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Targeted treatment of cerebral ischemia/reperfusion injury (CIRI) remains a problem due to the difficulty in drug delivery across the blood-brain barrier (BBB). In this study, we developed Bo-TSA-NP, a novel tanshinone IIA (TSA) loaded nanoparticles modified by borneol, which has long been proved with the ability to enhance other drugs' transport across the BBB. The Bo-TSA-NP, with a particle size of about 160 nm, drug loading of 3.6%, showed sustained release and P-glycoprotein (P-gp) inhibition property. It demonstrated a significantly higher uptake by 16HBE cells in vitro through the clathrin/caveolae-mediated endocytosis and micropinocytosis. Following intranasal (IN) administration, Bo-TSA-NP significantly improved the preventive effect on a rat model of CIRI with improved neurological scores, decreased cerebral infarction areas and a reduced content of malondialdehyde (MDA) and increased activity of superoxide dismutase (SOD) in rat brain. In conclusion, these results indicate that Bo-TSA-NP is a promising nose-to-brain delivery system that can enhance the prevention effect of TSA on CIRI.

Antigen-presenting cells (APCs) are powerful tools to expand antigen-specific T cells ex vivo and in vivo for tumor immunotherapy, but suffer from time-consuming generation and biosafety concerns raised by live cells. Alternatively, the cell-free artificial antigen-presenting cells (aAPCs) have been rapidly developed. Nanoscale aAPCs are recently proposed owing to their superior biodistribution and reduced embolism than conventional cell-sized aAPCs, but pose the challenges: easier cellular uptake and smaller contact surface area with T cells than the cell-sized counterparts. This study aimed to fabricate a new \"stealth\" nano-aAPCs with microscale contact surface area to minimize cellular uptake and activate antigen-specific T cells by combination uses of ellipsoidal stretch, PEGylation, and self-marker CD47-Fc conjugation. The spherical polylactic-co-glycolic acid nanoparticles were fabricated using a double-emulsion method, and then stretched twofold using film-stretching procedure followed by PEGylation and co-coupling with CD47-Fc, H-2K /TRP2 -Ig dimers, and anti-CD28. The resulting PEGylated and CD47-conjugated nanoellipsoidal aAPCs (EaAPC ) were co-cultured with macrophages or spleen lymphocytes and also infused into melanoma-bearing mice. The in vitro and in vivo effects were evaluated and compared with the nanospherical aAPCs (SaAPC), nanoellipsoidal aAPCs (EaAPC), or PEGylated nanoellipsoidal aAPC (EaAPC ). EaAPC markedly reduced cellular uptake in vitro and in vivo, as compared with EaAPC , EaAPC, SaAPC, and Blank-NPs and expanded naïve TRP2 -specific CD8 T cells in the co-cultures with spleen lymphocytes. After three infusions, the EaAPC showed much stronger effects on facilitating TRP2 -specific CD8 T-cell proliferation, local infiltration, and tumor necrosis in the melanoma-bearing mice and on inhibiting tumor growth than the control aAPCs. The superimposed or synergistic effects of ellipsoidal stretch, PEGylation, and CD47-Fc conjugation minimized cellular uptake of nano-aAPCs and enhanced their functionality to expand antigen-specific T cells and inhibit tumor growth, thus suggesting a more valuable strategy to design \"stealth\" nanoscale aAPCs suitable for tumor active immunotherapy.

The use of nanoparticles improves the stability, solubility, and skin permeability of natural compounds in skincare products. Based on these advantages, this study aimed to incorporate the Phlomis crinita extract into polymeric nanoparticles to improve its topical skin delivery for wound healing purposes. The study involved the preparation of nanoparticles of PLGA and PLGA-PEG (PCE-PLGA-NPs and PCE-PLGA-PEG-NPs) using the solvent displacement method, physicochemical and biopharmaceutical characterization, tolerance studies by the HET-CAM assay and evaluation of skin integrity parameters, and in vitro efficacy via a scratch wound healing experiment. The prepared nanoparticles were nanometer-sized with spherical form and demonstrated an encapsulation efficiency greater than 90%. The major component (luteolin) was released following a kinetic model of hyperbola for PCE-PLGA-PEG-NPs and one-phase exponential association for PCE-PLGA-NPs. Moreover, the important permeability of luteolin skin was observed, especially for PCE-PLGA-PEG-NPs. Both formulations exhibited no irritation and no damaging effects on skin integrity, suggesting their safety. Finally, the results of the scratch wound healing experiment using 3T3-L1 cells revealed significant cell migration and proliferation, with an improved efficacy for PCE-PLGA-PEG-NPs compared to the free extract, demonstrating the potential of this formulation in the treatment of wound healing.

Objective Thymopentin (5TP) significantly improved typical murine premature ovarian failure (POF) symptoms induced by a high‐fat and high‐sugar (HFHS) diet. However, its effect and mechanism remain unclear. Materials and methods RNA‐Seq was used to detect the differentially expressed genes among each group. HFHS‐induced POF mouse model was generated and injected with siRNA using Poly (lactic‐co‐glycolic acid) (PLGA) as a carrier. Results RNA‐Seq suggested that 5TP promoted the expression of Yin Yang 2 (YY2) in mouse ovarian granulosa cell (mOGC) of HFHS‐POF mice. Luciferase reporter assay indicated that 5TP promoted the binding of YY2 to the specific sequence C(C/T)AT(G/C)(G/T) on the Lin28A promoter and promoted Lin28A transcription and expression. We continuously injected PLGA‐cross‐linked siRNA nanoparticles targeting YY2 into HFHS‐POF mice (siYY2@PLGA), which significantly reduced the therapeutic effect of 5TP. siYY2@PLGA injection also significantly attenuated the upregulation of Lin28a expression in mOGCs induced by 5TP and enhanced the expression of let‐7 family microRNAs, thereby inhibiting the proliferation and division of mOGCs. qPCR results showed that there was a significant difference in the expression levels of exosome‐derived Yy2 mRNAs between POF patients and normal women, and that there was a specific correlation between the expression level of exosome‐derived Yy2 and the peripheral concentrations of the blood hormones pregnenolone, progesterone and oestradiol. Conclusions Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibits the activity of let‐7 family microRNAs and alleviates the ageing of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice. Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibit the activity of let‐7 family microRNAs, and alleviate the aging of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice.

In this study, we designed and developed a new drug delivery system of multifunctional composite microcapsules for oral administration of insulin. Firstly, in order to enhance the encapsulation efficiency, insulin was complexed with functional sodium deoxycholate to form insulin-sodium deoxycholate complex using hydrophobic ion pairing method. Then the complex was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles by emulsion solvent diffusion method. The PLGA nanoparticles have a mean size of 168 nm and a zeta potential of −29.2 mV. The encapsulation efficiency was increased to 94.2% for the complex. In order to deliver insulin to specific gastrointestinal regions and reduce the burst release of insulin from PLGA nanoparticles, hence enhancing the bioavailability of insulin, enteric targeting multifunctional composite microcapsules were further prepared by encapsulating PLGA nanoparticles into pH-sensitive hydroxypropyl methyl cellulose phthalate (HP55) using organic spray-drying method. A pH-dependent insulin release profile was observed for this drug delivery system in vitro. All these strategies help to enhance the encapsulation efficiency, control the drug release, and protect insulin from degradation. In diabetic fasted rats, administration of the composite microcapsules produced a great enhancement in the relative bioavailability, which illustrated that this formulation was an effective candidate for oral insulin delivery.

Glioblastoma (GBM) therapy is highly challenging, as the tumors are very aggressive due to infiltration into the surrounding normal brain tissue. Even a combination of the available therapeutic regimens may not debulk the tumor completely. GBM tumors are also known for recurrence, resulting in survival rates averaging <18 months. In addition, systemic chemotherapy for GBM has been challenged for its minimal desired therapeutic effects and unwanted side effects. We hypothesized that paclitaxel (PTX) and superparamagnetic iron oxide (SPIO)-loaded PEGylated poly(lactic- -glycolic acid) (PLGA)-based nanoparticles (NPs; PTX/SPIO-NPs) can serve as an effective nanocarrier system for magnetic targeting purposes, and we aimed to demonstrate the therapeutic efficacy of this system in an orthotopic murine GBM model. PTX/SPIO-NPs were prepared by emulsion-diffusion-evaporation method and characterized for physicochemical properties. In vitro cellular uptake of PTX/SPIO-NPs was evaluated by fluorescence microscopy and Prussian blue staining. Orthotopic U87MG tumor model was used to evaluate blood-brain barrier disruption using T contrast agent, ex vivo biodistribution, in vivo toxicity and in vivo antitumor efficacy of PTX/SPIO-NPs. PTX/SPIO-NPs were in the size of 250 nm with negative zeta potential. Qualitative cellular uptake studies showed that the internalization of NPs was concentration dependent. Through magnetic resonance imaging, we observed that the blood-brain barrier was disrupted in the GBM area. An ex vivo biodistribution study showed enhanced accumulation of NPs in the brain of GBM-bearing mice with magnetic targeting. Short-term in vivo safety evaluation showed that the NPs did not induce any systemic toxicity compared with Taxol (PTX). When tested for in vivo efficacy, the magnetic targeting treatment significantly prolonged the median survival time compared with the passive targeting and control treatments. Overall, PTX/SPIO-NPs with magnetic targeting could be considered as an effective anticancer targeting strategy for GBM chemotherapy.

The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic- -glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B. BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential -0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t ), a higher maximum plasma concentration ( ) and took longer to reach the maximum plasma concentration (T ) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment.

Advances in drug delivery systems (DDSs) have enabled the specific delivery of drugs to target cells. Subtilase cytotoxin (SubAB) produced by certain enterohemorrhagic Escherichia coli strains induces endoplasmic reticulum (ER) stress and suppresses nitric oxide generation in macrophages. We previously reported that modification of SubAB with poly(D,L-lactide-co-glycolic) acid (PLGA) nanoparticles (SubAB-PLGA NPs) increased intracellular uptake of SubAB and had an anti-inflammatory effect on macrophages. However, specific delivery of SubAB to macrophages could not be achieved because its effects on other cell types were not negligible. Therefore, to suppress non-specific SubAB binding, we used low-binding mutant SubABS35A (S35A) in which the 35th serine of the B subunit was mutated to alanine. In a macrophage cell line, PLGA NPs modified with S35A (S35A-PLGA NPs) induced ER stress and had anti-inflammatory effects similar to WT-PLGA NPs. However, in an epithelial cell line, S35A-PLGA NPs induced lower ER stress than WT-PLGA NPs. These results suggest that S35A is selectively delivered to macrophages rather than epithelial cells by modification with PLGA NPs and exerts anti-inflammatory effects. Our findings provide a useful technique for protein delivery to macrophages and encourage medical applications of DDSs for the treatment of inflammatory diseases.

Poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) are well recognized as an ideal drug delivery carrier for their biocompatibility and biodegradability. In order to overcome the disadvantage of drug burst release, chitosan (CS) was used to modify the PLGA nanoparticles. In this work, CS-PLGA nanoparticles with different ratio of CS to PLGA were prepared using high-gravity rotating packed bed (RPB). With the increase of amount of CS, the particle size increased from 132.8 ± 1.5 nm to 172.7 ± 3.2 nm, zeta potential increased from −20.8 ± 1.1 mV to 25.6 ± 0.6 mV, and drug encapsulation efficiency increased from 65.8% to 87.1%. The initial burst release of PLGA NPs reduced after being modified by CS, and the cumulative release was 66.9%, 41.9%, 23.8%, and 14.3%, after 2 h, respectively. The drug release of CS-modified PLGA NPs was faster at pH5.5 than that at pH 7.4. The cellular uptake of CS-modified PLGA NPs increased compared with PLGA NPs, while cell viability was reduced. In conclusion, these results indicated that CS-modified, PTX-loaded PLGA NPs have the advantages of sustained drug release and enhanced drug toxicity, suggesting that CS-modified NPs can be used as carriers of anticancer drugs.

Background Peptide based vaccines may suffer from limited stability and inefficient delivery to professional antigen-presenting cells (APCs), such as dendritic cells (DCs). In order to overcome such limitations, several types of biodegradable nanoparticles (NPs) have been developed as carrier system for antigens. The present study describes for the first time the extensive biological characterization of cationic NPs made of poly (D,L-lactide-co-glycolide) (PLGA) and polyethylenimine (PLGA/PEI) as delivery system for protein/peptide antigens, with potential in therapeutic cancer vaccine development. Results Flow cytometry as well as confocal laser scanning microscopy (CLSM) showed that PLGA/PEI NPs are more readily taken up than PLGA NPs by both human CD14 + monocytes and mouse Hepa 1–6 hepatoma cell line. No signs of toxicity were observed in either cellular setting. Sequential image acquisition by TEM showed an intracellular apical localization for PLGA NPs and a perinuclear localization for PLGA/PEI NPs. Both NPs showed a clathrin-dependent as well as a caveolin-dependent internalization pathway and, once in the cells, they formed multivesicular endosomes (MVE). Finally, an ex vivo priming experiment showed that PLGA/PEI NPs are comparable to PLGA NPs in delivering a non-self antigen (i.e., ovalbumin - OVA) to immature dendritic cells (imDCs), which matured and induced autologous naïve CD4 + T cells to differentiate to memory (i.e., central memory and effector memory) cells. Such a differentiation was associated with a Th1 phenotype suggesting a downstream activation and amplification of a CD8 + T cell cytotoxic response. The same OVA antigen in a soluble form was unable to induce maturation of DCs, indicating that both NP formulations provided an intrinsic adjuvanting effect combined to efficient antigen delivery. Conclusions Our study represents the first report on side-by-side comparison of PLGA and PLGA/PEI NPs as strategy for protein antigen delivery. PLGA/PEI NPs are superior for cellular uptake and antigen delivery as compared to PLGA NPs. Such an evidence suggests their great potential value for vaccine development, including therapeutic cancer vaccines.