PLGA Nanoparticles Research Articles

Exploring the translational potential of PLGA nanoparticles for intra-articular rapamycin delivery in osteoarthritis therapy

Osteoarthritis (OA) is a prevalent joint disease that affects all the tissues within the joint and currently lacks disease-modifying treatments in clinical practice. Despite the potential of rapamycin for OA disease alleviation, its clinical application is hindered by the challenge of achieving therapeutic concentrations, which necessitates multiple injections per week. To address this issue, rapamycin was loaded into poly(lactic-co-glycolic acid) nanoparticles (RNPs), which are nontoxic, have a high encapsulation efficiency and exhibit sustained release properties for OA treatment. The RNPs were found to promote chondrogenic differentiation of ATDC5 cells and prevent senescence caused by oxidative stress in primary mouse articular chondrocytes. Moreover, RNPs were capable to alleviate metabolism homeostatic imbalance of primary mouse articular chondrocytes in both monolayer and 3D cultures under inflammatory or oxidative stress. In the mouse destabilization of the medial meniscus (DMM) model, intra-articular injection of RNPs effectively mitigated joint cartilage destruction, osteophyte formation, chondrocytes hypertrophy, synovial inflammation, and pain. Our study demonstrates the feasibility of using RNPs as a potential clinically translational therapy to prevent the progression of post-traumatic OA.Graphical abstract

DNA vaccine incorporated poly (lactic-co-glycolic) acid (PLGA) microspheres offer enhanced protection against Aeromonas hydrophila infection

Encapsulation of DNA vaccines onto carriers enhances the immunogenicity of an antigen. Specifically, biodegradable polymers offer sustained release of vaccines which is crucial for any targeted delivery approach. Poly (lactic-co-glycolic) acid (PLGA) microspheres were used to load a DNA vaccine having a targeted gene of outer membrane protein (OMP) of Aeromonas hydrophila to clone and construct a DNA vaccine using a eukaryotic expression vector system (pVAX1-OMP DNA) and delivery in Carassius auratus against A. hydrophila infection. PLGA microspheres were prepared by emulsion technique oil-in-water and characterized by a High-Resolution Scanning Electron Microscope (HR-SEM). The results of PLGA-pVAX1-OMP DNA microspheres shows that average of 100–150 μm particle size and a loading efficiency (LE) of 68.8 %. Results indicate that C. auratus fed with PLGA-pVAX1-OMP DNA microspheres revealed a significant improvement in innate immune response, which includes, myeloperoxidase activity, respiratory burst and total immunoglobulin level compared with control group fish. The immune-related gene, IL1β, IL10, TGF, c-type, and g-type lysozyme also showed significantly higher expression after immunization. Furthermore, dietary supplementation of the PLGA-pVAX1-OMP DNA (G III) group exhibited a significantly higher survival rate (78 %) than the control group of fish. These results help us to understand the of mechanism of DNA vaccine administrated feed through PLGA nanoparticles resistance to infection by regulating systemic and innate immunity in Carassius auratus.

Nano-combination for Reviving the Activity of Fluconazole against Rhizopus delemar.

Rhizopus delemar, the main causative pathogen for the lethal mucormycosis and a severe threat during the COVID-19 pandemic, is resistant to most antifungals, including fluconazole, a known selective antifungal drug. On the other hand, antifungals are known to enhance fungal melanin synthesis. Rhizopus melanin plays an important role in fungal pathogenesis and in escaping the human defense mechanism, thus complicating the use of current antifungal drugs and fungal eradication. Because of drug resistance and the slow discovery of effective antifungals, sensitizing the activity of older ones seems a more promising strategy. In this study, a strategy was employed to revive the use and enhance the effectiveness of fluconazole against R. delemar. UOSC-13, a compound synthesized in-house to target the Rhizopus melanin, was combined with fluconazole either as is or after encapsulation in poly (lactic-coglycolic acid) nanoparticles (PLG-NPs). Both combinations were tested for the growth of R. delemar, and the MIC50 values were calculated and compared. The activity of fluconazole was found to be enhanced several folds following the use of both combined treatment and nanoencapsulation. The combination of fluconazole with UOSC-13 caused a 5-fold reduction in the MIC50 value of fluconazole. Furthermore, encapsulating UOSC-13 in PLG-NPs enhanced the activity of fluconazole by an additional 10 folds while providing a wide safety profile. Consistent with previous reports, the encapsulation of fluconazole without sensitization showed no significant difference in activity. Collectively, sensitization of fluconazole represents a promising strategy to revive the use of outdated antifungal drugs back in the market.

Immuno-Nanoparticles Developed Using Dexamethasone and Captopril Co-Loaded PLGA Improve Glomerulonephritis Through Modulating Macrophage Polarization

The purpose of this study was to prepare liposome-coated poly(lactic-co-glycolic acid) co-loaded with dexamethasone (DXMS, D) and captopril (CAP, C) loading with PLGA nanoparticles (P) and modified polyethylene glycol and integrin α8 antibody on the surface of nanoparticles to obtain double-drug-loaded core–shell immunoliposome composite nanoparticles (DCPI), and then studied the loading Kidney targeting, anti-inflammatory effects and effects on macrophage differentiation of drug nanoparticles. In vitro cell experiments showed that DCPI could reduce the secretion of M2 macrophage-specific cytokines and the RNA expression levels of markers, and promote M2 macrophages toward unpolarized macrophages differentiation. In vivo experiments showed that DCPI had significant renal targeting, normalized renal index, serum creatinine, and blood urea nitrogen levels in mice with mesangial proliferative glomerulonephritis, and reduced inflammatory cytokines in the kidney’s secretion, and decreased RNA expression of M1 and M2 macrophage markers in kidneys. In conclusion, kidney-targeted DCPI nanoparticles can effectively regulate the polarization of macrophages, play an “anti-inflammatory/anti-fibrotic” therapeutic effect, and be a target for glomerulonephritis. Treatment provides new strategies and evidence.

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Necrostatin-1 releasing nanoparticles: In vitro and in vivo efficacy for supporting immunoisolated islet transplantation outcomes.

Immunoisolation of pancreatic islets in alginate microcapsules allows for transplantation in the absence of immunosuppression but graft survival time is still limited. This limited graft survival is caused by a combination of tissue responses to the encapsulating biomaterial and islets. A significant loss of islet cells occurs in the immediate period after transplantation and is caused by a high susceptibility of islet cells to inflammatory stress during this period. Here we investigated whether necrostatin-1 (Nec-1), a necroptosis inhibitor, can reduce the loss of islet cells under stress in vitro and in vivo. To this end, we developed a Nec-1 controlled-release system using poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) as the application of Nec-1 in vivo is limited by low stability and possible side effects. The PLGA NPs stably released Nec-1 for 6 days in vitro and protected beta cells against hypoxia-induced cell death in vitro. Treatment with these Nec-1 NPs at days 0, 6, and 12 post-islet transplantation in streptozotocin-diabetic mice confirmed the absence of side effects as graft survival was similar in encapsulated islet grafts in the absence and presence of Nec-1. However, we found no further prolongation of graft survival of encapsulated grafts which might be explained by the high biocompatibility of the alginate encapsulation system that provoked a very mild tissue response. We expect that the Nec-1-releasing NPs could find application to immunoisolation systems that elicit stronger inflammatory responses, such as macrodevices and vasculogenic biomaterials.

Curcumin Co-Encapsulation Potentiates Anti-Arthritic Efficacy of Meloxicam Biodegradable Nanoparticles in Adjuvant-Induced Arthritis Animal Model.

This study aimed to evaluate the anti-arthritic activity of curcumin and meloxicam co-loaded PLGA nanoparticles in adjuvant-induced arthritic rats. PLGA nanoparticles encapsulating curcumin (nCur) and meloxicam (nMlx) alone and in combination (nCur/Mlx) were used to characterize zeta size and potential, polydispersity index, encapsulation efficiency (%), compound-polymer interactions (FT-IR analysis), and surface morphology (SEM imaging). In vivo, Complete Freund's adjuvant-induced arthritic rats were intraperitoneally (i.p.) administered with curcumin, meloxicam, curcumin plus meloxicam, nCur, nMlx, and nCur/Mlx for 28 consecutive days. Results showed that nCur, nMlx, and nCur/Mlx significantly (p ≤ 0.05) reduced paw swelling and arthritic score, restored body weight and the immune organ index (thymus and spleen), as well as attenuated serum inflammatory markers (RF, CRP, and PGE2) and oxidative stress parameters (MDA, SOD, and CAT) in adjuvant-induced arthritic rats compared to free compounds. In addition, mono- and dual-compound-loaded nanoparticles significantly (p ≤ 0.05) down-regulated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), up-regulated anti-inflammatory cytokines (IL-4, IL-10, and IFN-γ), and modulated OPG and RANKL expressions in paw tissue. The aforementioned results were further confirmed through radiological and histopathological examinations. Furthermore, the anti-arthritic effect of nCur/Mlx was notably (p ≤ 0.05) enhanced compared to nCur or nMlx alone. In conclusion, the co-nanoencapsulation of curcumin could potentiate the anti-arthritic activity of meloxicam and could provide a novel therapeutic approach for the formulation of nanocarrier pharmaceutical products for the management of arthritis.

Investigation of cellular and molecular mechanisms of caffeic acid phenethyl ester loaded nanoparticle systems in breast cancer cell lines

Breast cancer is associated with high morbidity and mortality in women since conventional treatment methods are limited due to toxicity problems and inadequate targeting of cancer cells. The aim of this study is to develop caffeic acid phenethyl ester (CAPE) loaded polymeric nanoparticles to provide treatment for breast cancer and investigate their anti-tumor activity on MCF-7 and MDA-MB-231 breast cancer cells. CAPE was encapsulated into poly lactic-co-glycolic acid (PLGA) polymer using single-emulsion (o/w) solvent evaporation method and characterization of CAPE loaded PLGA nanoparticles (CAPE-NPs) were performed by particle size, zeta potential, polydispersity index, in vitro release profile, and surface morphology. CAPE-NPs were tested for cytotoxicity, anti-migration, anti-proliferation and apoptotic activities on breast cancer cells. The mean nanoparticle size was found as 196,1 ± 8982 nm and polydispersity index (PDI) was 0186 ± 0069. The results of the in vitro cell culture studies indicated that treatment of breast cancer cells with CAPE and CAPE-NPs inhibited cell viability and proliferation. IC50 values for 48 h were determined as 28.35 μg/ml,19.57 μg/ml for CAPE and CAPE-NP, respectively. Additionally, CAPE-NPs induced intrinsic pathway of apoptosis in MCF-7 and MDA-MB-231 cell lines. Overall, CAPE-NPs showed more efficient anti-tumour activity on breast cancer cells by small size and enhanced bioavability.

Nanogel-Based Delivery System for Lemongrass Essential Oil: A Promising Approach to Overcome Antibiotic Resistance in Pseudomonas aeruginosa Infections.

The emergence of antibiotic-resistant strains of Pseudomonas aeruginosa (P. aeruginosa) presents a substantial obstacle in medical environments. To effectively tackle this problem, we suggest an innovative approach: employing a delivery system based on nanogels to administer lemongrass essential oil (LGO). Developed PVA and PLGA nanoparticle formulation efficiently encapsulates LGO with 56.23% encapsulation efficiency by solvent extraction technique, preserving stability and bioactivity. Nanogel: 116 nm size, low polydispersity (0.229), -9 mV zeta potential. The nanogel's controlled release facilitated targeted LGO delivery via pH-controlled dissolution. Pure LGO had the highest release rate, while LGO-NP and LGO-NP-CG exhibited slower rates. In 15 h, LGO-NP released 50.65%, and LGO-NP-CG released 63.58%, releasing 61.31% and 63.58% within 24 h. LGO-NP-CG demonstrated superior antioxidant activity, a lower MIC against P. aeruginosa, and the most potent bactericidal effect compared to other formulations. This underscores the versatile efficacy of LGO, suggesting its potential to combat antibiotic resistance and enhance treatment effectiveness. Moreover, employing a nanogel-based delivery approach for LGO offers an efficient solution to combat drug resistance in P. aeruginosa infections. By employing strategies such as nanogel encapsulation and controlled release, we can enhance the effectiveness of LGO against antibiotic-resistant strains. This study establishes a robust foundation for exploring innovative approaches to treating P. aeruginosa infections using nanomedicine and paves the way for investigating novel methods of delivering antimicrobial drugs. These efforts contribute to the ongoing battle against antibiotic resistance.

PLGA nanoparticle loaded with antioxidants and photosensitizer for ROS shock mediated phototherapy of triple negative breast cancer

The potential use of antioxidants for photodynamic therapy (PDT) is investigated in this study. PDT causes reactive oxygen species (ROS)-mediated cell death; on the contrary, antioxidants scavenge ROS. The use of a photosensitizer along with an antioxidant photosensitizer compensates for the loss of ROS due to the use of antioxidant, eventually leading to cell death. In this work, for PDT and photothermal therapy (PTT), we have combined the photosensitizer IR 792 perchlorate dye with the antioxidants alpha-tocopherol (A) and p-coumaric acid (C) encapsulated in a polymeric nanocarrier (AC IR NPs). We have reported the synthesis of AC IR NPs using poly lactic-co-glycolic acid (PLGA) by nanoprecipitation method. The size of the polymeric nanoparticles was found to be 80.4 ± 15.6 nm, with a spherical morphology observed by scanning electron microscopy and transmission electron microscopy. The synthesized AC IR NPs demonstrated good biocompatibility in fibroblast cell lines (L929). Furthermore, the efficacy assessment of the as prepared nanosystem in vitro on breast cancer cell lines (4T1) revealed a significant cell death of nearly 80%. This could be attributed to the ROS generation leading to oxidative stress and inhibition of metastasis. This study provides evidence that the combination of antioxidant drugs along with photosensitizers have the potential to be an effective therapy for treating triple negative breast cancer.

Revolutionizing Drug Delivery: The Potential of PLGA Nanoparticles in Nanomedicine

Abstract: Nanomedicine is an emerging field that utilizes nanoparticles to deliver drugs and other therapeutic agents to specific cells and tissues in the body. One of the most promising materials for creating these nanoparticles is Poly(Lactic-co-glycolic Acid) (PLGA), which has several unique properties that make it well-suited for biomedical applications. These nanomedicines, made from a combination of lactic acid and glycolic acid, can deliver drugs and other therapeutic agents directly to specific cells or tissues in the body. This allows for more precise and targeted treatment, reducing the potential for side effects and improving the effectiveness of the treatment. Additionally, PLGA nanomedicines are biocompatible and biodegradable, making them an attractive option for use in a wide range of biomedical applications to deliver a wide range of drugs, including proteins, peptides, nucleic acids, and small molecules for various biomedical applications such as neurodegenerative, cardiovascular diseases, inflammatory disorders, and cancer. In summary, research on PLGA nanoparticles for biomedical applications is ongoing and has the potential to lead a new and improved treatments for a wide range of diseases and conditions. Looking ahead, PLGA nanoparticles have the potential to revolutionize the way we treat diseases and improve human health. As research continues to advance, we can expect to see new and innovative uses for PLGA nanoparticles in the biomedical field, leading to the development of more effective and targeted therapeutics. The current review focuses on the synthesis, physicochemical properties, biodegradation properties of PLGA, method to prepare PLGA nanoparticles and biomedical application of PLGA. It examines the current progress and future directions for research on PLGA in drug delivery.

Surface Modification of Poly(lactide-co-glycolide) Nanoparticles for the Sustained in vitro Release and the Enhanced Cytotoxicity of Chelidonine.

Chelidonine is a potent anticancer against several cell lines. However, low bioavailability and water solubility restrict the clinical applications of this compound. The aim of this research was to develop a novel formulation of chelidonine encapsulated in the nanoparticles of poly(d l-lactic-co-glycolic acid) (PLGA) employing vitamin E D-α-tocopherol acid polyethylene glycol 1000 succinate (E TPGS) as a modifier to increase bioavailability. Chelidonine-encapsulated PLGA nanoparticles were fabricated using a single emulsion method and modified by various concentrations of E TPGS. Nanoparticles were recognized in terms of morphology, surface charge, drug release, size, drug loading, and encapsulation efficiency to obtain the optimized formulation. The cytotoxicity of different nanoformulations in HT-29 cells was evaluated using the MTT assay. The cells were stained with propidium iodide and annexin V solution to evaluate apoptosis using flow cytometry. Spherical nanoparticles prepared with 2% (w/v) of E TPGS had the optimum formulation in the nanometer size range (153 ± 12.3 nm), with a surface charge of -14.06 ± 2.21 mV, encapsulation efficiency of 95.58 ± 3.47%, drug loading of 33.13 ± 0.19%, and drug release profile of 73.54 ± 2.33. In comparison with non-modified nanoparticles and free chelidonine, E TPGS-modified nanoformulations improved anti-cancer capability even after three-months storage. Our results showed that E TPGS is an effective biomaterial for surface modification of nanoparticles, which can serve as a potential treatment for cancer.

Effect of surfactant stabilizers on physico-chemical properties of PLGA nanoparticles loaded with tetrahydrocannabinol

Effect of surfactant stabilizers on physico-chemical properties of PLGA nanoparticles loaded with tetrahydrocannabinol

Intranasal delivery of Borneol/R8dGR peptide modified PLGA nanoparticles co-loaded with curcumin and cisplatin alleviate hypoxia in pediatric brainstem glioma which improves the synergistic therapy

Cisplatin (cis) is a first-line chemotherapeutic used for the treatment of intractable pediatric brainstem glioma (PBSG). Its therapeutic effect in PBSG is, however, critically challenged by the hypoxic microenvironment of the tumor and the presence of the blood brain barrier (BBB). Herein, we report on the intranasal administration of borneol (Bo)/R8dGR peptide modified PLGA based nanoparticles (NP) co-loaded with curcumin and cisplatin (cur/cis). We observed that borneol modification improved the brain penetration of the nanoparticles by reduction of the expression of ZO-1 and occludin in nasal mucosa, while the R8dGR peptide modification allowed the targeting of the NP through the binding on integrin αvβ3 receptors which are present on PBSG cells. Following intranasal administration, BoR-cur/cis-NP attenuated hypoxia in the PBSG microenvironment and reduced angiogenesis, which prolonged survival of GL261-bearing PBSG mice. Therefore, intranasal administration of BoR-cur/cis-NP, which deeply penetrate PBSG, is an encouraging strategy to attenuate hypoxia which potentiates the efficacy of cisplatin in the treatment of PBSG.

Preparation, Characterization and Evaluation of Resveratrol Loaded Pegylated PLGA Nanoparticles

Preparation, Characterization and Evaluation of Resveratrol Loaded Pegylated PLGA Nanoparticles

Role of the Lactide:Glycolide Ratio in PLGA Nanoparticle Stability and Release under Lysosomal Conditions for Enzyme Replacement Therapy of Lysosomal Storage Disorders.

Prior studies demonstrated that encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) enhanced the delivery of enzymes used for replacement therapy (ERT) of lysosomal storage disorders (LSDs). This study examined how the copolymer lactide:glycolide ratio impacts encapsulation, physicochemical characteristics, stability, and release under lysosomal conditions. Hyaluronidase, deficient in mucopolysaccharidosis IX, was encapsulated in NPs synthesized using 50:50, 60:40, or 75:25 lactide:glycolide copolymers. All NPs had diameters compatible with cellular transport (≤168 nm) and polydispersity indexes (≤0.16) and ζ-potentials (≤-35 mV) compatible with colloidal stability. Yet, their encapsulation efficiency varied, with 75:25 NPs and 60:40 NPs having the lowest and highest EE, respectively (15% vs. 28%). Under lysosomal conditions, the 50:50 copolymer degraded fastest (41% in 1 week), as expected, and the presence of a targeting antibody coat did not alter this result. Additionally, 60:40 NPs destabilized fastest (<1 week) because of their smaller diameter, and 75:25 NPs did not destabilize in 4 weeks. All formulations presented burst release under lysosomal conditions (56-78% of the original load within 30 min), with 50:50 and 60:40 NPs releasing an additional small fraction after week 1. This provided 4 weeks of sustained catalytic activity, sufficient to fully degrade a substrate. Altogether, the 60:40 NP formulation is preferred given its higher EE, and 50:50 NPs represent a valid alternative, while the highest stability of 75:25 NPs may impair lysosomes. These results can guide future studies aiming to translate PLGA NP-based ERT for this and other LSDs.

Anti-inflammation-based treatment of atherosclerosis using Gliclazide-loaded biomimetic nanoghosts

In the study, a biomimetic platform for anti-inflammatory-based treatment of atherosclerotic plaque was developed. Gliclazide (GL) as an anti-inflammasome agent was encapsulated in PLGA nanoparticles (NP), which were coated by monocyte membrane using an extrusion procedure. The size and zeta potential of the nanoghost (NG) changed to 292 and – 10 nm from 189.5 to −34.1 in the core NP. In addition, the actual size of 62.5 nm with a coating layer of 5 nm was measured using TEM. The NG was also showed a sustained release profile with the drug loading content of about 4.7%. Beside to attenuated TNFα, decrease in gene expression levels of NLRP3, MyD88, NOS, IL-1β, IL-18 and caspases 1/3/8/9 in LPS-primed monocytes exposed to NG strongly indicated remarkable inflammation control. After systemic toxicity evaluation and pharmacokinetic analysis of NP and NG, intravenous NG treatment of rabbits with experimentally induced atherosclerosis revealed remarkably less plaque lesions, foam cells, lipid-laden macrophages, and pathological issues in tunica media of aorta sections. Higher expression of CD163 than CD68 in aorta of NG-treated rabbits strongly reveals higher M2/M1 macrophage polarization. The bio/hemocompatible, biomimetic and anti-inflammatory NG can be considered as a potential platform for immunotherapy of particularly atherosclerosis in the field of personalized medicine.

The Cooperation of IL-29 and PLGA Nanoparticles Improves the Protective Immunity of the gD-1 DNA Vaccine Against Herpes Simplex Virus Type 1 in Mice

ABSTRACT In clinical practice, the low immunogenicity and low stability of the DNA plasmid vaccine candidates are two significant shortcomings in their application against infectious diseases. To overcome these two disadvantages, the plasmid expressing IL-29 (pIL-29) as a genetic adjuvant and polylactic-co-glycolic acid (PLGA) as a non-viral delivery system were used, respectively. In this study, the pIL-29 encapsulated in PLGA nanoparticles (nanoIL-29) and the pgD1 encapsulated in PLGA nanoparticles (nanoVac) were simultaneously applied to boost immunologic responses against HSV-1. We generated spherical nanoparticles with encapsulation efficiency of 75 ± 5% and sustained the release of plasmids from them. Then, Balb/c mice were subcutaneously immunized twice with nanoVac+nanoIL-29, Vac+IL-29, nanoVac, Vac, nanoIL-29, and/or IL-29 in addition to negative and positive control groups. Cellular immunity was evaluated via lymphocyte proliferation assay, cytotoxicity test, and IFN-γ, IL-4, and IL-2 measurements. Mice were also challenged with 50X LD50 of HSV-1. The nanoVac+nanoIL-29 candidate vaccine efficiently enhances CTL and Th1-immune responses and increases the survival rates by 100% in mice vaccinated by co-administration of nanoVac and nanoIL-29 against the HSV-1 challenge. The newly proposed vaccine is worth studying in further clinical trials, because it could effectively improve cellular immune responses and protected mice against HSV-1.

Multitarget, multiagent PLGA nanoparticles for simultaneous tumor eradication and TME remodeling in a melanoma mouse model

Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages and fibroblasts were incubated with B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs were prepared, characterized, and tested in the target cell types. Organ distribution of fluorescein-loaded PLGA NPs was evaluated in a mouse model of melanoma. Finally, the local and systemic effects of different combination therapy programs were portrayed. The in vitro studies showed that the drug-loaded PLGA NPs could significantly ablate the immunosuppressive nature of Mel and skew TAMs and TAFs towards more favorable phenotypes. While in vivo, PLGA NPs were proven to exhibit long blood circulation time and to localize preferentially in the tumor and the spleen. The combination of either metformin or losartan with doxorubicin was superior to the monotherapy, both locally and systemically. However, the three-agent combo produced detrimental effects in the form of compromised well-being, immune depletion, and metastasis. These findings indicate the potential of TME remodeling as means to prime the tumors for successful chemoimmunotherapy. In addition, they shed light on the importance of the careful use of combination therapies and the necessity of employing dose-reduction strategies.Graphical D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded NPs, L-NPs losartan-loaded NPs, TAMs tumor-associated macrophages, TAFs tumor-associated fibroblasts, PD-L1 programmed death ligand 1, TNF-α tumor necrosis factor alpha, TGF-β transforming growth factor beta, CD206/40/86 cluster of differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases

Nose to Brain Delivery of Transferrin conjugated PLGA nanoparticles for clonidine

The present work focuses on the development of surface modified transferrin PLGA nanoparticles loaded with clonidine for nose to brain delivery. The CLD-Tf-PLGA-NPs were developed using double emulsification, followed by solvent evaporation and characterization. Particle size, PDI and Zeta potential of the nanoparticles was 199.5 ± 1.36 nm, 0.291, −17.4 ± 6.29 mV respectively with EE% 86.2 ± 2.12 %, and DL%, 7.8 ± 0.48 %. TEM, SEM and FTIR analysis were carried out to confirm the size and transferrin coating over the surface of nanoparticles. In-vitro drug release profile were studied in PBS (pH 7.4) and SNF (pH 5.5) for 72 h and highest release was observed in PBS 89.54 ± 3.17 %. Cellular assays were conducted on Neuro-2a cells to check the cytotoxicity and uptake of Tf-modified PLGA nanoparticles and the cell viability% was obtained to be 61.85 ± 4.48 % even at maximum concentration (40Cmax) with uptake of approximately 97 %. Histopathological studies were also performed to identify the cytotoxicity on nasal epithelium along with in-vivo biodistribution and pharmacodynamics studies to assess the concentration of drug in the mice brain and behavioural responses after intranasal delivery of surface modified nanoparticles. The results showed significant increase in concentration of drug in brain and behavioural improvements in mice (p < 0.05).