeted nanosystems for localized therapy in future in vivo models. Conclusions: This work has provided a potential clinical application for targeting GBM CSCs with simultaneous diagnostic imaging.”

PLGA-Amine from PolySciTech used in development of ROS-sensitive delivery system for Alzheimer’s treatment

Tuesday, June 8, 2021, 2:00 PM ET

Oxidative stress is a common situation for cells when they are either going through an inflammatory response or in a disease state. This condition usually manifests with an increase in reactive oxygen species (HO radical, O2-, H2O2 for examples) in the cellular structure and surrounding tissue. Being able to develop a system which primarily distributes drugs to cells in a condition of oxidative stress can improve delivery for difficult to treat diseases such as cancer and Alzheimer’s disease. Researchers at University of Modena and Reggio Emilia (Italy) used PLGA-NH2 (AI062) from PolySciTech (www.polyscitech.com) to generate a PLGA-TK polymer which breaks down in response to reactive oxygen species. This research holds promise to improve therapies against ROS-related diseases. Read more: Oddone, Natalia, Tosi, Giovanni, and Barbara Ruozi. "ROS-responsive polymer conjugates and prodrugs as innovative DDS aiming for the treatment of brain diseases." University of Modena and Reggio Emilia PhD Thesis 2021 https://www.researchgate.net/profile/Natalia-Oddone/publication/352001593_ROS-responsive_polymer_conjugates_and_prodrugs_as_innovative_DDS_aiming_for_the_treatment_of_brain_diseases/links/60b4f99745851557bab32938/ROS-responsive-polymer-conjugates-and-prodrugs-as-innovative-DDS-aiming-for-the-treatment-of-brain-diseases.pdf

“In order to obtain more selective and tunable Drug Delivery Systems (DDS), “Smart” DDS that can release their drugs in response to a specific stimulus (e.g. pH, GSH and ROS), are currently under investigation. Inflammatory diseases, neurodegenerative diseases and cancer, including Glioblastoma (GBM) are all sharing a relevant oxidative stress; therefore the design of ROS- responsive DDS for the treatment of these conditions could be a smart and very encouraging approach to access to a selective and specific delivery mediated by a pathological stimulus. Thus, the aim of this PhD thesis was to develop ROS-responsive polymeric conjugates and prodrugs linked to a ROS cleavable group, namely Thioketal (TK) diacid linker that could be used for the treatment of brain diseases. Aiming to validate the use of TK- containing ROS- responsive polymers and prodrugs, we firstly performed proof-of-concept studies by synthesizing a ROSresponsive methoxy polyethylene glycol (mPEG) polymer (mPEG-TK-COOH) and, by exploiting Cy5 fluorescent dye, ROS-responsive (mPEG-TK-Cy5) and non-ROSresponsive (mPEG-Cy5) polymer conjugates. Full chemical-physical and technological characterization was performed to confirm the success in polymer conjugation and to describe chemical-physical properties of the obtained conjugates; then the ability of these conjugates to respond to ROS was validated in ROS-simulated conditions as well as assessed in vitro on Glioblastoma multiforme (GBM) cell lines. These tests were performed in close collaboration with Prof. Grabrucker, University of Limerick, Ireland, and with Prof. Boury, University of Angers, France, during a period of international mobility. Results clearly indicated that mPEG-TK-Cy5 could be selectively released in “pathological” conditions (C6 GBM cells) over “healthy” conditions (DI TNC1 astrocyte cells). Secondly, a prodrug (mPEG-TK-MPH) for the ROS- responsive release of Melphalan (MPH), which is a poorly soluble and non-selective anticancer drug, was synthetized aiming to GBM treatment. A non-ROS responsive prodrug (mPEG-MPH) was also prepared through a similar synthetic procedure. Both prodrugs were characterized and demonstrated to undergo spontaneous auto- assembling into spherical nanometric structures. In vitro cytotoxicity assays performed on GBM cells, showed that mPEG-TK-MPH was significantly more cytotoxic than mPEG-MPH on High- ROS GBM cells (C6 and U251MG cells). Remarkably, none of the prodrugs showed to be cytotoxic on Low- ROS astrocyte cells (DI TNC1), demonstrating their safety. Finally, since PLGA (polylactic-co-glycolic acid) NPs demonstrated to be promising DDS for their application in several diseases, we produced and characterized other ROS-responsive polymeric conjugates with PLGA: PLGA-TK-COOH and PLGATK-PLGA, for the selective release of surface attached and encapsulated drugs into oxidative stress featuring diseases. We were able (starting from the PLGA conjugates produced) to formulate ROS-responsive TK-surface functionalized PLGA and PLGATK-PLGA NPs, respectively. We can conclude that due to its selective cytotoxicity in High-ROS GBM cells without being toxic to “healthy” cells, our developed ROS-responsive prodrugs show encouraging results for GBM treatment. On the other hand, the ROS-responsive PLGA NPs developed during this PhD project, could be considered as promising starting point for their future application in GBM as well as in relevant neurodegenerative diseases as Alzheimer’s disease.”

PLGA-PEG-Maleimide from PolySciTech used in development of nanoparticles for treating CNS-associated tuberculosis.

Tuesday, June 1, 2021, 3:33 PM ET

Tuberculosis is a bacterial disease which most commonly infects the lungs however it can spread to other parts of the body. This disease is treatable in most parts of the body using antibiotic agents however is difficult to treat in the brain due to the blood-brain-barrier. Recently, researchers at Universidade Federal do Rio de Janeiro, Oswaldo Cruz Foundation, (Brazil), Universidade do Porto (Portugal) used PLGA-PEG-Mal (AI110) from PolySciTech (www.polyscitech.com) to create labeled nanoparticles for treatment of tuberculosis across the blood-brain-barrier. This research holds promise to improve therapeutic options for this lethal disease. Read more: de Castro, Renata Ribeiro, Flavia Almada do Carmo, Cláudia Martins, Alice Simon, Valeria Pereira de Sousa, Carlos Rangel Rodrigues, Lucio Mendes Cabral, and Bruno Sarmento. "Clofazimine functionalized polymeric nanoparticles for brain delivery in the tuberculosis treatment." International Journal of Pharmaceutics 602 (2021): 120655. https://www.sciencedirect.com/science/article/pii/S0378517321004609

“Highlights Clofazimine-loaded PLGA-PEG nanoparticles (NP-CFZ) were produced by nanoprecipitation. NP-CFZ were functionalized with a peptide (NP-CFZ-Pep) that binds transferrin receptor. NP-CFZ-Pep reduced drug toxicity and enhanced drug permeability across hCMEC/D3 cell. NP-CFZ-Pep can be administered by intravenous route and drive the drug to the brain. The NP-CFZ-Pep is promising to central nervous system tuberculosis treatment. Central nervous system tuberculosis (CNS-TB) is the most severe form of the disease especially due to the inability of therapeutics to cross the blood–brain barrier (BBB). Clofazimine (CFZ) stands out for presenting high in vitro activity against multi-drug resistant strains of Mycobacterium tuberculosis, however, CFZ physicochemical and pharmacokinetics properties limit drug penetration into the CNS and, consequently, its clinical use. The aim of this work was to develop polymeric nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) loaded with CFZ and functionalized with a transferrin receptor (TfR)-binding peptide, aiming brain drug delivery for CNS-TB treatment by the intravenous route. The poor water solubility and high lipophilicity of CFZ was overcome through its entrapment into PLGA-PEG NPs manufactured by both conventional and microfluidic techniques using the nanoprecipitation principle. In vitro studies in brain endothelial hCMEC/D3 cells demonstrated that CFZ incorporation into the NPs was advantageous to reduce drug cytotoxicity. The TfR-binding peptide-functionalized NPs showed superior cell interaction and higher CFZ permeability across hCMEC/D3 cell monolayers compared to the non-functionalized NP control, thus indicating the efficacy of the functionalization strategy on providing CFZ transport through the BBB in vitro. The functionalized NPs demonstrate suitability for CFZ biological administration, suggested with low plasma protein binding, off-target biodistribution and precise delivery of CFZ towards the brain parenchyma. Keywords: Brain delivery Clofazimine Targeted nanoparticles Transferrin-receptor Tuberculosis treatment”

PLGA from PolySciTech used in development of glucose/transferrin targeted nanoparticles

Tuesday, June 1, 2021, 3:32 PM ET

Due to their extremely small size, nanoparticles have the capacity to be uptaken into cells via a variety of mechanisms. The potential for a human cell to internalize a given nanoparticle depends on a variety of factors about the cell as well as for the nanoparticle and surface modifications can improve the uptake of nanoparticles. Recently, researchers at Qatar University (Qatar) used PLGA (AP045) and PLGA-Glucose (AP027) from PolySciTech (www.polyscitech.com) to create targeted nanoparticles and track their uptake against cancer cells. This research holds promise to improve drug-delivery methodology. Read More: Sarra Benammar, Fatima Mraiche, Jensa Mariam Joseph, Katerina Goracinova “Glucose and transferrin liganded PLGA nanoparticles internalization in Non-small cell lung cancer cells” Poster QUARFE 2020 https://qspace.qu.edu.qa/handle/10576/16810

“Introduction: Recently, after a decade of confusing results, several studies pointed out that overexpression of GLUT1 (glucose transporter 1) is a biomarker of worse prognosis in NSCLC. Nonetheless, the presence of Transferrin (Tf receptor), which is overexpressed in most cancer tissues and most lung cancers as well, in NSCLC is also an indicator of very poor prognosis. Therefore, these ligands can be used for active targeting of lung cancer cells and improved efficacy of internalization of cancer therapy using nanomedicines. Objectives: Having the background, the main goal of the project was the assessment of the influence of the glucose and transferrin ligands on the efficacy of internalization of the designed (i) glucose decorated PLGA (poly lactic-co-glycolic acid) nanoparticles (Glu-PLGA NPs) and (ii) transferrin decorated PLGA nanoparticles (Tf-PLGA NPs) in comparison to (iii) non-liganded PLGA NPs using a A549 lung cancer cells. Methods: Glu-PLGA NPs, Tf-PLGA NPs and PLGA NP - fluorescently labelled), were designed using a sonication assisted nanoprecipitation method. Further, physicochemical properties characterization (particle size analysis, zeta potential, FTIR analysis, DSC analysis), cytotoxicity evaluation using MTT test, and cell internalization studies of DTAF labelled NPs using fluorimetry in A549 NSCLC cell line were performed. Results: The results pointed to a significantly improved internalization rate of the liganded compared to PLGA NPs. Glu-PLGA NPs showed higher internalization rate compared to Tf-PLGA and PLGA NPs, in the serum-supplemented and serum-free medium even at normal levels of glucose in the cell growth medium. Conclusion: The developed nanocarriers offer unique advantages of enhanced targetability, improved cell internalization and decreased toxicity which makes them promising solution for current therapeutic limitations ”

PLGA-PEG polymers from PolySciTech used in development of acoustic-microfluidic nanoparticles

Tuesday, May 18, 2021, 1:39 PM ET

Nanoparticles are an excellent means to deliver poorly soluble or difficult to target drug molecules to bodily systems. There are many methods to generate particles however the use of microfluidics provides for improved control of the manufacturing process. Recently, researchers at Duke University (North Carolina, USA) used PLGA-PEG-COOH (AI056, AI184, AI080) and PLGA-NH2 (AI017) from PolySciTech (www.polyscitech.com) to develop an acoustic-microfluidic method for nanoparticle generation. This research holds promise to improve drug delivery methodologies in the future. Read more: Zhao, Shuaiguo, Po-Hsun Huang, Heying Zhang, Joseph Rich, Hunter Bachman, Jennifer Ye, Wenfen Zhang et al. "Fabrication of tunable, high-molecular-weight polymeric nanoparticles via ultrafast acoustofluidic micromixing." Lab on a Chip (2021). https://pubs.rsc.org/en/content/articlehtml/2021/lc/d1lc00265a

“Abstract: High-molecular-weight polymeric nanoparticles are critical to increasing the loading efficacy and tuning the release profile of targeted molecules for medical diagnosis, imaging, and therapeutics. Although a number of microfluidic approaches have attained reproducible nanoparticle synthesis, it is still challenging to fabricate nanoparticles from high-molecular-weight polymers in a size and structure-controlled manner. In this work, an acoustofluidic platform is developed to synthesize size-tunable, high-molecular-weight (>45 kDa) poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA–PEG) nanoparticles without polymer aggregation by exploiting the characteristics of complete and ultrafast mixing. Moreover, the acoustofluidic approach achieves two features that have not been achieved by existing microfluidic approaches: (1) multi-step (≥2) sequential nanoprecipitation in a single device, and (2) synthesis of core–shell structured PLGA–PEG/lipid nanoparticles with high molecular weights. The developed platform expands microfluidic potential in nanomaterial synthesis, where high-molecular-weight polymers, multiple reagents, or sequential nanoprecipitations are needed.”

PLGA from PolySciTech used in a systematic study of nanoparticle emulsion stability by polymer properties

Monday, May 17, 2021, 1:58 PM ET

Nanoparticles references small particulate material in the nanometer scale range (<1 micrometer in size). Since the particles are significantly smaller than a human cell (~ 10 um) they can, under the right conditions, possess the ability to penetrate into cells and delivery drug payloads. They also provide for a wide array of other properties (high surface-to-area ratio, high activity, etc.) due to their small size and surface properties. To prevent particles from simply clumping together and settling out from a slurry, they must be stabilized by one mechanism or another. Recently researchers at Institut Galien Paris-Saclay, Université Paris-Saclay, and Sorbonne Université (France) use PLGA (AP041, AP082, AP022, AP023) from PolySciTech (www.polyscitech.com) to produce nanoparticles under a wide array of conditions. They systematically tested the resultant nanoparticle properties with an emphasis on emulsion stabilization approach. This research holds promise to improve the development of drug-delivery nanoparticles in the future. Read more: Robin, Baptiste, Claire Albert, Mohamed Beladjine, François-Xavier Legrand, Sandrine Geiger, Laurence Moine, Valérie Nicolas et al. "Tuning morphology of Pickering emulsions stabilised by biodegradable PLGA nanoparticles: How PLGA characteristics influence emulsion properties." Journal of Colloid and Interface Science 595 (2021): 202-211. https://www.sciencedirect.com/science/article/pii/S0021979721003544

“Abstract: In this study, we proved that the stabilisation of Pickering emulsions by polymer nanoparticles (NPs) heavily depends on polymer characteristics. We prepared NPs with four poly(lactide–co–glycolide) polymers (PLGA), of different molar masses (14,000 and 32,000 g/mol) and end groups (acid or alkylester). NPs were either bare (without stabilising polymer) or covered by polyvinyl alcohol (PVA). Pickering emulsions were prepared by mixing NP aqueous suspensions with various amounts of oil (Miglyol 812 N). First, NP wettability was directly affected by PLGA end group: ester-ending PLGA led to more hydrophobic NPs, compared to acid-ending PLGA. This effect of the end group could be slightly enhanced with smaller molar mass. Thus, bare PLGA NPs stabilised different types of emulsions (W/O/W and W/O), following Finkle’s rule. However, the effect of PLGA characteristics was masked when NPs were covered by PVA, as PVA drove the stabilisation of O/W emulsions. Secondly, PLGA molar mass and end group also influenced its glass transition temperature (Tg), with spectacular consequences on emulsion formation. Indeed, the shortest ester-ending PLGA exhibited a Tg close to room temperature, when measured in the emulsion. This Tg, easily exceeded during emulsification process, led to a soft solid emulsion, stabilised by a network of NP debris. Keywords: Pickering emulsions PLGA Nanoparticles Polymer end group Molar mass PVA Wettability Glass transition temperature Emulsion type Nanoparticle organization”

PLGA from PolySciTech used in development of Se-CeO2 nanoparticle preparation for treatment of spinal-cord injuries

Tuesday, May 11, 2021, 9:48 AM ET

Until very recently, injuries to the spinal column almost certainly lead to a lifetime of paralysis. Modern technology, however, is bringing about the potential for healing the delicate nerve tissues within the spinal column to restore functionality to the paralyzed portions of a patient’s body. Recently, researchers at Zhengzhou University (China) used PLGA (AP040) from PolySciTech (www.polyscitech.com) to develop nanoparticles including Se/CeO2 for use in improving healing of the spinal cord after injuries. This research holds promise to serve as a treatment for injury-induced paralysis. Read more: Wang, Xiaoying, Biao Li, Jingjing Fan, Shanshan Tian, and Xiangyang Wei. "Novel nanoformulated combination of Se and CeO2 particles loaded polylactic‐co‐glycolic acid vesicle to improved anti‐inflammation and auto‐regenerative for the treatment and care of spinal cord injury." Applied Organometallic Chemistry: e6269. https://onlinelibrary.wiley.com/doi/abs/10.1002/aoc.6269

“Abstract: Polymer functionalized nanoparticles (NPs) have a great attention in biomedical applications owing to their unique properties like regenerative antioxidant, anti‐inflammatory, auto‐catalytic properties, and biocompatibility. In this current work, we demonstrated a facile synthesis of Se‐CeO2 via chemical method followed by precipitation method. The prepared Se NPs were characterized by ultraviolet–visible (UV‐vis) spectroscopy, and the size and morphology of the NPs were analysed using transmission electron microscopy (TEM). Meanwhile, Se‐CeO2 NPs loaded on polylactic‐co‐glycolic acid (PLGA) nanocarrier were characterised by Fourier transform infrared (FT‐IR), scanning electron microscopy (SEM), X‐ray photoelectron spectroscopy (XPS), TEM, and energy dispersive X‐ray analysis (EDAX) mapping techniques. The morphological and spectroscopic investigations of prepared nanomaterials have exhibited favourable morphological structure and chemical interactions with respective polymeric molecules, which established that nanovesicle suitability for the SCI functional recovery. We first investigated Se nanoformulated CeO2 material for the potential healing of in vitro spinal cord study. Our results demonstrated that preparation of NPs loaded PLGA nanocarrier has provide effective spinal cord regeneration and imply that it was explored that promising nanocarrier in the SCI treatment. Se‐NPs encapsulated CeO2 nanostructures administrations for SCI therapies have greatly suppressed oxidative stress and induced anti‐inflammatory action, which leads to prospective therapeutic benefits of spinal cord regeneration. These investigative results demonstrate that Se‐CeO2 NPs with PLGA carrier could have great attention for effecient functional recovery treatment and care for spinal cord injury.”

PLGA-PEG-Mal from PolySciTech used in development of nanoparticle-based breast cancer therapy

Wednesday, May 5, 2021, 10:25 AM ET

The primary limitations on chemotherapeutics are related to their safety profiles as the damage these agents cause to normally healthy tissue is non-trivial and the side effects can be severe. Recently, researchers at Harbin Medical University and Tsinghua University (China) Used mPEG-PLGA (AK037) and Mal-PEG-PLGA (AI020) from PolySciTech (www.polyscitech.com) to create anti-HER2 targeted nanoparticles for targeting of breast cancer. This research holds promise to improve cancer therapies in the future. Read more: Ni, Ling, and You-Xin Li. "Anti-Human Epidermal Growth Factor Receptor 2 Single-Chain Fv Fragment-Decorated DM1 Nanoparticles for Specific Targeting of Human Epidermal Growth Factor Receptor 2-Positive Breast Tumor Cells." Journal of Biomedical Nanotechnology 17, no. 3 (2021): 447-455. https://www.ingentaconnect.com/contentone/asp/jbn/2021/00000017/00000003/art00010

“Abstract: Purpose: Although monoclonal antibodies are used to decorate nanoparticles to target specific cells, penetration of tumor tissues by monoclonal antibodies is limited by their large size. Therefore, we prepared DM1 nanoparticles decorated with the small anti-HER2 single-chain Fv fragment (scFvHER2) of trastuzumab (TMAB) for targeting to human epidermal growth factor receptor 2 (HER2) overexpressing in breast cancer effectively. Methods: ScFvHER2 fragment was coupled with DM1 nanoparticles (NPs) via covalent thiol-maleimide linkages. Their physicochemical properties, uptake by cells, and toxicity to tumor cells were investigated. Their vivo biodistribution was assessed employing liquid chromatographytandem mass spectrometry, while their antitumor activity was investigated in nude mice burdened with BT-474 tumor. Results: Viability of BT-474 cells incubated with scFvHER2-DM1-Nanoparticles (scFv-DM1-NPs) was significantly lower than that of BT-474 cell treated with TMAB-DM1-Nanoparticles (TMAB-DM1-NPs) (P < 0 05). Uptake by cells of scFvDM1-NPs was significantly higher than TMAB-DM1-NPs (P < 0 01). Accumulation of scFv-DM1-NPs in tumor tissue was notably higher than TMAB-DM1-NPs (P < 0 05). scFv-DM1-NPs exhibited improved antitumor effects compared to TMABDM1-NPs (P < 0 05), showing a tumor inhibition rate of more than 70%. Conclusions: ScFvHER2 fragment could serve as a more effective targeting ligand than TMAB, and scFv-DM1-NPs could be developed as a possible drug delivery system to target HER2-positive breast cancer.”

PLGA from PolySciTech used in development of novel hydrogel-supported long-acting injectable formulation

Thursday, April 29, 2021, 10:17 AM ET

All medicinal molecules administered to a patient will eventually be removed from the body by a variety of clearance mechanisms (e.g. excreted in urine, destroyed in the liver, exhaled through lungs etc.) and the rate of this clearance is described as the biological half-life of the particular molecule which is usually in the order of magnitude of minutes to hours. For an injected medicine, this means that to keep a therapeutic dose in a patient there would have to be repeating doses to replace the medicine that is cleared by the body. This is inconvenient and difficult to maintain compliance as patients generally don’t enjoy being repeatedly stabbed with a needle so it is better to provide a long-acting injectable formulation which requires only a single injected of the drug molecule encapsulated in a material which slowly releases the drug out into the bloodstream over an extended period of time. Recently, researchers from Kangwon National University, Chonnam National University, Seoul National University (Korea), Terasaki Institute for Biomedical Innovation, and University of California, Los Angeles, used PLGA (AP059) from PolySciTech (www.polyscitech.com) to create donepezil-loaded microparticles. These particles were subsequently loaded into a novel HA hydrogel system to create a long-acting injectable. This research holds promise to provide for improved drug-release systems in the future. Read more: Hwang, ChaeRim, Song Yi Lee, Han-Jun Kim, KangJu Lee, Junmin Lee, Dae-Duk Kim, and Hyun-Jong Cho. "Polypseudorotaxane and polydopamine linkage-based hyaluronic acid hydrogel network with a single syringe injection for sustained drug delivery." Carbohydrate Polymers (2021): 118104. https://www.sciencedirect.com/science/article/pii/S0144861721004914

“Highlights: Hyaluronic acid-dopamine-polyethylene glycol (HD-PEG) was synthesized and identified. HD-PEG was threaded with alpha-cyclodextrin (α-CD) and pH was adjusted to 8.5. Polypseudorotaxane structure and polydopamine bond-based hydrogel was fabricated. Donepezil-loaded microspheres were embedded in hydrogel system for sustained release. Rheological features of injectable hydrogel were tuned for slow biodegradation. Abstract: Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection. Keywords: Crosslinked hydrogel Polypseudorotaxane Polydopamine Single syringe injection Slow biodegradation Sustained drug release”

PLGA from PolySciTech used in development of Notch-signaling delivery nanoparticles to reduce fetal developmental problems

Monday, April 26, 2021, 11:09 AM ET

Notch signaling indicates a specific cellular signaling pathway which is involved in embryonic development. Failure for this pathway to continue its signaling cascade can lead to developmental problems in a growing embryo. Recently, researchers at University of Texas at Arlington used two different molecular weights of PLGA (AP081, AP154) from PolySciTech (www.polyscitech.com) to create nanoparticles for intracellular plasmid delivery. This research may help reduce fetal developmental problems. Read more: Messerschmidt, Victoria L., Aneetta E. Kuriakose, Uday Chintapula, Samantha Laboy, Thuy Thi Dang Truong, LeNaiya A. Kydd, Justyn Jaworski, Kytai T. Nguyen, and Juhyun Lee. "Notch Intracellular Domain Plasmid Delivery via Poly (lactic-co-glycolic acid) Nanoparticles to Upregulate Notch Signaling." bioRxiv (2021). https://www.biorxiv.org/content/10.1101/2021.04.16.440241v1.abstract

“Abstract: Notch signaling is a highly conserved signaling system that is required for embryonic development and regeneration of organs. When the signal is lost, maldevelopment occurs and leads to a lethal state. Liposomes and retroviruses are most commonly used to deliver genetic material to cells. However, there are many drawbacks to these systems such as increased toxicity, nonspecific delivery, short half-life, and stability after formulation. We utilized the negatively charged and FDA approved polymer poly(lactic-co-glycolic acid) to encapsulate Notch Intracellular Domain-containing plasmid in nanoparticles. In this study, we show that primary human umbilical vein endothelial cells readily uptake the nanoparticles with and without specific antibody targets. We demonstrated that our nanoparticles also are nontoxic, stable over time, and compatible with blood. We also determined that we can successfully transfect primary human umbilical vein endothelial cells (HUVECs) with our nanoparticles in static and dynamic environments. Lastly, we elucidated that our transfection upregulates the downstream genes of Notch signaling, indicating that the payload was viable and successfully altered the genetic downstream effects.”

Thermogelling PLGA-PEG-PLGA used in development of 4-aminopyridine delivery system for treatment of paralysis

Monday, April 26, 2021, 11:08 AM ET

Paralysis can occur in cases of traumatic injuries from a variety of causes (car-crash, military action, industrial accidents, etc.) which lead to either severing or substantial injury to nerve tissue. Because nerve tissue does not normally heal itself, often this paralysis can be permanent leaving a patient unable to move from the point of the injury down (i.e. confined to a wheelchair). Recently, researchers at Pennsylvania State University used PLGA-PEG-PLGA (AK097) to create a delivery system for 4-aminopyridine, a drug which acts to enhance nerve repair. This research holds promise to improve treatment options for debilitating injuries. Read more: Manto, Kristen M., Prem Kumar Govindappa, Daniele Parisi, Zara Karuman, Brandon Martinazzi, John P. Hegarty, MA Hassan Talukder, and John C. Elfar. "(4-Aminopyridine)–PLGA–PEG as a Novel Thermosensitive and Locally Injectable Treatment for Acute Peripheral Nerve Injury." ACS Applied Bio Materials (2021). https://pubs.acs.org/doi/abs/10.1021/acsabm.0c01566

“Traumatic peripheral nerve injury (TPNI) represents a major medical problem that results in loss of motor and sensory function, and in severe cases, limb paralysis and amputation. To date, there are no effective treatments beyond surgery in selective cases. In repurposing studies, we found that daily systemic administration of the FDA-approved drug 4-aminopyridine (4-AP) enhanced functional recovery after acute peripheral nerve injury. This study was aimed at constructing a novel local delivery system of 4-AP using thermogelling polymers. We optimized a thermosensitive (4-AP)–poly(lactide-co-glycolide)–b-poly(ethylene glycol)–b-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) block copolymer formulation. (4-AP)–PLGA–PEG exhibited controlled release of 4-AP both in vitro and in vivo for approximately 3 weeks, with clinically relevant safe serum levels in animals. Rheological investigation showed that (4-AP)–PLGA–PEG underwent a solution to gel transition at 32 °C, a physiologically relevant temperature, allowing us to administer it to an injured limb while subsequently forming an in situ gel. A single local administration of (4-AP)–PLGA–PEG remarkably enhanced motor and sensory functional recovery on post-sciatic nerve crush injury days 1, 3, 7, 14, and 21. Moreover, immunohistochemical studies of injured nerves treated with (4-AP)-PLGA-PEG demonstrated an increased expression of neurofilament heavy chain (NF-H) and myelin protein zero (MPZ) proteins, two major markers of nerve regeneration. These findings demonstrate that (4-AP)–PLGA–PEG may be a promising long-acting local therapeutic agent in TPNI, for which no pharmacologic treatment exists.”

Mal-PEG-PLGA from PolySciTech used in development of iron nanoparticle based thermal treatment of cancer

Tuesday, April 20, 2021, 3:36 PM ET

There are many ways to treat cancer all of which have their benefits and risks. One method is to locally heat the cancer up to 45 ⁰C (normal human body temperature is 37 ⁰C) so that the cancer cells break down from the excess heat. For obvious reasons, this heating must be localized to the smallest possible area to reduce damage to the patient. Recently, researchers at Shanghai Jiao Tong University (China) used PLGA-PEG-Mal (AI110) and mPEG-PLGA (AK029) from PolySciTech (www.polyscitech.com) to create iron-oxide loaded nanoparticles. These were used to sensitize cancer cells which were then exposed to near-IR light to create localized heating as a way to destroy cancer cells. This research holds promise to improve treatment options against cancer. Read more: ​​Xie, Shaowei, Wenshe Sun, Chunfu Zhang, Baijun Dong, Jingxing Yang, Mengfei Hou, Liqin Xiong, Biao Cai, Xuesong Liu, and Wei Xue. "Metabolic Control by Heat Stress Determining Cell Fate to Ferroptosis for Effective Cancer Therapy." ACS Nano (2021). https://pubs.acs.org/doi/pdf/10.1021/acsnano.1c00380

“Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe3O4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe3O4-containing nanoformulation (GBP@Fe3O4). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe3O4in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress. KEYWORDS: metabolic reprogramming ferroptosis heat stress iron oxide nanoparticles cancer therapy”

PLGA-PEG-Mal used in development of Polymer-DNA based nanoparticles for immunotherapy of cancer

Tuesday, April 20, 2021, 9:48 AM ET

Maleimide is a chemical moiety that can chemically react with thiol (-SH) units at neutral pH and room temperature (i.e. gentle conditions unlikely to damage biomolecules) to bind to them. A useful property of this is attaching a biological molecule (protein, DNA, etc.) which has a thiol unit on it to synthetic polymer such as PEG-PLGA to create a combination semi-synthetic material. Recently, PLGA-PEG-Mal (AI053) from PolySciTech (www.polyscitech.com) used in development of polymer-DNA nanoparticles for use in immunotherapy approaches. This research holds promise to improve therapies against cancer. Read more: Huang, Xiao, Jasper Z. Williams, Ryan Chang, Zhongbo Li, Cassandra E. Burnett, Rogelio Hernandez-Lopez, Initha Setiady et al. "DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation." Nature Nanotechnology 16, no. 2 (2021): 214-223. https://www.nature.com/articles/s41565-020-00813-z

“Biomaterials can improve the safety and presentation of therapeutic agents for effective immunotherapy, and a high level of control over surface functionalization is essential for immune cell modulation. Here, we developed biocompatible immune cell-engaging particles (ICEp) that use synthetic short DNA as scaffolds for efficient and tunable protein loading. To improve the safety of chimeric antigen receptor (CAR) T cell therapies, micrometre-sized ICEp were injected intratumorally to present a priming signal for systemically administered AND-gate CAR-T cells. Locally retained ICEp presenting a high density of priming antigens activated CAR T cells, driving local tumour clearance while sparing uninjected tumours in immunodeficient mice. The ratiometric control of costimulatory ligands (anti-CD3 and anti-CD28 antibodies) and the surface presentation of a cytokine (IL-2) on ICEp were shown to substantially impact human primary T cell activation phenotypes. This modular and versatile biomaterial functionalization platform can provide new opportunities for immunotherapies.”

PLGA-PEG-Mal from PolySciTech used in investigating hypergravity effects on intestinal permeability during space travel.

Tuesday, April 6, 2021, 1:53 PM ET

Various physiological conditions are affected by surrounding environment. In general, on Earth, the gravitational force is constant (1G) in the absence of rapid acceleration or spinning motion. Within the context of an eventual time when space-travel becomes common-place enough for such parameters as gravitational force to matter, there should be at least some understanding around intestinal uptake under this condition. Recently, researchers at Universidade do Porto (Portugal), European Space Agency, Amsterdam University Medical Center (Netherlands), and CESPU (Portugal) used PLGA-PEG-Mal (AI110) from PolySciTech (www.polyscitech.com) to create particles decorated with Fc receptors to investigate intestinal uptake under varying gravitational forces. Having some understanding around this process will become relevant in the future with increased space travel. Read more: Azevedo, Cláudia, Maria Helena Macedo, Andreia Almeida, Soraia Pinto, Jack JWA van Loon, and Bruno Sarmento. "The effect of hypergravity in intestinal permeability of nanoformulations and molecules." European Journal of Pharmaceutics and Biopharmaceutics (2021). https://www.sciencedirect.com/science/article/pii/S0939641121000801

“Highlights: First study describing the impact of hypergravity on intestinal absorption. Metabolic activity and integrity of intestinal cells are not influenced by hypergravity. Hypergravity can affect the expression of different proteins on intestinal cells. The effect of hypergravity on intestinal absorption is dependent of the molecule and absorption mechanism. Abstract: The oral administration of drugs remains a challenge due to rapid enzymatic degradation and minimal absorption in the gastrointestinal tract. Mechanical forces, namely hypergravity, can interfere with cellular integrity and drug absorption, and there is no study describing its influence in the intestinal permeability. In this work, it was studied the effect of hypergravity on intestinal Caco-2 cells and its influence in the intestinal permeability of different nanoformulations and molecules. It was shown that the cellular metabolic activity and integrity were maintained after exposure to different gravity-levels (g-levels). Expression of important drug transporters and tight junctions’ proteins was evaluated and, most proteins demonstrated a switch of behavior in their expression. Furthermore, paracellular transport of FITC-Dextran showed to significantly increase with hypergravity, which agrees with the decrease of transepithelial electrical resistance and the increase of claudin-2 at higher g-levels. The diffusion of camptothecin released from polymeric micelles revealed a significant decrease, which agrees with the increased expression of the P-gp observed with the increase in g-levels, responsible for pumping this drug out. The neonatal Fc receptor-mediated transport of albumin-functionalized nanoparticles loaded with insulin showed no significant changes when increasing the g-levels. Thus, this study supports the effect of hypergravity on intestinal permeability is dependent on the molecule studied and the mechanism by which it is absorbed in the intestine.”

Thermogelling PLGA-PEG-PLGA from PolySciTech used in the development of Albumin-delivery system

Tuesday, April 6, 2021, 1:52 PM ET

Albumin is a naturally occurring protein that is commonly used to transport molecules which makes it an attractive target for use in drug delivery. Recently, researchers at University of Mississippi used PLGA-PEG-PLGA (AK097) from PolySciTech (www.polyscitech.com) to develop injectable albumin systems and used fluorescence to track the albumin motion and uptake. This research holds promise to provide for improved drug-delivery formulations in the future. Read more: Patel, Nidhi, Nan Ji, Yingzhe Wang, Xingcong Li, Nigel Langley, and Chalet Tan. "Subcutaneous Delivery of Albumin: Impact of Thermosensitive Hydrogels." AAPS PharmSciTech 22, no. 3 (2021): 1-8. https://link.springer.com/article/10.1208/s12249-021-01982-3

“Abstract: Albumin demonstrates remarkable promises as a versatile carrier for therapeutic and diagnostic agents. However, noninvasive delivery of albumin-based therapeutics has been largely unexplored. In this study, injectable thermosensitive hydrogels were evaluated as sustained delivery systems for Cy5.5-labeled bovine serum albumin (BSA-Cy5.5). These hydrogels were prepared using aqueous solutions of Poloxamer 407 (P407) or poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), which could undergo temperature-triggered phase transition and spontaneously solidify into hydrogels near body temperature, serving as in situ depot for tunable cargo release. In vitro, these hydrogels were found to release BSA-Cy5.5 in a sustained manner with the release half-life of BSA-Cy5.5 from P407 and PLGA-PEG-PLGA hydrogels at 16 h and 105 h, respectively. Without affecting the bioavailability, subcutaneous administration of BSA-Cy5.5-laden P407 hydrogel resulted in delayed BSA-Cy5.5 absorption, which reached the maximum plasma level (Tmax) at 24 h, whereas the Tmax for subcutaneously administered free BSA-Cy5.5 solution was 8 h. Unexpectedly, subcutaneously injected BSA-Cy5.5-laden PLGA-PEG-PLGA hydrogel did not yield sustained BSA-Cy5.5 plasma level, the bioavailability of which was significantly lower than that of P407 hydrogel (p < 0.05). The near-infrared imaging of BSA-Cy5.5-treated mice revealed that a notable portion of BSA-Cy5.5 remained trapped within the subcutaneous tissues after 6 days following the subcutaneous administration of free solution or hydrogels, suggesting the discontinuation of BSA-Cy5.5 absorption irrespective of the formulations. These results suggest the opportunities of developing injectable thermoresponsive hydrogel formulations for subcutaneous delivery of albumin-based therapeutics.”

mPEG-PLA from PolySciTech used in development of solid-tumor immunotherapy

Tuesday, April 6, 2021, 1:51 PM ET

Immunotherapy is a process by which the human immune system is leveraged to attack the cancer directly. This must be done with care, however, as the human immune system can cause a great deal of damage if it is not well directed even potentially killing a patient through anaphylaxis. For this reason, localized immunotherapy is better than priming the systemic immune system for attack. Recently, researchers at Cello Therapeutics, Inc. and University of California San Diego used PEG-PLA (AK054) from PolySciTech (www.polyscitech.com) to create pegylated nanoparticles. The used these to test the impact of toll-like receptor agonists on immune response in solid tumors. This research holds promise to improve cancer therapies in the future. Read more: Bahmani, Baharak, Hua Gong, Brian T. Luk, Kristofer J. Haushalter, Ethel DeTeresa, Mark Previti, Jiarong Zhou et al. "Intratumoral immunotherapy using platelet-cloaked nanoparticles enhances antitumor immunity in solid tumors." Nature Communications 12, no. 1 (2021): 1-12. https://www.nature.com/articles/s41467-021-22311-z

“Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.”

PLGA from PolySciTech used in development of chemo-catalytic therapy for treatment of cancer

Tuesday, April 6, 2021, 1:50 PM ET

Despite their exotic structures, enzymes are merely machines of the body which individually serve very simple functions based on their chemical reactive sites and their overall shape. This opens up the potential to make ‘artificial’ enzymes simply by providing an item which has a similar shape and chemical reactivity, regardless of its overall chemical design. One method of treating cancer is to generate nanoparticles which have the ability to behave like enzymes in catalyzing certain interactions which lead to destruction of the cancer cells. This can be combined with other forms of chemotherapy for a powerful treatment method. Recently, researchers at Yangzhou University, Chinese Academy of Sciences, and First Affiliated Hospital of Soochow University (China) used PLGA (AP132) from PolySciTech (www.polyscitech.com) to create manganese-oxide based artificial oxidase-enzyme like structures and combined these with artesunate drug. This research holds promise to improve therapies against cancer. Read more: Xi, Juqun, Yaling Huang, Jie Chen, Jingjing Zhang, Lizeng Gao, Lei Fan, and Xiaodong Qian. "Artesunate-loaded poly (lactic-co-glycolic acid)/polydopamine-manganese oxides nanoparticles as an oxidase mimic for tumor chemo-catalytic therapy." International Journal of Biological Macromolecules (2021). https://www.sciencedirect.com/science/article/pii/S0141813021006590

“Conventional tumor chemotherapy is limited by its low therapeutic efficacy and side effects, which severely hold back its further application as a first-line agent in clinic. To improve the cure efficacy of cancer, nanozyme with enzyme-like activity has now been extensively investigated as a new strategy for tumor treatment. Herein, an anti-tumor platform based on manganese oxides (MnOx) modified poly (lactic-co-glycolic acid) (PLGA)@polydopamine (PDA) nanoparticles (PP-MnOx NPs) as an oxidase mimic was developed. PP-MnOx NPs could not only produce abundant reactive oxygen species to inhibit tumor growth taking advantage of their oxidase-like activity, but also encapsulate and release antitumor drug (artesunate) to function as chemotherapy, achieving remarkable synergistic chemo-catalytic therapeutic effects. As an oxidase mimics, PP-MnOx NPs induced the decrease of mitochondrial membrane potential, down-regulation of Bcl-2, as well as activation of Bax and Caspase-3, demonstrating that the apoptosis triggered by PP-MnOx NPs was mediated via mitochondrial pathways. Importantly, the artesunate in PP-MnOx NPs further promoted this apoptosis. In addition, Mn ions released from PP-MnOx NPs facilitated the tumor-microenvironment-specific T1-weighted magnetic resonance imaging. Taken together, this study well clarifies the antitumor mechanism of artesunate-loaded PP-MnOx NPs and offer a synergistic chemo-catalytic strategy for tumor theranostics. Keywords: MnOx modified PLGA/polydopamine nanoparticles Oxidase Reactive oxygen species Chemo-catalytic tumor therapy”

PEG-PCL/PEG-PLA polymers from PolySciTech used in research on structure of self-assembled nanocarriers

Tuesday, April 6, 2021, 1:46 PM ET

Despite their popular use, much remains to be learned about the structure and nature of self-assembled PEGylated nanocarriers comprised of PEG-block polymers. One means to do this is to load tetra tert-butyl zinc(II) phthalocyanine spectroscopic probes into the carrier and then bombard them with radio-frequency electromagnetic radiation under powerful magnetic fields and measure their UV-Vis spectra, as one normally does. Recently, researchers at Wroclaw University of Science and Technology (Poland) used mPEG-PCL (AK074) and mPEG-PLA (AK084) from PolySciTech (www.polyscitech.com) to conduct advanced research on the nanoparticle structure. This holds promise to improve the use of these carriers in a variety of formulation approaches. Read more: Lamch, Łukasz, Roman Gancarz, Marta Tsirigotis-Maniecka, Izabela M. Moszyńska, Justyna Ciejka, and Kazimiera A. Wilk. "Studying the “Rigid–Flexible” Properties of Polymeric Micelle Core-Forming Segments with a Hydrophobic Phthalocyanine Probe Using NMR and UV Spectroscopy." Langmuir (2021). https://pubs.acs.org/doi/abs/10.1021/acs.langmuir.1c00328

“Abstract: The aim of the performed studies was to thoroughly examine the internal structure of self-assembled nanocarriers (i.e., polymeric micelles—PMs) by means of a hydrophobic phthalocyanine probe in order to identify the crucial features that are required to enhance the photoactive probe stability and reactivity. PMs of hydrophilic poly(ethylene glycol) and hydrophobic poly(ε-caprolactone) (PCL) or poly(d,l-lactide) (PDLLA) were fabricated and loaded with tetra tert-butyl zinc(II) phthalocyanine (ZnPc-t-but4), a multifunctional spectroscopic probe with a profound ability to generate singlet oxygen upon irradiation. The presence of subdomains, comprising “rigid” and “flexible” regions, in the studied block copolymers’ micelles as well as their interactions with the probe molecules, were assessed by various high-resolution NMR measurements [e.g., through-space magnetic interactions by the 1D NOE effect, pulsed field gradient spin-echo, and spin–lattice relaxation time (T1) techniques]. The studies of the impact of the core-type microenvironment on the ZnPc-t-but4 photochemical performance also included photobleaching and reactive oxygen species measurements. ZnPc-t-but4 molecules were found to exhibit spatial proximity effects with both (PCL and PDLLA) hydrophobic polymer chains and interact with both subdomains, which are characterized by different rigidities. It was deduced that the interfaces between particular subdomains constitute an optimal host space for probe molecules, especially in the context of photochemical stability, photoactivity (i.e., for significant enhancement of singlet oxygen generation rates), and aggregation prevention. The present contribution proves that the combination of an appropriate probe, high-resolution NMR techniques, and UV–vis spectroscopy enables one to gain complex information about the subtle structure of PMs essential for their application as nanocarriers for photoactive compounds, for example, in photodynamic therapy, nanotheranostics, combination therapy, or photocatalysis, where the micelles constitute the optimal microenvironment for the desired photoreactions.”

Thermogelling PLGA-PEG-PLGA from PolySciTech used in testing of cardiovascular healing post stenosis

Monday, March 29, 2021, 4:11 PM ET

Heart disease remains the most common cause of death world-wide. Although emplacement of cardiovascular stent can reduce damage from heart attack by maintaining blood flow there is the potential for restenosis as the tissue can in-grow into the stent structure and reclose the vessel. Recently, researchers at University of Virginia, University of Wisconsin, and Ohio State University used PLGA-PEG-PLGA (AK012) from PolySciTech (www.polyscitech.com) to create thermogels that provide for controlled delivery of a PLK4 inhibitor (centrinone-B) to enable study into the post-stent healing process. This research holds promise to improve outcomes from cardiovascular repair operations. Read more: Li, Jing, Go Urabe, Yitao Huang, Mengxue Zhang, Bowen Wang, Lynn Marcho, Hongtao Shen, K. Craig Kent, and Lian-Wang Guo. "A role for polo-like kinase 4 in vascular fibroblast cell-type transition." Basic to Translational Science 6, no. 3 (2021): 257-283. https://www.jacc.org/doi/abs/10.1016/j.jacbts.2020.12.015

“Highlights: PLK4, previously known as a centriole-associated factor, regulates the transcription factor activity of serum response factor. PLK4 inhibition blocks the profibrogenic cell state transition of vascular fibroblasts. PLK4’s activation and gene expression are regulated by PDGF receptor and epigenetic reader BRD4, respectively. Summary: Periadventitial administration of a PLK4 inhibitor mitigates vascular fibrosis. Polo-like kinase 4 (PLK4) is canonically known for its cytoplasmic function in centriole duplication. Here we show a noncanonical PLK4 function of regulating the transcription factor SRF’s nuclear activity and associated myofibroblast-like cell-type transition. In this context, we have further found that PLK4’s phosphorylation and transcription are respectively regulated by PDGF receptor and epigenetic factor BRD4. Furthermore, in vivo experiments suggest PLK4 inhibition as a potential approach to mitigating vascular fibrosis.”

Poloxamer-diacrylate from PolySciTech used in research on tough and adhesive hydrogels

Monday, March 29, 2021, 4:10 PM ET

The potential for use of adhesive hydrogels in medicine opens up a world in terms of surgical treatment and wound-repair options. For this, however, a hydrogel must be carefully designed which has the correct properties of biocompatibility and bioadhesion. Recently, researchers at Harvard University used poloxamer-diacrylate (AI146) from PolySciTech (www.polyscitech.com) to create strong, chemically crosslinked hydrogels and tested these for adhesion, degradation, and biocompatibility. This research holds promise to improve wound healing and traumatic injury repair in the future. Read more: Freedman, Benjamin R., Oktay Uzun, Nadja M. Maldonado Luna, Anna Rock, Charles Clifford, Emily Stoler, Gabrielle Östlund‐Sholars, Christopher Johnson, and David J. Mooney. "Degradable and Removable Tough Adhesive Hydrogels." Advanced Materials (2021): 2008553. https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.202008553

“Abstract: The development of tough adhesive hydrogels has enabled unprecedented adhesion to wet and moving tissue surfaces throughout the body, but they are typically composed of nondegradable components. Here, a family of degradable tough adhesive hydrogels containing ≈90% water by incorporating covalently networked degradable crosslinkers and hydrolyzable ionically crosslinked main‐chain polymers is developed. Mechanical toughness, adhesion, and degradation of these new formulations are tested in both accelerated in vitro conditions and up to 16 weeks in vivo. These degradable tough adhesives are engineered with equivalent mechanical and adhesive properties to nondegradable tough adhesives, capable of achieving stretches >20 times their initial length, fracture energies >6 kJ m−2, and adhesion energies >1000 J m−2. All degradable systems show complete degradation within 2 weeks under accelerated aging conditions in vitro and weeks to months in vivo depending on the degradable crosslinker selected. Excellent biocompatibility is observed for all groups after 1, 2, 4, 8, and 16 weeks of implantation, with minimal fibrous encapsulation and no signs of organ toxicity. On‐demand removal of the adhesive is achieved with treatment of chemical agents which do not cause damage to underlying skin tissue in mice. The broad versatility of this family of adhesives provides the foundation for numerous in vivo indications.”

PLGA-PEG-Mal used in research on intestinal permeation for oral bioavailability research

Monday, March 29, 2021, 4:09 PM ET

Oral bioavailability references the ability of a drug taken orally (either as a tablet or as a drinkable liquid) to be successfully taken into the bloodstream and circulate throughout the patient’s body. One classic example of oral bioavailability is acetylsalicylic acid (Aspirin) which has roughly 50% bioavailability. In the case of aspirin, the drug is readily available and cheaply manufactured so the incredibly unimaginative and yet wildly effective manner of dealing with 50% bioavailability was to double the dose given to the patient, knowing that about 50% of the drug will simply be lost without any benefit. Not all bioavailability problems can be addressed in such a simplistic manner as some molecules have little to no bioavailability or require carefully controlled dosing. In this case, understanding the exact bioavailability is critical and one of the most important rate-limiting steps of bioavailability is the ability for drugs to cross the intestinal mucosa layer into the blood stream. The small intestine is, metaphorically, the ‘Suez Canal’ of the human body and understanding uptake across the intestine is critical to bioavailability. Recently, researchers at University of Porto (Portugal), University of Oslo (Norway), Harvard Medical School, Massachusetts Institute of Technology, and Universitário de Ciências da Saúde (Portugal) used PLGA-PEG-Mal (AI110) from PolySciTech (www.polyscitech.com) to create particles decorated with neonatal Fc receptor to test their intestinal permeation model of specially prepared porcine mucosa. This research holds promise to improve oral delivery of medicines. Read more: Azevedo, Cláudia, Jan Terje Andersen, Giovanni Traverso, and Bruno Sarmento. "The potential of porcine ex vivo platform for intestinal permeability screening of FcRn-targeted drugs." European Journal of Pharmaceutics and Biopharmaceutics (2021). https://www.sciencedirect.com/science/article/abs/pii/S0939641121000746

“Highlights: FcRn is expressed across the gastrointestinal tract. FcRn expression in ex vivo porcine tissue is maintained up to 7 days in culture. Free KP present higher permeability in porcine ex vivo platform. The porcine ex vivo platform was revealed to be a potential model for the screening of FcRn-targeted oral drug formulations. Abstract: Conventionally, the intestinal permeability of drugs is evaluated using cell monolayer models that lack morphological, physiological and architectural features, as well as realistic neonatal Fc receptor (FcRn) expression. In addition, it is time-consuming, expensive and excessive to use a large number of mice for large-scale screening of FcRn-targeted candidates. For preclinical validation, it is critical to use suitable models that mimic the human intestine; the porcine ex vivo model is widely used for intestinal permeability studies, due to its physiological and anatomical similarities to humans. This study intended to analyze the potential to measure the intestinal permeability of FcRn-targeted substances using a porcine ex vivo platform, which is able to analyze 96 samples at the same time. In addition, the platform allows the screening of FcRn-targeting substances for transmucosal delivery, taking into consideration (cross-species) receptor-ligand binding kinetics. After analyzing the morphology of the porcine tissue, the FcRn expression across the gastrointestinal tract was verified. By studying the stomach, duodenum and jejunum, it was demonstrated that FcRn expression is maintained for up to 7 days. When evaluating the duodenum permeability of free engineered human albumin variants, it was shown that the variant with the mutation K573P (KP) is more efficiently transported. Given this, the porcine ex vivo platform was revealed to be a potential model for the screening of FcRn-targeted oral drug formulations.”

PLGA from PolySciTech used in development of vaccine to protect against heart disease

Wednesday, March 24, 2021, 9:58 AM ET

Heart disease has been the number one cause of death globally for a long time. Through the use of vaccines and related technologies, humans have the ability to prime and adjust the human immune system to leverage this powerful agent to effect changes within the body. One novel approach is to use this system to reduce arterial blockage and heart disease. Researchers at University of California-San Diego used PLGA (AP041) from PolySciTech (www.polyscitech.com) to create time-delayed antigen release systems to create a vaccine against cardiovascular disease by targeting the immune system against cholesterol-promoting proteins. This holds promise to provide for therapy against heart disease which is currently the most common cause of death. Read more: Ortega‐Rivera, Oscar A., Jonathan K. Pokorski, and Nicole F. Steinmetz. "A Single‐Dose, Implant‐Based, Trivalent Virus‐like Particle Vaccine against “Cholesterol Checkpoint” Proteins." Advanced Therapeutics: 2100014. https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.202100014

“Cardiovascular disease is the number one cause of death globally. Lowering cholesterol levels in plasma is the mainstay therapy; however lifelong treatment and adverse effects call for improved therapeutic interventions. A trivalent vaccine candidate targeting proprotein convertase subtilisin/kexin-9 (PCSK9), apolipoprotein B (ApoB), and cholesteryl ester transfer protein (CETP) is developed. Vaccine candidates are developed using bacteriophage Q𝜷-based virus-like particles (VLPs) displaying antigens of PCKS9, ApoB, and CETP, respectively. Vaccine candidate mixtures are formulated as slow-release PLGA:VLP implants using hot-melt extrusion. The delivery of the trivalent vaccine candidate via the implant produced antibodies against the cholesterol checkpoint proteins at levels comparable to a three-dose injection schedule with soluble mixtures. The reduction in PCSK9 and ApoB levels in plasma, inhibition of CETP (in vitro), and total plasma cholesterol decrease is achieved. Altogether, a platform technology for a single-dose multi-agent proteins is presented.”

PLGA-PEG-COOH from PolySciTech used in development of ultrasound-triggered delivery of miRNA/Gene Therapy for treatment of cancer

Tuesday, March 16, 2021, 10:54 AM ET

The delivery of genetic materials, RNA/DNA, to cells holds potential for the treatment of several disease states. That being said, getting these materials into the area of action is not a trivial task as endogenous RNAse and DNAse enzymes will often break them down as well as permeation across various membranes is not good. Recently researchers at Stanford University and Bracco Suisse SA use PLGA-PEG-COOH (AI034) from PolySciTech (www.polyscitech.com) to create ultrasound-responsive PLGA-PEG-PEI nanoparticles to deliver RNA/Gene therapy materials to cancer cells as a treatment regimen. This research holds promise to improve therapies against cancer. Read more: Kumar, Sukumar Uday, Huaijun Wang, Arsenii V. Telichko, Arutselvan Natarajan, Thierry Bettinger, Samir Cherkaoui, Tarik F. Massoud, Jeremy J. Dahl, and Ramasamy Paulmurugan. "Ultrasound Triggered Co‐Delivery of Therapeutic MicroRNAs and a Triple Suicide Gene Therapy Vector by Using Biocompatible Polymer Nanoparticles for Improved Cancer Therapy in Mouse Models." Advanced Therapeutics: 2000197. https://onlinelibrary.wiley.com/doi/abs/10.1002/adtp.202000197

“Microbubbles (MBs) exhibit cavitation upon exposure to ultrasound (US), which creates opportunities to adopt them in new therapeutic approaches. The present study reports an efficient, translatable approach to precisely control the spaciotemporal delivery of therapeutic microRNAs (AmiR‐21 and miR‐100) and TK‐p53‐NTR triple therapeutic gene, co‐loaded in PLGA‐PEG‐PEI polymer nanoparticles (NPs) to tumor models of triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) using US‐mediated targeted destruction of BR38 MBs. PLGA‐PEG‐PEI conjugated triblock co‐polymer NPs are synthesized and characterized for their physicochemical properties, and optimized for co‐loading of miRNAs and TK‐p53‐NTR. Quantitative in vivo imaging and ex vivo tissue analysis of 4T1 (TNBC) subcutaneous tumors in BALB/c mice reveal 19 ± 0.5% (p < 0.01) increase in delivery of miRNAs, and 48 ± 1.79% (p < 0.001) increase in delivery of TK‐p53‐NTR upon US treatment, which results to 48 ± 6.98% (p < 0.01) reduction in tumor growth as compared to contralateral tumors without US. This significantly increases the survival rate of animals as compared to pDNA control group. Similar treatment effects are observed in both TNBC and HCC tumor models. This novel combined therapeutic approach, entailing both miRNAs and suicide gene therapy has strong potential for future applications in cancer therapy.”

PEG-PLGA from PolySciTech used in research on microfluidic nanoparticle preparation

Wednesday, March 10, 2021, 10:07 AM ET

There are many different methods available by which nanoparticles can be formulated. One method is to use microfluidic systems to create the particles under carefully controlled conditions. Recently, researchers at The University of Queensland (Australia) used mPEG-PLGA (AK026) from PolySciTech (www.polyscitech.com) to research nanoprecipitation methods to create drug-loaded nanoparticles. This research holds promise to provide for improved nanoparticle manufacturing capabilities. Read more: Li, Wei, Qiaoli Chen, Thejus Baby, Song Jin, Yun Liu, Guangze Yang, and Chun-Xia Zhao. "Insight into drug encapsulation in polymeric nanoparticles using microfluidic nanoprecipitation." Chemical Engineering Science 235 (2021): 116468. https://www.sciencedirect.com/science/article/pii/S0009250921000336

“Highlights: A combined computational fluid dynamics (CFD) and experimental approach to illustrate microfluidic nanoprecipitation. Mixing times of a polymer and a drug are determined using a CFD method. Drug loading is dependent on the mixing time of the polymer and drug. The precipitation time of polymer and drug should be matched for drug encapsulation. Abstract: Synthesis of polymeric nanoparticles (NPs) through self-assembly of di-block copolymers have attracted substantial interest in the past decades for drug delivery and controlled release. Microfluidics offers a facile approach for making such NPs and drug encapsulation. However, a fundamental understanding of the drug encapsulation process is lacking. In this paper, we report a combined computational fluid dynamics (CFD) and experimental approach to illustrate the fundamental principle that governs the encapsulation of a drug in polymeric NPs through microfluidic nanoprecipitation. Taking a drug curcumin and a polymer poly (ethylene glycol)-block-poly (d, l-lactide-co-glycolide) (PEG-PLGA) as a model system, we demonstrated the different precipitation times of curcumin and PEG-PLGA as well as their mixing times in the microfluidic device. The big difference in their mixing times led to very low drug loading. This study provides a new perspective in understanding and controlling the formation of drug-loaded polymeric NPs and offers a new design rule for selecting the right combinations of drugs, polymers, solvents, and devices. Keywords Microfluidic Self-assembly Nanoparticles mPEG-PLGA Polymer nanoparticles Nanoprecipitation Drug encapsulation”

These posts are syndicated from John Garner's blog at http://jgakinainc.blogspot.com/ where you can post a question or comment. (Load took 0.29334092140198 seconds)


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