PLGA-PEG derivatives from PolySciTech used in development of muscle-targeting nanoparticles for muscular dystrophy treatment

Muscular dystrophy (Duchenne) is the most common inherited muscular disease which leads to degeneration of muscle tissue until the patient can no longer breathe at which point it becomes fatal. This disease is driven by a lack of functional dystrophin in muscle fibers which reduces their resistance to mechanical stress during contraction. Recently, researchers at Purdue University used mPEG-PLGA (AK037), PLGA-PEG-NHS (AI111), PLGA-PEG-NH2 (AI188) from PolySciTech (www.polyscitech.com) to create muscle-targeting nanoparticles to deliver VO-OHpic which prevents PTEN pathway of muscular degradation. This research holds promise to provide a treatment for this debilitating disease. Read more: Huang, Di, Feng Yue, Jiamin Qiu, Meng Deng, and Shihuan Kuang. "Polymeric nanoparticles functionalized with muscle-homing peptides for targeted delivery of phosphatase and tensin homolog inhibitor to skeletal muscle." Acta Biomaterialia (2020). https://www.sciencedirect.com/science/article/pii/S1742706120305985

“Phosphatase and tensin homolog (PTEN) antagonizes muscle growth and repair, and inhibition of PTEN has been shown to improve the pathophysiology and dystrophic muscle function in a mouse model of Duchenne muscular dystrophy (DMD). However, conventional pharmacological delivery of PTEN inhibitors carries a high risk of off-target side effects in other non-muscle organs due to broad targeting spectrums. Here we report a muscle-targeted nanoparticulate platform for cell-specific delivery of a PTEN inhibitor. Poly(lactide-co-glycolide)-b-poly(ethylene glycol) nanoparticles (NPs) are functionalized with a muscle-homing peptide M12 to promote the selective uptake by muscle cells/tissue in vitro and in vivo. Moreover, the NPs are formulated to slowly release the PTEN inhibitor, preventing cytotoxicity associated with direct exposure to the drug and facilitating sustained inhibition of PTEN. This advanced delivery approach taking advantages of polymeric nanomaterials and muscle-homing peptides opens a new avenue for the development of long-term therapeutic strategies in DMD treatment. Pharmacological inhibition of phosphatase and tensin homolog (PTEN) has been demonstrated to improve muscle function in a mouse model of Duchenne muscular dystrophy (DMD), but translation of this approach into clinical settings remains challenging due to potential risks of off-target side effects. Herein, we developed a nanoparticulate platform, consisting of poly(lactide-co-glycolide)-b-poly(ethylene glycol) and a muscle-homing peptide M12, for cell-specific delivery of a PTEN inhibitor. M12 facilitates the cellular internalization of nanoparticles in myoblasts and their selective localization in skeletal muscle. Moreover, the slowly released drug from nanoparticles reduces its cytotoxicity and achieves sustained PTEN inhibition. This advanced delivery approach taking advantages of nanomaterials and targeting peptides opens a new avenue for the development of long-term therapeutic strategies in DMD treatment.”

PolySciTech Products used in several Doctorate Research Thesis

 

Commonly research products provided by PolySciTech (www.polyscitech.com) are used as part of graduate research programs which leads to several thesis publications including the PLGA’s, PEG-PLGA’s and other block polymers from PolySciTech incorporated as part of the research methods. Two of these recently published including Sheardown, Heather, and Varun Chaudhary. "PNIPAAM Immobilized Nanoparticles for Posterior Ocular Delivery." PhD diss., McMaster University, 2020 (https://macsphere.mcmaster.ca/handle/11375/25892). Which used PLGA (AP196) to create drug-eluting nanoparticles and Stowell, Chelsea Elizabeth. "Design and Validation of Resorbable Vascular Grafts in Large Animals." PhD diss., Cornell University, 2020 (http://search.proquest.com/openview/439e7614ee33ff4de5ba8a38e35686fc/1?pq-origsite=gscholar&cbl=18750&diss=y). Which used PLCL (AP015) to create biodegradable vascular grafts. These are just two examples of several thesis projects which have been completed or are in progress right now using PolySciTech research products.

PEG-PLGA from PolySciTech used in development of arthritis treatment

 

Arthritis is a disease in which the cartilidge in joints begins to break down leading to severe damage and pain. This disease is driven by a pathological immune imbalance in which the immune system starts attacking at the sight of the cartilidge leading to severe inflammation. Recently, researchers at University of Pittsburgh used PEG-PLGA (AK037) from PolySciTech (www.polyscitech.com) to create a delivery system to decrease the hyperactive immune response in joints and reduce the progression of arthritis. This research holds promise to prevent this potentially debilitating disease. Read more: Bassin, Ethan J., Abigail R. Buckley, Jon D. Piganelli, and Steven R. Little. "TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model." PloS one 15, no. 9 (2020): e0239396. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239396

“Abstract: Despite recent progress in the treatment of rheumatoid arthritis (RA), many patients still fail to achieve remission or low disease activity. An imbalance between auto-reactive effector T cells (Teff) and regulatory T cells (Treg) may contribute to joint inflammation and damage in RA. Therefore, restoring this balance is a promising approach for the treatment of inflammatory arthritis. Accordingly, our group has previously shown that the combination of TGF-β-releasing microparticles (MP), rapamycin-releasing MP, and IL-2-releasing MP (TRI MP) can effectively increase the ratio of Tregs to Teff in vivo and provide disease protection in several preclinical models. In this study TRI MP was evaluated in the collagen-induced arthritis (CIA) model. Although this formulation has been tested previously in models of destructive inflammation and transplantation, this is the first model of autoimmunity for which this therapy has been applied. In this context, TRI MP effectively reduced arthritis incidence, the severity of arthritis scores, and bone erosion. The proposed mechanism of action includes not only reducing CD4+ T cell proliferation, but also expanding a regulatory population in the periphery soon after TRI MP administration. These changes were reflected in the CD4+ T cell population that infiltrated the paws at the onset of arthritis and were associated with a reduction of immune infiltrate and inflammatory myeloid cells in the paws. TRI MP administration also reduced the titer of collagen antibodies, however the contribution of this reduced titer to disease protection remains uncertain since there was no correlation between collagen antibody titer and arthritis score.”

PLGA from PolySciTech used in development of 3D printed antibiotic scaffold

 

Any time the skin is punctured the potential for bacterial infiltration exists and can lead to localized infection. Recently, researchers at University of Prince Edward Island and Regis and Joan Duffy Research Centre (Canada) Used PLGA (AP036, AP149, AP020) From PolySciTech (www.polyscitech.com) to create a scaffold that releases antibiotics from a piercing to reduce the potential for infection. This research holds promise to prevent piercing-related infections. Read more: Naseri, Emad, Christopher Cartmell, Matthew Saab, Russell G. Kerr, and Ali Ahmadi. "Development of 3D Printed Drug-Eluting Scaffolds for Preventing Piercing Infection." Pharmaceutics 12, no. 9 (2020): 901. https://www.mdpi.com/1999-4923/12/9/901

“Abstract: Herein, novel drug-eluting, bio-absorbable scaffold intended to cover piercing studs is introduced. This “biopierce” will stay in human tissue following piercing, and will slowly release an antimicrobial agent to prevent infection while the wound heals. Nearly 20% of all piercings lead to local infection. Therefore, it is imperative to develop alternative methods of piercing aftercare to prevent infection. Biopierces were made using mupirocin loaded poly-lactic-co-glycolic acid (PLGA) biomaterial ink, and a low-temperature 3D printing technique was used to fabricate the biopierces. Proton nuclear magnetic resonance (1H NMR) spectroscopy was used to confirm the complete removal of the solvent, and liquid chromatography high-resolution mass spectrometry (LC-HRMS) was used to confirm the structural integrity of mupirocin and to quantify the amount of the released drug over time. The efficacy of the biopierces against Staphylococcus aureus, one of the most common piercing-site pathogens, was confirmed over two weeks using in vitro antimicrobial susceptibility testing. Keywords: biopierce; 3D printing; PLGA; bacterial test; drug eluting scaffolds”

PCL-PEI from PolySciTech used in development of Immunotherapy system

 

Immunotherapy is a promising area of treatment for cancer as it allows the bodies natural defense system to attack the tumor directly. Recently, researchers at Yeungnam University, Hanyang University, Daegu Haany University (Korea), Phenikaa University, and PHENIKAA Research and Technology Institute (Vietnam) used PCL-PEI (AO043) from PolySciTech (www.polyscitech.com) to create dabrafenib and miR-200c loaded nanoparticles to modify the immune response against cancer. This research holds promise to improve therapy against cancer. Read more: Nguyen, Hanh Thuy, Cao Dai Phung, Tuan Hiep Tran, Tung Thanh Pham, Tiep Tien Nguyen, Jee-Heon Jeong, Han-Gon Choi, Sae Kwang Ku, Chul Soon Yong, and Jong Oh Kim. "Manipulating immune system using nanoparticles for an effective cancer treatment: Combination of targeted therapy and checkpoint blockage miRNA." Journal of Controlled Release (2020). https://www.sciencedirect.com/science/article/pii/S0168365920305514

“Abstract: Accumulating clinical data shows that less than half of patients are beneficial from PD-1/PD-L1 blockage therapy owing to the limited infiltration of effector immune cells into the tumor and abundant of the immunosuppressive factors in the tumor microenvironment. In this study, PD-L1 inhibition therapy and BRAF-targeted therapy, which showed clinical benefit, were combined in a CXCR4-targeted nanoparticle co-delivering dabrafenib (Dab), a BRAF inhibitor, and miR-200c which can down-regulate PD-L1 expression. The cationic PCL-PEI core containing Dab- and miR-200c- were coated with poly-L-glutamic acid conjugated with LY2510924, a CXCR-4 antagonist peptide, (PGA-pep) to obtain miR@PCL-PEI/Dab@PGA-pep nanoformulation. The stimulus pH- and redox- reactive of PGA-pep was ascribed to exhibit an enhanced release of drug in the tumor microenvironment as well as improve the stability of miR-200c during the blood circulation. In addition, the presence of LY2510924 peptide would enhance the binding affinity of miR@PCL-PEI/Dab@PGA-pep NPs to cancer cells, leading to improved cellular uptake, cytotoxicity, and in vivo accumulation into tumor area. The in vivo results indicated that both, the immunogenic cell death (ICD) and the inhibition of PD-L1 expression, induced by treatment with CXCR-4 targeted nanoparticles, enables to improve the DC maturation in lymph node and CD8+ T cell activation in the spleen. More importantly, effector T cells were increasingly infiltrated into the tumor, whereas the immunosuppressive factors like PD-L1 expression and regulatory T cells were significantly reduced. They, all together, promote the immune responses against the tumor, indicating the therapeutic efficiency of the current strategy in cancer treatment.”

PLGA from PolySciTech used in development of Donepezil-loaded drug-releasing hydrogel for Alzheimer’s treatment

 

Injectable hydrogels have the capacity to provide for creating a soft, biocompatible structure which can be put into a patient and used to deliver a wide array of drugs or provide a tissue scaffold for cell growth. Recently, researchers at Kangwon National University, Seoul National University (Korea), University of California-Los Angeles, and Terasaki Institute for Biomedical Innovation (California, USA) used PLGA (AP059) from PolySciTech (www.polyscitech.com) to create donepezil-loaded microparticles inside of a HA-DOPA injectable hydrogel. This research holds promise to provide for sustained drug delivery of this molecule as a treatment option for Alzheimer’s disease. Read more: Seo, Ji-Hye, Song Yi Lee, Sungyun Kim, Mingyu Yang, Da In Jeong, ChaeRim Hwang, Min-Hwan Kim et al. "Monopotassium phosphate-reinforced in situ forming injectable hyaluronic acid hydrogels for subcutaneous injection." International Journal of Biological Macromolecules (2020). https://www.sciencedirect.com/science/article/pii/S0141813020344500

“Highlights: Monopotassium phosphate-incorporated hyaluronic acid hydrogel was fabricated. Both incorporation of KH2PO4 and pH modulation were engaged for gel crosslinking. Sustained drug release and prolonged in vivo retention of hydrogel were observed. Abstract: Monopotassium phosphate and pH modulation-reinforced hydrogel based on hyaluronic acid (HA) grafted with dopamine (dopa) was fabricated as one of subcutaneous injection formulations of donepezil (DPZ). Both incorporation of KH2PO4 and pH adjustment finally attributed to tuning viscoelastic and biodegradable properties of hydrogel system. Appropriate gelation time for in situ gel formation, single syringe injectability, self-healing capability, and viscoelastic features were accomplished with the optimization of KH2PO4 concentration in hydrogel systems. DPZ base (as a poorly water soluble drug) was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) and it was further embedded in the hydrogel structure for sustained drug release. Biodegradability of designed KH2PO4-incorporated HA-dopa/DPZ MS hydrogel system was assessed by optical imaging and the remained gel weight of crosslinked HA-dopa hydrogel group was 3.4-fold higher than that of unmodified HA-dopa mixture group on day 14 (p < 0.05). Subcutaneous injection of KH2PO4-incorporated HA-dopa/DPZ MS hydrogel did not induce any severe systemic toxicities. All these data suggest that designed HA-dopa/DPZ MS hydrogel structure crosslinked by KH2PO4 incorporation and pH adjustment can be one of promising subcutaneous injection formulations for sustained drug delivery. Keywords: Catechol Crosslinking Hyaluronic acid Hydrogel Potassium phosphate”

Mal-PEG-PLGA from PolySciTech used in development of Dp44mT-Loaded cancer-targeting nanoparticles

 

A major drawback of chemotherapeutics is they systemically affect the entire body leading to serious side effects. Recently, researchers at University of Houston used Mal-PEG-PLGA (AI020), PLGA (AP041), and PEG-PLGA (AK027) from PolySciTech (www.polyscitech.com) to create Dp44mT loaded nanoparticles for cancer treatment. This research holds promise to improve chemotherapy regimens. Read more: Holley, C. K., and S. Majd. "Examining the Anti-Tumor Activity of Dp44mT-Loaded Nanoparticles In Vitro." In 2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), pp. 5029-5032. IEEE, 2020. https://ieeexplore.ieee.org/abstract/document/9176197/

“We have recently reported encapsulating an antitumor iron chelator, Dp44mT (Di-2-pyridylketone-4,4dimethyl-3-thiosemicarbazone), in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA). In this paper, we examine the effectiveness of this nano-formulation, referred to as Dp44mT-NPs, against several cancer cell lines in vitro; specifically, we evaluate the cytotoxicity of this formulation in glioma (U87, U251), breast (MCF7), and colorectal (HT29) cancer cell lines. Cell viability results from treatment of glioma cells with Dp44mT-NPs for 24-72 hrs revealed that these NPs were highly toxic towards these malignant cells with very low IC 50 values (<100 nM). Although addition of a PEG (poly(ethylene glycol)) layer to the surface of NPs reduced their toxicity in glioma cells, they remained highly toxic towards these cells (IC 50 of 135-210 nM). Dp44mT-NPs were also toxic towards breast MCF7 and colorectal HT29 cells, but at higher dosages (IC 50 >1 µM) compared to glioma cells. Addition of PEG to these NPs, again lowered their toxicity in these cells. Varying the percentage of PEG on NPs resulted in changes in their cytotoxicity, highlighting the necessity of further optimization of this parameter. This study, overall, demonstrates the therapeutic potential of Dp44mT-NPs against different malignant cells, with particularly promising results in highly-aggressive glioma tumor cells.”