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The aim of this research was to improve transdermal delivery and distribution of tetramethylpyrazine (TMP) in the brain, by adding borneol (BN) and iontophoresis (ITP), and using microneedles (MN), to prevent middle cerebral artery occlusion (MCAO). BN was encapsulated into sulfobutylated-β-cyclodextrin (BN-SBE-β-CD), and then dispersed together with TMP. Four delivery groups were tested: passive (with no ITP and MN), ITP, MN, and MN combined with ITP (MN-ITP). In vitro transdermal fluxes of the drugs in those groups and in that corresponding order were 79.12 ± 14.5, 395.43 ± 12.37, 319.16 ± 29.99, and 1018.07 ± 108.92 μg/cm 2 (for TMP), and 39.34 ± 1.31, 202.81 ± 53.56, 715.47 ± 75.52, and 1088.60 ± 53.90 μg/cm 2 (for BN), respectively, which indicated that the use of MN-ITP greatly enhanced transdermal TMP and BN delivery compared to the other groups. The AUC 0-t for the combined use of TMP and BN drugs was measured using two in vivo studies, cutaneous microdialysis and pharmacodynamic, yielding increased folds of 3.69 and 1.98 in ITP, 6.05 and 2.73 in MN, and 12.43 and 7.47 in MN-ITP groups, respectively, as compared to those in the passive group. In addition, the combined use of TMP and BN increased TMP distribution in the heart and the brain, indicated by TMP C max of 1.76- and 1.59-fold higher (p < 0.05), and TMP AUC 0-t of 1.50 times and 1.19-fold higher (p < 0.01), than with administration of TMP in absence of BN, respectively. The brain infarction area and IL-β expression in the MCAO rat were significantly decreased in the MN-ITP group, compared with the control group (p < 0.05). In conclusion, combination of MN and ITP resulted in a synergistic enhancement of transdermal delivery and distribution of TMP in the brain, when in combination with BN, thereby significantly decreasing the infarct volumes and improving the neurological scores of MCAO., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nanostructured lipid carriers (NLCs) can enhance the safe transdermal delivery system of drugs. Moreover, dissolving microneedles (MNs) can enhance the permeability and controlled drug release. In this study, NLCs were formulated as a suitable vehicle for aconitine (ACO) delivery to effectively inhibit the inflammation of fibroblast-like synoviocytes isolated from a rat model of adjuvant-induced arthritis (AA-FLS). To improve drug delivery, the ACO-loaded NLCs (ACO-NLCs) were embedded in polyvinylpyrrolidone-based dissolving MNs fabricated by an ultraviolet cross-linking method. The nanoparticles maintained good physical stability in the dissolving MNs. The insertion capabilities of the ACO-NLCs-MNs were determined by observing histological sections of the skin after insertion, and scanning electron microscopy was used to observe the changes in the MNs over time. In vivo microdialysis showed that the NLCs-MNs enhanced the transdermal delivery of ACO through disrupting the barrier function of the stratum corneum (SC) and releasing the drug continuously. The ACO-NLCs-MNs showed a significant inhibitory effect on the paw swelling and inflammation in AA model rats. Moreover, this dual approach involving NLCs-loaded dissolving MNs formed a drug reservoir and effectively improved the ACO-induced arrhythmia. These results indicate that NLCs-containing MNs could be promising systems for the effective transdermal delivery and controlled local administration of ACO., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Breast cancer remains a major threat to women's health, and the incidence of breast cancer continues to increase each year. Paclitaxel (PTX) is commonly used to treat breast cancer, but shows limited solubility and is associated with major side effects, limiting its clinical applications. Photodynamic therapy (PDT) is a promising treatment for breast cancer but is limited by the poor solubility of photosensitizers and difficulties in targeting and enriching the tumor tissue with photosensitizers. Here, we prepared a new nanocarrier system using nanostructured lipid carriers (PTX@FA-NLC-PEG-Ce6) harboring PTX, chlorin e6 (Ce6), and folic acid-targeted head to overcome the limitations of PTX and Ce6 in hydrophobicity and increase the target efficiency of chemotherapy drugs and photosensitizers at the tumor. The results showed that the drug-loading system met the requirements for intravenous injection, had tumor targeting ability, and could be easily taken up by MDA-MB-231 cells. Moreover, Ce6 could be dissociated from the surface of the drug-loading system and evenly distributed in cells after a period of time when the nanostructured lipid carriers had entered lysosomes through endocytosis. Additionally, reactive oxygen species were then produced to induce PDT at a specific wavelength of illumination. In vitro pharmacodynamic experiments showed that combined PDT and chemotherapy had synergistic effects (combination index: 0.647). Furthermore, pharmacodynamic experiments in nude mice showed that the drug-loading system had ideal antitumor effects without obvious side effects. Thus, PTX@FA-NLC-PEG-Ce6 may have applications as a promising drug-loading system for PDT combined with chemotherapy in patients with breast cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

trans-Ferulic acid (TFA) has antioxidative, anti-inflammatory, and cardioprotective effects, but its poor solubility in water results in unsatisfactory oral bioavailability when administered conventionally at a standard dosage. However, the limited bioavailability of TFA can be overcome by delivering it in nanostructured lipid carriers (NLCs). In this study, a microemulsion (ME)-based method was used to prepare NLCs with ethyl oleate as the liquid lipid component and glyceryl behenate as the solid lipid component. These NLCs and solid lipid nanoparticles (SLNs) were then used as vehicles for TFA. Their entrapment efficiencies (EE), stability during storage, in vitro release profiles, and in vivo pharmacokinetics were compared. The NLC formulation afforded a drug entrapment efficiency that was significantly greater than that of the SLN formulation, which was made using a single solid lipid. Furthermore, the TFA that was dispersed in the disordered binary lipid matrix of the NLC formulation was more stable than that in the SLN formulation, and thus showed less expulsion from the vehicle during storage. In in vivo pharmacokinetic studies, the NLC TFA formulation yielded a greater Cmax and AUC than that produced by the SLN formulation and an aqueous TFA suspension. This showed that the oral bioavailability of TFA was markedly improved by packaging in NLCs. NLCs are thus a promising vehicle for oral TFA administration, with significant advantages over SLNs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Isooctyl p-methoxycinnamate(OMC) is a commonly used chemical ultraviolet B sunscreen that suffers rapid degradation with current delivery systems following sun exposure. In this study, deoxycholate-mediated liposome (DOC-LS) endocytosis was employed to improve the antioxidation effects of OMC following topical administration, and the in vitro cell uptake was investigated to understand the enhanced cutaneous absorption of the drug via this nanocarrier. Following topical application, structural changes in the stratum corneum were identified. With the increase of DOC content, the drug deposition in skin decreased; from this, a DOC-LS formulation was selected that showed significantly more drug delivery in skin than did the other preparations (P<0.05). DOC-LS decreased skin resistance, suggesting its ability to induce skin barrier disruption. In vitro HaCaT keratinocyte cell uptake of coumarin-6 incorporated in the two types of phosphatidylcholine (PC) vesicles (i.e., LS or DOC-LS) yielded similar fluorescence intensities following incubation for different periods (P<0.05). However, CCC-ESF-1 embryonic fibroblast cell uptake of the fluorescence revealed time-dependence, and the emitted light from DOC-LS incubated cells was stronger than that from cells incubated with LS (P<0.05). These findings might be associated with the endocytic pathway of HaCaT, which mainly exhibited adsorption or physical adhesion of the fluorescent vesicles, whereas CCC-ESF-1 markedly internalized the PC vesicles via the lysosomes, as shown by intracellular fluorescence co-location studies. Following loading with the same amount of OMC, the DOC-LS vesicles exhibited superior skin tissue antioxidative capacity among the preparations tested, corroborating the in vivo skin drug deposition results. Thus, our results suggest that DOC-LS is a promising system for OMC dermal delivery without promoting skin irritation, which is quite advantageous for therapeutic purposes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Span 40-based niosomes were employed as nanocarriers to improve cutaneous absorption of salidroside. The niosomal formulation with a molar proportion of Span 40 to cholesterol of 4:3 showed the highest transdermal flux and skin deposition of salidroside. The transdermal flux of the 4:3 niosomal formulation was significantly greater than that of the aqueous solution. Salidroside-loaded niosomes showed good biocompatibility with skin tissue, human epidermal immortal keratinocytes (HaCaT), and human embryonic skin fibroblasts (CCC-ESF). The fluorescence intensity of HaCaT cells after uptake of coumarin 6-labeled niosomes was similar to that observed after uptake of the aqueous suspension. The fluorescence intensity of CCC-ESF cells was greater than that of the aqueous suspension after incubation for 10 min, but was not significantly different after 60 min. Further investigation revealed that internalization of niosomes by HaCaT cells may be achieved through pinocytotic vesicles and macropinocytosis, which consumes energy, rather than via lysosomes. In CCC-ESF cells, pinocytotic vesicles and lysosomes were both important mediators of endocytosis. The niosome formulations reported here could improve the dermal and transdermal salidroside delivery, and the in vitro cell uptake evaluation results serve as a basis for further research into the mechanisms through which niosomes enhance drug permeability., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Wheat germ agglutinin (WGA)-grafted lipid nanoparticles has been prepared and its in vitro association with Caco-2 cells has been studied previously. The purpose of this study was to further investigate the potential of WGA-grafted lipid nanoparticles for oral delivery of bufalin, a poorly water soluble drug, by evaluating its ex vivo bioadhesion with intestinal mucosal segments and in vivo bioavailability. A significant higher adhesion between WGA-grafted lipid nanoparticles and intestinal mucosa was found compared with that of WGA-free lipid nanoparticles (p<0.05). The in vivo pharmacodynamic studies were performed by oral administration of WGA-grafted lipid nanoparticles and suspensions to fasted rats. Compared with suspensions, WGA-grafted lipid nanoparticles showed much larger AUC and C(max), and a 2.7-fold improvement in oral bioavailability. These results illustrate the potential utility of WGA-grafted lipid nanoparticles for oral delivery of a poorly water-soluble drug such as bufalin., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We developed solid dispersions, using the gas anti-solvent technique (GAS), to improve the oral bioavailability of the poorly water-soluble active component oridonin. The solubility of oridonin in supercritical carbon dioxide was measured under various pressures and temperatures. To prepare oridonin solid dispersions using the GAS technique, ethanol was used as the solvent, CO(2) was used as the anti-solvent and the hydrophilic polymer polyvinylpyrrolidone K17 (PVP K17) was used as the drug carrier matrix. Characterization of the obtained preparations was undertaken using scanning electron microscopy (SEM), X-ray diffraction (XRD) analyses and a drug release study. Oridonin solid dispersions were formed and oridonin was present in an amorphous form in these dispersions. Oridonin solid dispersions significantly increased the drug dissolution rate compared with that of oridonin powder, primarily through drug amorphization. Compared with the physical mixture of oridonin and PVP K17, oridonin solid dispersions gave higher values of AUC and C(max), and the absorption of oridonin from solid dispersions resulted in 26.4-fold improvement in bioavailability. The present study illustrated the feasibility of applying the GAS technique to prepare oridonin solid dispersions, and of using them for the delivery of oridonin via the oral route., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A bioadhesive drug delivery system, wheat germ agglutinin (WGA)-grafted lipid nanoparticles, was developed for the oral delivery of bufalin (a hydrophobic active component extracted from the traditional Chinese medicine Chan'su). The lipid nanoparticles associated with poly(vinyl alcohol) (PVA) were prepared by high-pressure homogenization. WGA was coupled to lipid nanoparticles by activating the hydroxyl group using glutaraldehyde, and then conjugating the nanoparticles with WGA. WGA-grafted lipid nanoparticles with a mean particle size of 164 nm and zeta potential of -10.6 mV were obtained with bufalin encapsulation of 68.2%. The amount of bound WGA was approximately 28.9% of the amount of WGA initially added. The association study between fluorescent 6-coumarin-loaded WGA-grafted lipid nanoparticles and Caco-2 monolayers showed that WGA enhanced the cellular uptake of nanoparticles compared with WGA-free lipid nanoparticles. These results suggest that WGA-grafted lipid nanoparticles could be a promising carrier to enhance cellular uptake. They could also improve drug bioavailability through the oral route., (Copyright 2010 Elsevier B.V. All rights reserved.)

The objective of this study was to optimize and characterize an oridonin self-microemulsifying drug delivery system (SMEDDS) formulation. A central composite design (CCD) was used to investigate the influence of factors (oil percentage and surfactant to co-surfactant ratio (Sur/Co-s ratio)) on the responses including droplet size, polydispersity, equilibrium solubility and in situ intestine absorption rate. Furthermore, the desirability function approach was applied to obtain the best compromise among the multiple responses. It was found that oil percentage played a significant role on the droplet size and polydispersity. The drug equilibrium solubility was mainly contributed to oil percentage and less to Sur/Co-s ratio. The in situ intestinal absorption was influenced by both of the two factors, whereas the oil percentage played a more important role in absorption. The practical response values under the optimized formulation were in good accordance with the predicted values. Our results demonstrate CCD is of value in optimizing the SMEDDS formulation and understanding the effects of formulation compositions on SMEDDS properties.