PLGA Research Articles

USP’s characterization of commercial poly(lactic-co-glycolic acid) utilizing SEC-Multi-Angle Light Scattering and Refractive Index techniques via Absolute Method approach

This research focuses on evaluating the data quality and reliability of Size Exclusion Chromatography with Multi-Angle Light Scattering and Refractive Index (SEC-MALS/RI) chromatography in determining molecular weight-related parameters in poly(lactic-co-glycolic) acid (PLGA) polymers. The study utilizes key metrics, particularly percent relative standard deviation (%RSD), to evaluate the precision across different data processing conditions. Exploring baseline selection of the chromatograms reveals that selection of the baseline based on the intrinsic shape of the chromatogram, rather than relying on elution peaks, improves consistency. The study emphasizes the critical role of result fitting in addressing systematic errors and sample heterogeneity, recommending the minima of the elution peak selection range for realistic molecular weight distribution representation. Analysis of light-scattering (LS) detector chromatograms highlights varying effects on different PLGA polymers, emphasizing the need for careful assessment and potential exclusion for precision improvement, especially in the presence of experimental artifacts. Across diverse PLGA polymers, the utilization of different column types, along with considerations such as baseline determination and peak selection, shows minimal variations in Mn, Mw, and polydispersity index (PDI), affirming the consistency of the methodology. The %RSD analysis further supports the methodology's precision, with values well within acceptable limits. In summary, this comprehensive evaluation of methodological conditions, including baseline selection, result fitting, LS detector data management, and column types, establishes a reliable SEC-MALS/RI chromatographic approach by Absolute Method for determining molecular weight parameters in PLGA polymers.

Sustained release system from PLGA particles co-encapsulated with inactivated influenza virus with natural killer T cell agonist α-galactosylceramide

Vaccines against influenza and many other infectious diseases require multiple boosters in addition to the primary dose to improve efficacy, but this approach is not ideal for compliance. The multiple doses could potentially be replaced by sustained or pulsatile release of antigens encapsulated in degradable microparticles (MPs). The efficacy of a vaccine is improved by adding an adjuvant, which can be co-delivered from the particles to enhance immunogenicity. Here, we developed degradable poly-lactic-co-glycolic acid (PLGA) (7–17 kDa) MPs capable of sustained release of ultraviolet killed influenza virus (A/PR/8/34) (kPR8) vaccine and the natural killer T (NKT) cell agonist alpha-galactosylceramide (α-GalCer) and tested their effectiveness at providing long-term protection against influenza virus infection in mice. Multiple formulations were developed for encapsulating the virus and adjuvant separately, and in combination. The MPs exhibited sustained release of both the virus and the adjuvant lasting more than a month. Co-encapsulation significantly increased the encapsulation efficiency (EE) of the vaccine but reduced the release duration. On the other hand, co-encapsulation led to a reduction in EE for the α-GalCer and a change in release profile to a higher initial burst followed by a linear release compared to a low initial burst and slower linear release. The α-GalCer also had considerably longer release duration compared to the vaccine. Mice injected with particle formulations co-encapsulating kPR8 and α-GalCer were protected from a lethal influenza virus infection 30 weeks after vaccination. This study demonstrates that PLGA MP based vaccines are promising for providing effective vaccination and possibly for replacing multiple doses with a single injection.

Converging paths: Microneedle-based dual intervention of IL-23/IL-17 axis and granuloma formation in rheumatoid nodules

Rheumatoid nodules (RNs) are an extra-articular manifestation of rheumatoid arthritis and are frequently observed in patients with autoimmune and inflammatory conditions. The development of RNs involves several stages, including inflammation of blood vessels, cell death triggered by medications, and infiltration of inflammatory cells leading to nodule formation. Recent studies highlight the importance of the IL-23/IL-17 axis and the migration of chronic inflammatory cells in this process, forming palisading granulomas. Current treatments often fail to manage RNs effectively because they tend to reoccur and appear in multiple locations. This study proposes a new therapeutic strategy combining corticosteroid treatment with gene silencing therapy using small interfering RNA (siRNA) targeting IL-23. Targeting these inflammatory pathways simultaneously aims to reduce both the size and number of nodules, potentially shortening the treatment duration. An innovative delivery system utilizing lipid-polymer hybrid nanoparticles (LPNs) and hyaluronic acid-based dissolving microneedles (MNs) is proposed to be developed. The LPNs will be designed with DOTAP (1,2-dioleoyl-3-trimethylammonium propane) and DSPE-PEG (distearoyl-phosphoethanolamine-polyethylene glycol) as the lipid core, along with poly-lactic-co-glycolic acid (PLGA) polymer. These MN patches would improve the skin’s permeability, allowing LPN carrying the siRNA and corticosteroid to penetrate effectively. This non-invasive approach is expected to enhance the diffusion of LPNs into the skin, thereby increasing the availability of the therapeutic payload. Therefore, we hypothesize that targeting the IL-23/IL-17 axis and granuloma formation with the synergistic combination of targeted therapy and advanced delivery technology will revolutionize the treatment of RNs.

PLGA nanoparticle-encapsulated lysostaphin for the treatment of Staphylococcus aureus infections

Staphylococcus aureus possesses the ability to become pathogenic, leading to severe and life-threatening infections. Its methicillin-resistant variant MRSA has garnered high-priority status due to its increased morbidity and associated mortality. This emphasizes the urgency for novel anti-staphylococcal agents. The bacteriocin lysostaphin stands out for its remarkable bactericidal activity against S. aureus, including MRSA, outperforming conventional antibiotics. However, the clinical application of lysostaphin faces challenges, including enzymatic activity loss under physiological conditions and potential immunogenicity. This study introduces a novel approach by encapsulating lysostaphin within polylactic-co-glycolic acid (PLGA) nanoparticles, a biodegradable copolymer known for its biocompatibility and sustained drug release ability. The study assesses the antimicrobial activity of lysostaphin-loaded PLGA nanoparticles against different S. aureus strains, and we also used GFP-expressing S. aureus for facilitating its traceability in planktonic, biofilm, and intracellular infection models. The results showed the significant reduction in bacteria viability both in planktonic and biofilm states. The in vitro intracellular infection model demonstrated the significantly enhanced efficiency of the developed nanoparticles compared to the treatment with the free bacteriocin. This research presents lysostaphin encapsulation within PLGA nanoparticles and offers promising avenues for enhancing lysostaphin's therapeutic efficacy against S. aureus infections.

Nanoparticle-based delivery of harmine: A comprehensive study on synthesis, characterization, anticancer activity, angiogenesis and toxicity Evaluation

The effective treatment of cancer presents numerous challenges, including drug resistance and the risk of detrimental effects on normal tissues. Harmine, a beta-carboline alkaloid, has demonstrated diverse biological properties. This study aimed to synthesize and characterize harmine encapsulated in polylactic-co-glycolic acid (PLGA) nanoparticles (Ha-PLGA-NPs) to investigate their potential as agents against cancer and angiogenesis. The synthesized Ha-PLGA-NPs were thoroughly characterized, exhibiting a connected rod-shaped crystal which some retaining the spherical shape of nanoparticles with an average size of 302.96 nm. Furthermore, the nanoparticles demonstrated a dispersion index of 0.23 and a surface charge of −16.51 mV. In vitro cytotoxicity assays conducted on the breast cancer cell line (MCF-7) revealed that Ha-PLGA-NPs possessed significant cytotoxic properties, with an observed IC50 value of 87.74 μg/mL. Notably, no substantial cytotoxicity was observed in human foreskin fibroblasts, indicating a favorable selectivity towards cancer cells. Evaluation of the anti-angiogenic activity of Ha-PLGA-NPs demonstrated a concentration-dependent inhibition of angiogenesis. Mechanistic investigations indicated that the observed inhibition was mediated through the regulation of key genes involved in angiogenesis, including caspase 3, caspase 9, VEGF, and VEGF-R. In vivo studies involving dietary administration of Ha-PLGA-NPs in mice revealed improvements in weight gain, feed intake, liver enzyme levels, and redox potential. These findings underscore the potential of Ha-PLGA-NPs as a promising therapeutic agent for cancer treatment. The observed effects are attributed to their ability to induce programmed cell death and inhibit angiogenesis, thus offering a multifaceted approach to combat cancer.

Systematic Scrutinization of Vital factors for the Development of Efficient Cisplatin-Quercetin Loaded Bionanomicelles

The present work aims to optimize and assess the Cisplatin (CIS) and Quercetin (QCT)-loaded biodegradable polymeric nanomicelles (PNM). The development of a quantitative method for the estimation of CIS and QCT in pharmaceutical dosage form was another objective. The aluminum plates coated with silica gel F254 used for separation of both the drugs employing Toluene: Methanol: Ethyl acetate: DMF: Triethylamine (5:0.5:3.5:1:1 drop % v/v/v/v/v) as mobile phase. Results of the validation parameter indicate that the developed method was precise, accurate, and robust. CIS and QCT-loaded PNM formulated using solvent evaporation technique employing poly lactic-co-glycolic acid (PLGA) 50:50. The Quality by Design (QbD) was accomplished to identify the critical manufacturing attributes and critical process parameters. Optimization of the formulation was performed by central composite design using particle size and % encapsulation efficiency as dependent variables. The amount of PLGA and Span selected as independent variables. Statistically substantial variables identified using regression analysis and analysis of variance. A diffusion study revealed that optimized nanomicelles were capable to sustain the drug release up to 8h. Zeta sizer, TEM confirmed the stability and nano-sized nanoparticles. CIS-QCT PNM was found to be an alternate route to systemic treatment.

Directed Assembly of Elastic Fibers via Coacervate Droplet Deposition on Electrospun Templates.

Elastic fibers provide critical elasticity to the arteries, lungs, and other organs. Elastic fiber assembly is a process where soluble tropoelastin is coacervated into liquid droplets, cross-linked, and deposited onto and into microfibrils. While much progress has been made in understanding the biology of this process, questions remain regarding the timing of interactions during assembly. Furthermore, it is unclear to what extent fibrous templates are needed to guide coacervate droplets into the correct architecture. The organization and shaping of coacervate droplets onto a fiber template have never been previously modeled or employed as a strategy for shaping elastin fiber materials. Using an in vitro system consisting of elastin-like polypeptides (ELPs), genipin cross-linker, electrospun polylactic-co-glycolic acid (PLGA) fibers, and tannic acid surface coatings for fibers, we explored ELP coacervation, cross-linking, and deposition onto fiber templates. We demonstrate that integration of coacervate droplets into a fibrous template is primarily influenced by two factors: (1) the balance of coacervation and cross-linking and (2) the surface energy of the fiber templates. The success of this integration affects the mechanical properties of the final fiber network. Our resulting membrane materials exhibit highly tunable morphologies and a range of elastic moduli (0.8-1.6 MPa) comparable to native elastic fibers.

Decitabine-based nanoparticles for enhanced immunotherapy of hepatocellular carcinoma via DNA hypermethylation reversal

DNA methyltransferase (DNMT) inhibitor represents the first clinical breakthrough via targeting aberrant cancer epigenomes. Demethylation drugs such as decitabine can restore tumor suppressor gene (TSG) expression and function to achieve anti-tumor effect. Despite DNMT inhibitors have shown significant efficacy for treating leukemia, their application in solid tumor such as HCC is limited due to short in vivo half-lives. In this study, the DNMT1 inhibitor decitabine was first loaded into the Polylactic-co-glycolic acid (PLGA) spherical nanoparticles (Dec@PLGA). The vesicle of PD-L1 antibody and macrophage membrane (aMM) was further coated onto the surface of Dec@PLGA to finally synthesize Dec@PLGA@aMM. Dec@PLGA@aMM was in uniformed spherical structure with hydrodynamic particle size of 95.7 ± 9.1 nm and surface zeta potential of −15.1 ± 3.3 mV. Dec@PLGA@aMM significantly increased the expression of both p14 and p16 in a concentration-dependent manner. Dec@PLGA@aMM could enhance the tumor suppression through restoration of TSGs, which were epigenetically silenced by DNA hypermethylation. The Dec@PLGA@aMM group showed significantly (P < 0.05) less tumor volume than PBS group, PLGA@MM group, aPD-L1 group, PLGA@aMM group, decitabine group, Dec + aPD-L1 group, and Dec@PLGA@MM group. The decitabine could enhance aPD-L1-mediated immunotherapy of HCC via epigenetic alteration. This novel targeted PLGA NPs are aimed to treat HCC by decreasing DNA methylation and blocking PD-L1, thus providing new ideas for effective treatments via epigenetic alteration for HCC patients clinically.

Inhaled Macrophage Apoptotic Bodies-Engineered Microparticle Enabling Construction of Pro-Regenerative Microenvironment to Fight Hypoxic Lung Injury in Mice.

Oxygen therapy cannot rescue local lung hypoxia in patients with severe respiratory failure. Here, an inhalable platform is reported for overcoming the aberrant hypoxia-induced immune changes and alveolar damage using camouflaged poly(lactic-co-glycolic) acid (PLGA) microparticles with macrophage apoptotic body membrane (cMAB). cMABs are preloaded with mitochondria-targeting superoxide dismutase/catalase nanocomplexes (NCs) and modified with pathology-responsive macrophage growth factor colony-stimulating factor (CSF) chains, which form a core-shell platform called C-cMAB/NC with efficient deposition in deeper alveoli and high affinity to alveolar epithelial cells (AECs) after CSF chains are cleaved by matrix metalloproteinase 9. Therefore, NCs can be effectively transported into mitochondria to inhibit inflammasome-mediated AECs damage in mouse models of hypoxic acute lung injury. Additionally, the at-site CSF release is sufficient to rescue circulating monocytes and macrophages and alter their phenotypes, maximizing synergetic effects of NCs on creating a pro-regenerative microenvironment that enables resolution of lung injury and inflammation. This inhalable platform may have applications to numerous inflammatory lung diseases.

Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy

BackgroundActive targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering.MethodsNExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice.ResultsWe report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer.ConclusionsThese advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Nerve tissue regeneration based on magnetic and conductive bifunctional hydrogel scaffold

The growth of neurons is often influenced by magnetic and electrical physical factors, and there is more and more research focused on designing a magnetic and conductive engineering scaffolds for nerve injury repair. In this study, electrospun poly lactic-co-glycolic acid (PLGA) fibers containing Fe3O4 magnetic nanoparticles were cryo-cut into magnetic short fibers (MSFs) and subsequently incorporated into sodium alginate (SA)/carboxymethyl chitosan (CMCS) hydrogel along with the addition of multi-wall carbon nanotubes (MWCNTs). MSFs can also achieve alignment by external magnetic fields within the hydrogel to construct magnetic and conductive bifunctional MSF/MWCNT/SA/CMCS hydrogel with anisotropic structure. The magnetic-conductive bifunctional hydrogel exhibited good magnetic responsiveness, electrically activity and mechanical property, in which both conductivity and mechanical property increased with the enhancement of MWCNTs contents. Notably, appearing of aligned structure significantly promoted the mechanical property of MSF/SA/CMCS hydrogel. The MSF/SA/CMCS hydrogel with aligned structure also facilitated greater primary neuron cells proliferation than random ones. Compared with individual magnetic or conductive hydrogel, there was a significant increase in cell viability in the primary cultured cortical neurons on MSF/MWCNT/SA/CMCS hydrogel with aligned structure. Simultaneously, electrical stimulation (ES) combined with magnetic stimulation (MS) delivered via magnetic and conductive bifunctional MSF/MWCNT/SA/CMCS hydrogel with aligned structure produced a better effect on promoting neuronal growth compared with individual ES or MS. Besides, hot plate measurement indicated that MSF/MWCNT/SA/CMCS hydrogel with aligned structure and MS significantly decreased the mice licking latency after sciatic nerve injury. Animal behavior studies confirmed the protective role of synergistic MS with magnetic hydrogel. Such hydrogel scaffolds have long-term potential for nerve tissue regeneration.

Targeting pentamidine towards CD44-overexpressing cells using hyaluronated lipid-polymer hybrid nanoparticles.

Biodegradable nanocarriers possess enormous potential for use as drug delivery systems that can accomplish controlled and targeted drug release, and a wide range of nanosystems have been reported for the treatment and/or diagnosis of various diseases and disorders. Of the various nanocarriers currently available, liposomes and polymer nanoparticles have been extensively studied and some formulations have already reached the market. However, a combination of properties to create a single hybrid system can give these carriers significant advantages, such as improvement in encapsulation efficacy, higher stability, and active targeting towards specific cells or tissues, over lipid or polymer-based platforms. To this aim, this work presents the formulation of poly(lactic-co-glycolic) acid (PLGA) nanoparticles in the presence of a hyaluronic acid (HA)-phospholipid conjugate (HA-DPPE), which was used to anchor HA onto the nanoparticle surface and therefore create an actively targeted hybrid nanosystem. Furthermore, ionic interactions have been proposed for drug encapsulation, leading us to select the free base form of pentamidine (PTM-B) as the model drug. We herein report the preparation of hybrid nanocarriers that were loaded via ion-pairing between the negatively charged PLGA and HA and the positively charged PTM-B, demonstrating an improved loading capacity compared to PLGA-based nanoparticles. The nanocarriers displayed a size of below 150nm, a negative zeta potential of -35mV, a core-shell internal arrangement and high encapsulation efficiency (90%). Finally, the ability to be taken up and exert preferential and receptor-mediated cytotoxicity on cancer cells that overexpress the HA specific receptor (CD44) has been evaluated. Competition assays supported the hypothesis that PLGA/HA-DPPE nanoparticles deliver their cargo within cells in a CD44-dependent manner.

Double synergic chitosan-coated poly (lactic-co-glycolic) acid nanospheres loaded with nucleic acids as an intranasally administered vaccine delivery system to control the infection of foot-and-mouth disease virus

The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

Encapsulation of silver nanoplates into poly(lactic-co-glycolic) acid nanoparticles and the antibacterial activity against intracellular bacteria

Abstract We encapsulated silver nanoplates (AgNPLs) into poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The encapsulation stabilized the AgNPLs in a physiological environment and the antibacterial activity of the AgNPLs against planktonic bacteria was reduced. However, the PLGA nanoparticles encapsulating the AgNPLs were internalized into macrophages and showed antibacterial activity against intracellular bacteria. AgNPL-loaded PLGA nanoparticles are promising for treating intractable infectious diseases caused by bacteria-infecting macrophages.

Application of PLGA in Tumor Immunotherapy.

Biodegradable polymers have been extensively researched in the field of biomedicine. Polylactic-co-glycolic acid (PLGA), a biodegradable polymer material, has been widely used in drug delivery systems and has shown great potential in various medical fields, including vaccines, tissue engineering such as bone regeneration and wound healing, and 3D printing. Cancer, a group of diseases with high mortality rates worldwide, has recently garnered significant attention in the field of immune therapy research. In recent years, there has been growing interest in the delivery function of PLGA in tumor immunotherapy. In tumor immunotherapy, PLGA can serve as a carrier to load antigens on its surface, thereby enhancing the immune system's ability to attack tumor cells. Additionally, PLGA can be used to formulate tumor vaccines and immunoadjuvants, thereby enhancing the efficacy of tumor immunotherapy. PLGA nanoparticles (NPs) can also enhance the effectiveness of tumor immunotherapy by regulating the activity and differentiation of immune cells, and by improving the expression and presentation of tumor antigens. Furthermore, due to the diverse physical properties and surface modifications of PLGA, it has a wider range of potential applications in tumor immunotherapy through the loading of various types of drugs or other innovative substances. We aim to highlight the recent advances and challenges of plga in the field of oncology therapy to stimulate further research and development of innovative PLGA-based approaches, and more effective and personalized cancer therapies.

Drug-loaded polymer-coated silver nanoparticles for lung cancer theranostics.

Lung cancer is the leading cause of death in cancer across the globe. To minimize these deaths, the replacement of traditional chemotherapy with novel strategies is significant. We have developed a nanotheranostic approach using silver nanoparticles for imaging and treatment. Silver nanoparticles (AgNPs) are fabricated by chemical reduction method. The formulation of AgNPs was confirmed by different characterization techniques like stability test, UV-Visible spectroscopy, Confocal Raman Spectroscopy, and Energy-Dispersive X-ray analysis. Further, AgNPs are coated with poly lactic-co-glycolic acid (PLGA) and then loaded with paclitaxel(Pac). Then the drug-loaded PLGA-coated AgNPs were characterized for size and zeta potential measurement by zetasizer, surface morphology study by atomic force microscopy, Fourier transform infrared spectroscopy, and release kinetics study. The imaging and anticancer properties of these nanoformulations are investigated using lung cancer cell lines. The results proved that the particles are in the nanometer range with smooth surface morphology. Moreover, the drug-loaded NPs showed a sustained release of the drug for a longer period of time. Further the formulations showed imaging property with greater anticancer efficacy. Thus, the results suggest the effective use of these nanoformulation in both lung cancer imaging and treatment using a simple and efficient approach.

Dual targeting of inflammation and β-cell dysfunction for therapy of diabetes mellitus

Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by β-cell loss and inflammation. From a therapeutic standpoint, it would be necessary to halt the uncontrolled inflammatory response and to enable the regeneration of the damaged β-cells. In this work, to achieve the latter two drug-loaded nanocarrier systems have been developed and evaluated in-vivo in DM mouse model. For β-cell proliferation, small chitosan (CS) nanoparticles (NPs) (201 ± 30 nm) were loaded with 4b, a selective inhibitor of DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A). To reduce inflammation, large poly lactic-co-glycolic acid (PLGA) microparticles (MPs) (1172 ± 77 nm) were encapsulated with BI-605906, an inhibitor of IKKβ (inhibitor of kappa B kinase beta), acting as an inhibitor of an inhibitor. The EE% values were 90 ± 4.2 % and 87 ± 4.46 % for 4b–CS–NPs and BI-605906-PLGA-MPs, respectively. In-vivo biodistribution studies indicated the ability of both particles to accumulate in the pancreas. For CS-NPs, this was achieved as a function of the increased vascular permeability in DM, whereas for PLGA-MPs, this was achieved as function of macrophage uptake. Treatment with 4b–CS–NPs (but not the unloaded drug) reduced blood glucose levels (BGLs) and elevated cyclin D1 (CD1) gene expression indicating the successful ability of the NP system in promoting β-cells proliferation. Although treatment with free BI-605906 showed a modest reduction in BGLs, BI-605906-PLGA-MPs showed no improvement in BGLs. The latter could possibly be attributed to sub-optimal dosing. These results indicate that 4b–CS–NPs have the potential to lower BGLs by promoting β-cell proliferation and restoring pancreatic function. Further optimization is needed for BI-605906-PLGA-MPs, which may enhance therapeutic outcome by dual therapy.

Nanofiber Hydrogel Drug Delivery System for Prevention of Postsurgical Intestinal Adhesion.

Intestinal adhesion is one of the complications that occurs more frequently after abdominal surgery. Postsurgical intestinal adhesion (PIA) can lead to a series of health problems, including abdominal pain, intestinal obstruction, and female infertility. Currently, hydrogels and nanofibrous films as barriers are often used for preventing PIA formation; however, these kinds of materials have their intrinsic disadvantages. Herein, we developed a dual-structure drug delivery patch consisting of poly lactic-co-glycolic acid (PLGA) nanofibers and a chitosan hydrogel (NHP). PLGA nanofibers loaded with deferoxamine mesylate (DFO) were incorporated into the hydrogel; meanwhile, the hydrogel was loaded with anti-inflammatory drug dexamethasone (DXMS). The rapid degradation of the hydrogel facilitated the release of DXMS at the acute inflammatory stage of the early injury and provided effective anti-inflammatory effects for wound sites. Moreover, PLGA composite nanofibers could provide sustained and stable release of DFO for promoting the peritoneal repair by the angiogenesis effects of DFO. The in vivo results indicated that NHP can effectively prevent PIA formation by restraining inflammation and vascularization, promoting peritoneal repair. Therefore, we believe that our NHP has a great potential application in inhibition of PIA.

Design and in vitro evaluation of curcumin-loaded PLGA nanoparticle-embedded sodium alginate/gelatin 3D printed scaffolds for Alzheimer's disease

BackgroundTargeted nanoparticles (NPs) are aimed at improving clinical outcomes by enhancing the diagnostic and therapeutic efficacy of drugs in the treatment of Alzheimer's disease (AD). MethodsCurcumin (CUR)-loaded poly-lactic-co-glycolic acid (PLGA) NPs (CNPs) were produced to demonstrate a prolonged release and successfully embedded into 3D printed sodium alginate (SA)/gelatin (GEL) scaffolds that can dissolve rapidly sublingually. Characterization and in vitro activity of the NPs and scaffolds were evaluated. ResultsBased on the in vitro drug release studies, 99.6 % of the encapsulated CUR was released in a controlled manner within 18 days for the CNPs. In vitro cell culture studies showed that all samples exhibited cell viability above 84.2 % and no significant cytotoxic effect on SH-SY5Y cells. The samples were analyzed through 2 different pathways by PCR analysis. Real-time PCR results indicated that CNP and CNP-embedded SA/GEL scaffolds (CNPSGS) may show neuroprotective effects by modulating the Wnt/β-catenin pathway. The gene expression level of β-catenin slightly increased compared to the gene expression levels of other proteins and enzymes with these treatments. However, the PI3K/Akt/GSK-3β signaling pathway was regulated at the same time because of the crosstalk between these 2 pathways. ConclusionCNPSGS might be an effective therapeutic alternative for AD treatment.

Engineering pH-sensitive dissolution of lipid-polymer nanoparticles by Eudragit integration impacts plasmid DNA (pDNA) transfection

Lipid-polymer nanoparticles offer a promising strategy for improving gene nanomedicines by combining the benefits of biocompatibility and stability associated with the individual systems. However, research to date has focused on poly-lactic-co-glycolic acid (PLGA) and resulted in inefficient transfection. In this study, biocompatible Eudragit constructs E100 and RS100 were formulated as lipid-polymer nanoparticles loaded with pDNA expressing red fluorescent protein (RFP) as a model therapeutic. Using a facile nanoprecipitation technique, a core–shell structure stabilised by lipid-polyethylene glycol (PEG) surfactant was produced and displayed resistance to ultracentrifugation. Both cationic polymers E100 (pH-sensitive dissolution at 5) and RS100 (pH-insensitive dissolution) produced 150–200 nm sized particles with a small positive surface charge (+3–5 mV) and high pDNA encapsulation efficiencies (EE) of 75–90%. The dissolution properties of the Eudragit polymers significantly impacted the biological performance in human embryonic kidney cells (HEK293T). Nanoparticles composed of polymer RS100 resulted in consistently high cell viability (80–100%), whereas polymer E100 demonstrated dose-dependent behaviour (20–90% cell viability). The low dissolution of polymer RS100 over the full pH range and the resulting nanoparticles failed to induce RFP expression in HEK293T cells. In contrast, polymer E100-constructed nanoparticles resulted in reproducible and gradually increasing RFP expression of 26–42% at 48–72 h. Intraperitoneal (IP) injection of the polymer E100-based nanoparticles in C57BL/6 mice resulted in targeted RFP expression in mouse testes with favourable biocompatibility one-week post-administration. These findings predicate Eudragit based lipid-polymer nanoparticles as a novel and effective carrier for nucleic acids, which could facilitate pre-clinical evaluation and translation of gene nanomedicines.