PLGA Nanoparticles Research Articles

Therapeutic Potential of 18-β-Glycyrrhetinic Acid-loaded Poly (lactic-co-glycolic acid) Nanoparticles on Cigarette Smoke-Induced in-vitro model of COPD

Chronic obstructive pulmonary disease (COPD) is strongly linked to cigarette smoke, which contains toxins that induce oxidative stress and airway inflammation, ultimately leading to premature airway epithelial cell senescence and exacerbating COPD progression. Current treatments for COPD are symptomatic and hampered by limited efficacy and severe side effects. This highlights the need to search for an optimal therapeutic candidate to address the root causes of these conditions. This study investigates the possible potential of poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles encapsulating the plant-based bioactive compound 18-β-glycyrrhetinic acid (18βGA) as a strategy to intervene in cigarette smoke extract (CSE)-induced oxidative stress, inflammation, and senescence, in vitro. We prepared 18βGA-PLGA nanoparticles, and assessed their effects on cell viability, reactive oxygen species (ROS) production, anti-senescence properties (expression of senescence-associated β galactosidase and p21 mRNA), and expression of pro-inflammatory genes (CXCL-1, IL-6, TNF-α) and inflammation-related proteins (IL-8, IL-15, RANTES, MIF). The highest non-toxic concentration of 18βGA-PLGA nanoparticles to healthy human broncho epithelial cell line BCiNS1.1 was identified as 5µM. These nanoparticles effectively mitigated cigarette smoke-induced inflammation, reduced ROS production, protected against cellular aging, and counteracted the effects of CSE on the expression of the inflammation-related genes and proteins. This study underscores the potential of 18βGA encapsulated in PLGA nanoparticles as a promising therapeutic approach to alleviate cigarette smoke-induced oxidative stress, inflammation, and senescence. Further research is needed to explore the translational potential of these findings in clinical and in vivo settings.

Pluronic F127/lecithin PLGA nanoparticles as carriers of monocyte-targeted jakinibs: a potential therapeutic platform.

Aim: In this study, PLGA nanoparticles (PNPs) emulsified in Pluronic F127 (F127)/Lecithin (LEC) were designed to load Itacitinib (ITA), a selective JAK1 inhibitor, for targeting human monocytes.Materials & methods: The physicochemical characteristics of empty and ITA-loaded F127/LEC PNPs were analyzed. The binding and internalization of NPs in leukocytes were evaluated. The effect of NPs on monocyte activation and JAK1 inhibition was assessed.Results: F127/LEC PNPs were selectively bound and internalized by monocytes, sparing other leukocytes. ITA-F127/LEC PNPs significantly dampened monocyte activation. They also inhibited the monocyte's ability to promote T-cell proliferation and inhibited proinflammatory cytokine production.Conclusion: ITA-loaded F127/LEC PNPs showed potential for monocyte-targeted therapy, offering new avenues for disease treatment.

Macrophage Membrane-Coated Nanoparticles for the Delivery of Natamycin Exhibit Increased Antifungal and Anti-Inflammatory Activities in Fungal Keratitis.

This study aims to explore the efficacy and safety of macrophage membrane-coated nanoparticles for the delivery of natamycin (NAT) in the therapy of fungal keratitis (FK). Macrophage membranes were isolated and identified by immunofluorescence staining (IFS). NAT was encapsulated into poly(lactic-co-glycolic acid) (PLGA). Fungal stimulated macrophage membranes (M1) or unstimulated membranes (M) were separately mixed and sonicated with PLGA nanoparticles. The biocompatible nanoparticles (PLGA-NAT, PLGA-NAT@M, and PLGA-NAT@M1) were characterized with zeta-sizer analysis, transmission electron microscopy (TEM), and Western blot. Drug encapsulation and loading efficiency and the release of NAT in the nanoparticles were detected by ultraviolet spectrophotometry. The cytotoxicity, ocular surface toxicity and irritability, and systemic safety of nanoparticles with different concentrations were assessed. In vitro, we examined the antifungal properties of the nanoparticles. The eye surface retention time, drug release, and curative effects on FK were evaluated in vitro and in vivo. IFS results showed the separation of the macrophage membrane and nucleus. The prepared nanoparticles had a typical "core-shell" structure and uniform nanometer size, and the membrane proteins were retained on the membrane allowing to exert functional effects of macrophage. The loading efficiencies of PLGA-NAT@M and PLGA-NAT@M1 were 7.6 and 6.7%, respectively. The encapsulation efficiencies of PLGA-NAT@M and PLGA-NAT@M1 were 51.2 and 41.5%, respectively. PLGA-NAT@M and PLGA-NAT@M1 could gradually release NAT and reduce the clearance of the ocular surface. Macrophage membranes enhanced the antifungal activity of PLGA-NAT. Furthermore, the membrane coated with macrophage increased the biocompatibility and decreased the corneal toxicity of nanoparticles. In vivo, PLGA-NAT@M1 significantly alleviated the severity of FK. In vitro, PLGA@M and PLGA@M1 reduced the protein levels of inflammatory cytokines after fungal stimulation. The prepared PLGA-NAT@M1 has good physical properties and biosafety. It could evade ocular surface clearance, release NAT gradually, and achieve high antifungal and anti-inflammatory efficiencies to FK. Macrophage membrane-coated nanoparticles clinically have high application potential to the treatment of FK.

A baculoviral gene and drug-eluting (GDES) stent to promote re-endothelialization and prevent restenosis caused by atherosclerosis

Abstract Background Coronary artery disease (CAD) is a prevalent condition affecting approximately one in every 20 individuals over the age of 20, resulting in significant health and economic burdens worldwide. Atherosclerosis, characterized by plaque buildup in the arteries, is a leading cause of CAD, involving endothelial dysfunction, inflammation, and smooth muscle cell hyperproliferation. The standard interventions for CAD, namely bare-metal stents (BMS) or drug-eluting stents (DES), often lead to complications such as blood clotting, inflammation, and arterial re-narrowing, necessitating further interventions and potentially leading to severe outcomes like heart failure, stroke, or death. Additionally, the TGFβ1 gene regulates SMC proliferation and ECM secretion, promoting endothelial cell proliferation, inhibiting smooth muscle cell hyperproliferation, reducing reactive oxygen species production. Purpose This innovative stent aims to mitigate complications associated with conventional stents by promoting endothelial health and preventing inflammation and hyperproliferation downstream. The purpose of this study is to design a new gene and drug eluting stent and evaluate their preclinical efficacy and safety in addressing some of the key limitations of currently available coronary stents. Methods The TGFβ1 expressing baculoviruses loaded PLGA nanoparticles are prepared by double emulsion solvent evaporation method. The formulated nanoparticles were characterized by their surface morphology, particle size, zeta potential, and in vitro release. Moreover, the designed nanoparticles undergo a further investigation for their therapeutic efficiency using cell lines. The GDES is synthesized by dip-coating a BMS into a solution containing Everolimus and genipin carrying baculoviruses expressing TGFβ1 in nanoparticles. The stent elutes the gene and drug over specific durations pertaining to a sustained release profile. The study assesses the functionality and safety of the GDES through in vitro and in vivo experiments, including cell culture studies and animal models. Results The PLGA nanoparticles at 115.3±1.4 nm with a polydipersity (pdi) index of 0.152 have a sustained release profile for the TGFβ1 expressing baculovirus. The findings demonstrate that the GDES effectively promotes endothelial health and prevents inflammation and hyperproliferation downstream. The expression of TGFβ1 facilitates the formation of a fully reconstituted endothelial lining, reducing the risk of complications. Additionally, the prolonged release of Everolimus prevents inflammation and the progression of neointimal hyperplasia. The stent coating and system exhibit non-cytotoxicity and hemocompatibility, ensuring safety during expansion and degradation over time. Overall, the combined action of gene and drug elution in the GDES shows promising results in addressing current complications associated with cardiovascular stents.

Berberine-loaded PLGA nanoparticles alleviate ulcerative colitis by targeting IL-6/IL-6R axis

AimsThe present study aims to develop a nano-delivery system that encapsulates berberine (BBR) into PLGA-based nanoparticles (BPL-NPs), to treat ulcerative colitis (UC). Furthermore, the therapeutic efficacy and molecular targeting mechanisms of BPL-NPs in the management of UC are thoroughly examined.MethodsEmulsion solvent-driven methods were used to self-assemble BBR and PLGA into nanoparticles, resulting in the development of the nano-delivery system (BPL-NPs). The therapeutic effectiveness of BPL-NPs was evaluated using a dextran sulfate sodium (DSS)-induced model of ulcerative colitis in mice and a lipopolysaccharide (LPS)-induced model of inflammation in THP-1 macrophages. The interaction between Mφs and NCM-460 cells was investigated using a co-culture system. The molecular targeting ability of BPL-NPs in the treatment of UC was validated through in vitro as well as in vivo experiments.ResultsThe BPL-NPs demonstrated a particle size of 184 ± 22.4 nm, enhanced dispersibility in deionized water, and a notable encapsulation efficiency of 31.1 ± 0.2%. The use of BPL-NPs clearly improved the clinical symptoms and pathological changes associated with UC in mice while also ensuring minimal toxicity. In addition, BPL-NPs improved intestinal epithelial cell apoptosis and enhanced the function of the intestinal barrier by inhibiting M1 Mφs infiltration and IL-6 signaling pathway in mice with UC. Furthermore, the BPL-NPs were found to selectively target the IL-6/IL-6R axis during the M1 Mφs-induced apoptosis of NCM460 cells.ConclusionThe BPL-NPs were confirmed to harbor anti-inflammatory effects both in vitro and in vivo, along with enhanced water solubility and bioactivity. In addition, the precise targeting of the IL-6/IL-6R axis was confirmed as the mechanism by which the BPL-NPs exerted therapeutic effects in UC, as demonstrated in both in vitro as well as in vivo studies.Graphical

Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy.

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy.

Enhancing Vaccine Efficacy with Polyethylenimine-Modified Lovastatin-Loaded Nanoparticle Pickering Emulsion Adjuvant.

Despite the potent immunoadjuvant properties of mevalonate pathway inhibitors, their application is constrained by poor solubility and instability. In this study, we developed a cationic nanoparticle-stabilized Pickering emulsion loaded with lovastatin (Lov-PPE), using polyethylenimine (PEI)-modified PLGA nanoparticles and squalene as carriers. The system was prepared and tested by evaluating the physicochemical properties and adjuvant efficacy of the Lov-PPE. Lov-PPE/O demonstrated good particle size distribution and zeta potential, with an adsorption efficiency of up to 73.07%. The immunization results showed that Lov-PPE/O significantly promoted the production of OVA-specific IgG antibodies, activated CD4+ and CD8+ T cells, and induced a strong mixed Th1/2 immune response. Additionally, safety assessments indicated that Lov-PPE/O has good in vivo safety. This study demonstrates that the PEI-modified lovastatin PLGA nanoparticle Pickering emulsion (Lov-PPE) is an effective vaccine adjuvant capable of significantly enhancing humoral and cellular immune responses while possessing good safety, offering a new strategy for vaccine formulation development.

Exploring Nanocarriers for Boosting Entacapone Bioavailability: A Journey through System Characterization and Assessment of Toxicity and Pharmacological and 2D Permeability Paybacks.

Catechol-O-methyltransferase inhibitors (iCOMT), such as entacapone, have been successfully employed to treat tremor-related symptoms of Parkinson's disease. However, iCOMT has been associated with a short half-life and poor oral bioavailability. Nanobased drug delivery systems have often been used to overcome this type of setbacks. Therefore, entacapone was encapsulated in PEGylated poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) via a nanoprecipitation process, as well as in PEGylated nanostructured lipid carriers (NLCs) using a solvent emulsification/evaporation method. Both nanoformulations presented sub-200 nm populations, with zeta-potential (ZP) values close to -30 mV, and showed stability at different pHs, while maintaining their physicochemical properties mostly intact, presenting only a change in their superficial charge (ZP values), indicating their interaction. Both nanoformulations presented interaction with mucins, which anticipates good permeation and bioavailability for oral and topical administration. No cytotoxic effects were observed for lyophilized PLGA NPs encapsulating entacapone, in which 2-hydroxypropyl-ß-cyclodextrin (HPβCD) was used as a cryoprotectant at 3% concentration (HP-PLGA@Ent), in human hepatocellular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), or human epithelial colorectal adenocarcinoma (Caco-2) cell lines. Conversely, NLCs encapsulating entacapone (W-NLCs@Ent) presented cytotoxic effects on the HepG2 cell line, likely due to intracellular lipid accumulation or storage. Both nanoformulations maintained a COMT inhibition effect in HepG2 cells, using 3-BTD as the COMT probe. An increase of entacapone permeability in both monolayer and coculture models (Caco-2 and Caco-2/HT29-MTX, respectively) was observed for the developed nanoformulations. Overall, this work shows that encapsulated entacapone in different nanocarriers could be a stimulating alternative to solve entacapone setbacks, since they improve its physicochemical properties and permeability while still maintaining the COMT inhibitory activity.

Curcumin attenuates smoking and drinking activated NF-κB/IL-6 inflammatory signaling axis in cervical cancer

BackgroundHigh-risk strains of HPV are known to cause cervical cancer. Multiple clinical studies have emphasized that smoking and drinking are critical risk factors for cervical cancer and its high-grade precursors. In this study, we investigated if smoking and/or drinking augment the molecular mechanisms of cervical carcinogenesis and defined a potential therapeutic approach for their attenuation.MethodsThe impact of benzo[a]pyrene (B[a]P) and/or ethanol (EtOH) exposure on cervical cancer cells was assessed by measuring changes in their cell migration and invasion characteristics. Expression of HPV16 E6/E7, NF-κB, cytokines, and inflammation mediators was determined using qRT-PCR, immunoblotting, ELISA, luciferase reporter assay, and confocal microscopy. Herein, we used curcumin (Cur), and PLGA nanoparticle formulation of curcumin (PLGA-Cur) and determined effectiveness of free Cur and PLGA-Cur formulation on smoking and drinking activated NF-κB/IL-6 mediated inflammatory signaling pathways using in vitro cervical cancer models.ResultsTreatments with B[a]P and/or EtOH altered the expression of HPV16 E6/E7 oncogenes and EMT markers in cervical cancer cells; it also enhanced migration and invasion. In addition, B[a]P and/or EtOH exposure promoted inflammation pathways through TNF-α and NF-κB signaling, leading to IL-6 upregulation and activation of VEGF. The molecular effects caused by B[a]P and/or EtOH exposure were effectively attenuated by curcumin (Cur)/PLGA-Cur treatment.ConclusionsThese data suggest a molecular link between smoking, drinking, and HPV infectivity in cervical carcinogenesis. In addition, attenuation of these effects by treatment with Cur/PLGA-Cur treatment, implies the role of curcumin in cervical cancer prevention and treatment.

Partial Protection of Goats against Haemonchus contortus Achieved with ADP-Ribosylation Factor 1 Encapsulated in PLGA Nanoparticles.

Haemonchus contortus (H. contortus), a nematode with global prevalence, poses a major threat to the gastrointestinal health of sheep and goats. In an effort to combat this parasite, a nanovaccine was created using a recombinant ADP-ribosylation factor 1 (ARF1) antigen encapsulated within poly lactic-co-glycolic acid (PLGA). This study aimed to assess the effectiveness of this nanovaccine in providing protection against H. contortus infection. Fifteen goats were randomly divided into three groups. The experimental group received two doses of the PLGA encapsulated rHcARF1 (rHcARF1-PLGA) nanovaccine on days 0 and 14. Fourteen days after the second immunization, both the experimental and positive control groups were challenged with 8000 infective larvae (L3) of H. contortus, while the negative control group remained unvaccinated and unchallenged. At the end of the experiment on the 63rd day, all animals were humanly euthanized. The results showed that the experimental group had significantly higher levels of sera IgG, IgA, and IgE antibodies, as well as increased concentrations of cytokines, such as IL-4, IL-9, IL-17, and TGF-β, compared to the negative control group after immunization. Following the L3 challenge, the experimental group exhibited a 47.5% reduction in mean eggs per gram of feces (EPG) and a 55.7% reduction in worm burden as compared to the positive control group. These findings indicate that the nanovaccine expressing rHcARF1 offers significant protective efficacy against H. contortus infection in goats. The results also suggest the need for more precise optimization of the antigen dose or a reassessment of the vaccination regimen. Additionally, the small sample size limits the statistical rigor and the broader applicability of the findings.

An Updated Review Summarizing the Anticancer Potential of Poly(Lactic-co-Glycolic Acid) (PLGA) Based Curcumin, Epigallocatechin Gallate, and Resveratrol Nanocarriers.

The utilization of nanoformulations derived from natural products for the treatment of many human diseases, including cancer, is a rapidly developing field. Conventional therapies used for cancer treatment have limited efficacy and a greater number of adverse effects. Hence, it is imperative to develop innovative anticancer drugs with superior effectiveness. Among the diverse array of natural anticancer compounds, resveratrol, curcumin, and epigallocatechin gallate (EGCG) have gained considerable attention in recent years. Despite their strong anticancer properties, medicinally significant phytochemicals such as resveratrol, curcumin, and EGCG have certain disadvantages, such as limited solubility in water, stability, and bioavailability problems. Encapsulating these phytochemicals in poly(lactic-co-glycolic acid) (PLGA), a polymer that is nontoxic, biodegradable, and biocompatible, is an effective method for delivering medication to the tumor location. In addition, PLGA nanoparticles can be modified with targeting molecules to specifically target cancer cells, thereby improving the effectiveness of phytochemicals in fighting tumors. Combining plant-based medicine (phytotherapy) with nanotechnology in a clinical environment has the potential to enhance the effectiveness of drugs and improve the overall health outcomes of patients. Therefore, it is crucial to have a comprehensive understanding of the different aspects and recent advancements in using PLGA-based nanocarriers for delivering anticancer phytochemicals. This review addresses the most recent advancements in PLGA-based delivery systems for resveratrol, EGCG, and curcumin, emphasizing the possibility of resolving issues related to the therapeutic efficacy and bioavailability of these compounds.

Li-Fraumeni Syndrome in Breast Cancer: Development of Theranostic Probes on Variation of P53

Li-Fraumeni Syndrome (LFS) is a hereditary condition characterized by a high predisposition to various cancers due to mutations in the p53 protein. Effectively targeting and treating this syndrome requires early detection and personalized treatment according to one’s specific nucleotide sequence. With the use of various forms of theranostics, LFS can be treated, increasing life expectancy; however, there is no absolute cure that could immediately end this syndrome. This paper delves into three different theranostic approaches: Gendicine (rAd-p53), Phesgo, and gold nanoshell poly(D, L-lactic-co-glycolic acid) nanoparticles (PLGA NPs). While each approach has limitations, PLGA nanoparticles exhibit advantages that outweigh their drawbacks, making it an attractive solution. This proposal will describe improvements to PLGA nanoparticles, which are a promising area of research for the development of new LFS treatments.

Silk fibroin/chitosan thiourea hydrogel scaffold with vancomycin and quercetin-loaded PLGA nanoparticles for treating chronic MRSA osteomyelitis in rats

Chronic osteomyelitis presents significant treatment challenges, necessitating an efficient system for infection elimination and bone repair. This study developed a natural hydrogel scaffold using silk fibroin (SF) and chitosan thiourea (CST), incorporating vancomycin (VC) and quercetin (QC) loaded PLGA nanoparticles (NPs) for dual-purpose treatment. SF/CST hydrogel scaffolds exhibited homogeneous porosity and smaller interconnected pore size than pure SF and pure CST hydrogel scaffolds. Optimal PLGA/QC NPs measured 206 nm in size, displayed spherical morphology, had uniform distribution, and achieved 87 % QC loading. The release study showed sustained long-term release of VC and QC from the hydrogel scaffolds for over 20 days. Biocompatibility tests indicated that hydrogel scaffolds promoted osteoblast adhesion without cytotoxicity, with QC-containing scaffolds enhancing osteoblast growth. Antibacterial tests confirmed retained VC activity against methicillin-resistant Staphylococcus aureus (MRSA) in SF/CST. An experimental study assessed the efficacy of the hydrogel scaffolds in a MRSA-infected rat osteomyelitis model. Radiographic scores demonstrated a significant reduction for SF/CST-VC-PLGA/QC NPs compared to control, indicating reduced osteomyelitis effects. Macroscopic evaluations showed notable reductions in gross pathological effects for VC-containing groups. Histopathological assessments revealed significantly lower osteomyelitis scores and higher healing scores in the SF/CST-VC-PLGA/QC NPs, with reduced inflammatory cell infiltration and more organized connective tissue formation. In conclusion, SF/CST-VC-PLGA/QC NPs is an effective dual drug delivery system for osteomyelitis treatment, demonstrating significant antibacterial activity, enhanced bone regeneration, and reduced infection rate.

Formulation development, characterization, and evaluation of sorafenib-loaded PLGA-chitosan nanoparticles.

The basic purpose of this work was to develop environmentally friendly, biodegradable, and biocompatible polymeric nanoparticles of sorafenib that can effectively release the desired drug in a customized and controlled manner for targeting hepatocellular carcinoma. The solvent evaporation technique was employed for the synthesis of sorafenib-loaded PLGA-chitosan nanoparticles, followed by various experimental specifications and compatibility studies using poloxamer 407 as the stabilizer. The best nanoparticles thus synthesized were selected to be used for cytotoxicity investigations through in vitro and in vivo assessments. For the in vitro drug release tests, the dialysis bag diffusion technique was used. For both chitosan nanoparticles and PLGA loaded with sorafenib, a biphasic release pattern was found, exhibiting a protracted release lasting 10 days after a 24-h burst release. As experimental animals, rabbits were utilized to evaluate different in vivo pharmacokinetic properties of the selected formulations. Plasma samples were extracted with acetonitrile and analyzed through the developed HPLC method. Pharmacokinetic parameters such as AUC0-t, Cmax MRT, Vd, and half-life (t1/2) were enhanced significantly (p ≤ 0.001), while clearance was considerably decreased (p ≤ 0.001) for the chosen synthesized nanoparticles in contrast to the commercially accessible sorafenib formulation (Nexavar®). The cytotoxicity of the reference drug and sorafenib-loaded PLGA and chitosan nanoparticles was calculated by performing an MTT assay against HepG2 cell lines. The developed polymeric sorafenib nanoformulations possess the appropriate physicochemical properties, better targeting, surface morphology, and prolonged release kinetics. The pharmacokinetic parameters were improved significantly when the results were compared with commercially available sorafenib formulations.

Mannose targeting of poly(lactic-co-glycolic acid): a promising approach for improving sublingual allergen-specific immunotherapy

Objective One of the most effective treatments for allergic respiratory diseases is allergen-specific sublingual immunotherapy (SLIT). While, mannose targeting has been applied in various immunostimulatory approaches, but it has not been investigated in sublingual allergen-specific immunosuppressive treatment. This study assesses mannose targeting for the ovalbumin (Ova) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles(NPs). Methods The emulsion-solvent evaporation method was employed for the synthesis of PLGA NPs containing Ova, and subsequently they attached to D-mannose. Ova-sensitized mice underwent treatment in different ways: subcutaneous administration of 10 µg Ova, sublingual administration of 5 and 10 µg Ova loaded in PLGA NPs, 5 and 10 µg Ova loaded in mannose-targeted PLGA NPs, 10 µg Ova, and 10 µg Ova loaded in dendritic cell-specific aptamer-attached PLGA NPs. Serum Ova-specific IgE and IgG2a levels, as well as IFN-γ, IL-4, IL-10, and IL-17a levels in the supernatant of Ova-stimulated splenocytes were measured. Splenocyte proliferation was assessed using an MTT assay, and also lung histological examinations, and nasal lavage fluid cell counting were performed. Results Ova-specific IgE, IL-4, IL-17a levels, eosinophil cell count, and splenocyte proliferation were remarkably reduced in the mice treated with mannose or aptamer targeted NPs compared to other groups. Also, IL-10 and IFN-γ levels were remarkably increased in the targeted NPs groups. Conclusion Our findings indicated that mannose targeting of PLGA NPs could decrease allergen dose and improve immunomodulatory effects of SLIT. However, this approach suggests an effective formulation for SLIT in the mice model, further studies with common allergens are needed for application in humans.

Mannose-Functionalized Chitosan-Coated PLGA Nanoparticles for Brain-Targeted Codelivery of CBD and BDNF for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease causing cognitive and memory decline. AD is characterized by the deposition of amyloid-β and hypophosphorylated forms of tau protein. AD brains are found to be associated with neurodegeneration, oxidative stress, and inflammation. Cannabidiol (CBD) shows neuroprotective, antioxidant, and anti-inflammatory properties and simultaneously reduces amyloid-β production and tau hyperphosphorylation. The brain-derived neurotrophic factor (BDNF) plays a vital role in the development and maintenance of the plasticity of the central nervous system. A decline of BDNF levels in AD patients results in reduced plasticity and neuronal cell death. Current therapeutics against AD are limited to only symptomatic relief, necessitating a therapeutic strategy that reverses cognitive decline. In this scenario, combination therapy of CBD and BDNF could be a fruitful strategy for the treatment of AD. We designed mannose-conjugated chitosan-coated poly(d,l-lactide-co-glycolide (PLGA) (CHTMAN-PLGA) nanoparticles for the codelivery of CBD and BDNF to the brain. Chitosan is modified with mannose to specifically target the glucose transporter-1 (GLUT-1) receptor abundantly present in the blood-brain barrier for selectively delivering therapeutics to the brain. The CBD-encapsulated nanoparticles showed an average hydrodynamic diameter of 306 ± 8.12 nm and a zeta potential of 31.7 ± 1.53 mV. The coated nanoparticles prolonged encapsulated CBD release from the PLGA matrix. The coated nanoparticles exhibited sustained release of CBD for up to 22 days with 91.68 ± 2.91% release of the encapsulated drug. The coated nanoparticles, which had a high positive zeta potential (31.7 ± 1.53 mV), encapsulated the plasmid DNA. The qualitative transfection efficiency was investigated using CHTMAN-PLGA-CBD/pGFP in bEND.3, primary astrocytes, and primary neurons, while the quantitative transfection efficiency of the delivery system was determined using CHTMAN-PLGA-CBD/pBDNF. In vitro, the pBDNF transfection study revealed that the BDNF expression was 4-fold higher for CHTMAN-PLGA-CBD/pBDNF than for naked pBDNF in all of the cell lines. The cytotoxicity and hemocompatibility of the designed nanoparticles were tested in bEND.3 cells and red blood cells, respectively, and the nanoparticles were found to be nontoxic and hemocompatible. Hence, mannose-conjugated chitosan-coated PLGA nanoparticles could be useful as brain-targeting delivery vehicles for the codelivery of CBD and BDNF for possible AD treatment.

Enhancing the Safety and Efficacy of Trastuzumab Emtansine (T-DM1) Through Nano-Delivery System in Breast Cancer Therapy.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate, revolutionizes breast cancer therapy by specifically delivering DM1 to human epidermal growth factor receptor 2 (HER2) overexpressing tumor cells, effectively inhibiting cell division and proliferation. While T-DM1 demonstrates superior efficacy and tolerability, T-DM1-induced thrombocytopenia remains a significant adverse event leading to treatment discontinuation. To address this issue, the study investigates the feasibility of using poly(lactic-co-glycolic acid) (PLGA)nanoparticles as a delivery vehicle to conjugate T-DM1, aiming to alleviate T-DM1-induced thrombocytopenia. The T-DM1-conjugated PLGA nanoparticles (NPs-T-DM1) reduce binding to megakaryocytes without compromising the targeting ability for HER2. Administration of NPs-T-DM1 not only significantly inhibits tumor growth but also reduces damage to megakaryocytes, inhibits T-DM1-induced thrombocytopenia, and remarkably improves the safety of antibody-conjugated drugs. This work presents a promising strategy to enhance the safety and efficacy of T-DM1 in antitumor therapy, offering significant potential for advancing clinical application in HER2-positive breast cancer patients.

Poly(Lactic-co-Glycolic Acid Nanoparticles Loaded with Docetaxel and Coated with Chitosan, Carboxymethyl Chitosan, or Glycol Chitosan.

Docetaxel (DTX) is a chemotherapeutic drug that has high toxicity and low bioavailability. To solve these problems, PLGA nanoparticles (NPs) were loaded with DTX and coated with mucoadhesive polymers; chitosan (CS), carboxymethyl chitosan (CMCS), or glycol chitosan(GCS). The NPs were characterized for size, charge, and polydispersity. The particles were explored using SEM, FTIR, DSC, and XRD. In vitro studies were performed to evaluate the mucoadhesive properties of the NPs and the drug release. The results validated the successful formation of spherical and monodispersed DTX NPs. The coated NPs exhibited highly positive charges, reaching +44.30±0.21 mV, whereas the uncoated NPs were almost neutral. The formulations demonstrated excellent encapsulation efficiency (>98%) and loading capacity (>45%). All polymers used in the coating process enhanced the mucoadhesive properties of PLGA NPs and sustained DTX release. Both the mucoadhesiveness and release were related to the used coating polymer and its concentration. The formulations were stable for up to three months in the refrigerator. In conclusion, loading DTX in PLGA NPs and coating them with CS, CMCS, or GCS provides a promising strategy to increase the NPs' residence time on mucosal surfaces, which is expected to decrease the required dose of DTX and reduce its side effects.

Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription.

Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition alleviated various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, an elevated expression of immunoproteasome subunits LMP2 and LMP7 in the macrophages isolated from mouse with LPS/Elastase-induced emphysema and polarized macrophages in vitro is observed. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated COPD-associated airway inflammation and improved lung function in mice by suppressing macrophage polarization. Additionally, ONX-0914 capsulated in PLGA nanoparticles exhibited more pronounced therapeutic effect on COPD than naked ONX-0914 by targeting immunoproteasome in polarized macrophages. Mechanistically, ONX-0914 activated autophagy and endoplasmic reticulum (ER) stress are not attribute to the ONX-0914 mediated suppression of macrophage polarization. Intriguingly, ONX-0914 inhibited M1 polarization through the nuclear factor erythroid 2-related factor-1 (NRF1) and NRF2-P62 axis, while the suppression of M2 polarization is regulated by inhibiting the transcription of interferon regulatory factor 4 (IRF4). In summary, the findings suggest that targeting immunoproteasome in macrophages holds promise as a therapeutic strategy for COPD.

Research Progress on Immunomodulatory Effects of Poly (Lactic-co- Glycolic Acid) Nanoparticles Loaded with Traditional Chinese Medicine Monomers.

Immunomodulatory mechanisms are indispensable and key factors in maintaining the balance of the environment in humans. When the immune function of the immune system is impaired, autoimmune diseases occur. Excessive body fatigue, natural aging of the human body, malnutrition, genetic factors and other reasons cause low immune function, due to which the body is prone to being infected by bacteria or cancer. Clinically, the existing therapeutic drugs still have problems such as high toxicity, long treatment cycle, drug resistance and high price, so we still need to explore and develop a high efficiency and low toxicity drug. Poly(lactic-co-glycolic acid) (PLGA) refers to a nontoxic polymer compound that exhibits excellent biocompatibility. Traditional Chinese medicine (TCM) monomers come from natural plants, and have the characteristics of high efficiency and low toxicity. Applying PLGA to TCM monomers can make up for the defects of traditional dosage forms, improve bioavailability, reduce the frequency and dosage of drug use, and reduce toxicity and side effects, thus having the characteristics of sustained release and targeting. Accordingly, PLGA nanoparticles loaded with TCM monomers have been the focus of development. The previous research on drug loading advantages, preparation methods, and immune regulation of TCM PLGA nanoparticles is summarized in the following sections.