Lactoferrin/phenylboronic acid-functionalized hyaluronic acid nanogels loading doxorubicin hydrochloride for targeting glioma.

Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.

Understanding the cellular uptake and biodistribution of a dual-targeting carrier based on redox-sensitive hyaluronic acid-ss-curcumin micelles for treating brain glioma.

The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles. HA was conjugated to CUR through a disulfide bond, which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis. Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.

Tween 80-modified hyaluronic acid-ss-curcumin micelles for targeting glioma: Synthesis, characterization and their in vitro evaluation.

Redox-sensitive micelles based onhydrophilic hyaluronic acid-ss-hydrophobic curcumin conjugate were designed as a novel delivery system for gliomas targeting. Furthermore, the obtained micelles were further functionalized with Tween 80 (CUR-THSC) for better brain penetration. Dynamic light scattering experiment and in vitro release study showed that the synthetic disulfide-linked conjugate possessed redox-sensitivity under high glutathione conditions. Spherical micelles with a mean particle size of 74.2 nm, negative zeta potential (-30.25 mV), high entrapment efficiency (94.12%) and drug loading (8.9%) were obtained. XRD analysis of micelles revealed amorphous form of the encapsulated drug. CUR-THSC micelles showed good plasma stability and did not induce any hemolysis in erythrocytes. In addition, highest cytotoxicity in G422 cells was observed compared to the free curcumin group and non-sensitive micelles group. These results indicate that the Tween 80-modified hyaluronic acid-ss-curcumin micelles could emerge as a promising platform for the delivery of curcumin in the treatment of gliomas.

The effect of the molecular weight of hyaluronic acid on the physicochemical characterization of hyaluronic acid-curcumin conjugates and in vitro evaluation in glioma cells.

In this study, a redox-sensitive glioma-targeting micelle system was designed to deliver curcumin (CUR) by conjugating it to hyaluronic acid (HA-s-s-CUR, HSC) via disulfide linkage. The effect of the molecular weight of HA on the physicochemical characteristics of HSC conjugates and their in vitro effects in glioma cells were also explored. These conjugates formed nano-scale micelles (209-926 nm) independently in aqueous solution. The micelles greatly increased the solubility of CUR and improved its stability, which is crucial for harnessing the therapeutic potential of this active molecule. The redox sensitivities of different HSC micelles were measured by using a dynamic light scattering method and in vitro release assay, which showed that the low (50 kDa) and medium molecular weight (200 kDa and 500 kD) HA-based conjugates were sensitive to GSH, whereas higher molecular weights (1000 kDa and 2000 kDa) did not show redox-sensitivity. Increased cytotoxicity and uptake of low and medium molecular weight-modified HSC conjugates by the glioma cells further confirmed that the sensitive micelles are more effective for intracellular drug delivery compared to the high molecular weight-modified HSC conjugates or the plain CUR. In summary, the molecular weight of HA affects the physicochemical attributes of HSC conjugates. Only HSC micelles made with HA molecules less than 500 kDa exhibit redox sensitivity.

In vitro and in vivo evaluation of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) nanoparticles prepared by miniemulsion polymerization.

In this paper, 10-hydroxycamptothecin (HCPT)-loaded poly (n-butyl cyanoacrylate) nanoparticles (HCPT-PBCA-NPs) co-modified with polysorbate 80, soybean phospholipids, and polyethylene glycol (100) monostearate were successfully prepared via miniemulsion polymerization, and were characterized for particle size, morphology, zeta potential, encapsulation efficiency (EE) and drug loading capacity (DL). The chemical structure of HCPT-PBCA-NPs and the state of HCPT in the PBCA-NPs were investigated by DSC, FTIR and 1H NMR. Additionally, drug release, cytotoxicity, cellular uptake capacity, cellular uptake mechanism, and in vivo behavior of NPs were investigated as well. The particles were 92.7nm in size with a high EE of 94.24%. FTIR, 1H NMR, and DSC demonstrated complete polymerization of BCA monomers and the drug was in a molecular or amorphous form inside the NPs. In vitro release of the drug from HCPT-PBCA-NPs exhibited sustained-release and less than 60% of HCPT was released from the NPs within 24h of dialysis. Cellular uptake study displayed that Caco-2 cell uptake of NPs was governed by active endocytosis, clathrin- and caveolin-mediated process, and increased with the increase of the NPs concentration and the time. The pharmacokinetic study in rats showed that encapsulation of HCPT into PBCA-NPs increased the Cmax and AUC0-t about 6.52 and 7.56 times, respectively, in comparison with the HCPT suspension. It was concluded that HCPT loaded PBCA-NPs prepared by miniemulsion polymerization could be promising in oral drug delivery.

Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers.

The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors' ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA-polyethylene glycol 100-monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (<150 nm), high drug encapsulation (>90%), drug loading (about 3%), negative ζ-potential (-7 to -3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs.

N-acetyl-L-cysteine functionalized nanostructured lipid carrier for improving oral bioavailability of curcumin: preparation, in vitro and in vivo evaluations.

The application of orally administered nanoparticles in the circulation system is limited by the secretion and shedding of intestinal tract mucous layer. In order to enhance mucoadhesion and mucus penetration of curcumin (Cur)-loaded nanostructured lipid carrier (NLC) after oral administration, a new multifunctional conjugate, N-acetyl-L-cysteine-polyethylene glycol (100)-monostearate (NAPG), was synthesized. Functionalized nanocarriers (Cur-NAPG-NLC) modified by different amounts of NAPG (the amounts of NAPG were 20, 50, and 100 mg) were prepared and investigated for in vitro and in vivo behavior. Mean particle sizes of 89-141 nm with negative zeta potential (-15 to -11 mV) and high encapsulation efficiency (EE, >90%) possessing spherical and stable nanocarriers were observed. Sustained drug release was also observed for the NAPG-NLC. In situ intestinal perfusion studies showed that with increasing the amount of NAPG increase absorption of Cur. In vivo oral pharmacokinetic evaluation suggested that the bioavailability of Cur in rats was proportional to the degree of functionalization of NLCs with NAPG. AUC0-t of Cur-NAPG100-NLC was improved by 499.45 and 116.89 folds as compared to that of Cur solution and unmodified Cur-NLC, respectively. In conclusion, NAPG modified NLC could be a promising drug delivery system for improving oral performance of BCS class IV drugs.