Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis.

Angiogenesis is an organized series of events, beginning with vessel destabilization, followed by endothelial cell re-organization, and ending with vessel maturation. The formation of a mature vascular network requires precise spatial and temporal regulation of a large number of angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor (PDGF). VEGF aids in vascular permeability and endothelial cell recruitment, FGF-2 activates endothelial cell proliferation and migration while PDGF stimulates vascular stability. Accordingly, VEGF may inhibit vessel stabilization while PDGF may inhibit endothelial cell recruitment. Therefore, a new polymeric system was prepared by the supercritical carbon dioxide foaming technology, which realized sequential delivery of two or more growth factors with the controlled dose and rate. Increased release of VEGF (71.10%) and FGF-2 (69.76%) compared to PDGF (43.17%) was observed for the first 7 days. Thereafter, up till 21 days, an increased rate of release of BMP-2 compared to VEGF 165 was observed. The effects of PDGF-PLAms/VEGF-FGF-2-PLGA scaffolds on angiogenesis were investigated by human umbilical vein endothelial cells (HUVECs) angiogenic differentiation in vitro and chorioallantoic membrane (CAM) angiogenesis in vivo. Sequential delivery of VEGF, FGF-2 and PDGF from structural polymer scaffolds with distinct kinetics resulted in significant angiogenic differentiation of HUVECs and rapid formation of mature vascular networks in chorioallantoic membrane. This study reported a composite scaffold with distinct release kinetics, and these results clearly indicated the importance of sequential delivery of multiple growth factors in tissue regeneration and engineering.

Formulation and evaluation of gastroretentive floating drug delivery system of dipyridamole.

A multiple-unit floating alginate bead drug delivery system with prolonged stomach retention time was developed in this study. The floating alginate beads were prepared by ionic cross-linking method, using CaCO3 as the gas-forming agent. Over 92% of the beads remained floating after 9 h. In order to prepare sustained-release dosage forms of dipyridamole, the solid dispersion technique was applied using a blend of Eudragit L100 and Eudragit RLPO. Afterwards, the solid dispersions of dipyridamole were incorporated into the floating alginate beads. The drug release was modified by changing the ratio of Eudragit RLPO and Eudragit L100 in the solid dispersions. The in vivo results showed that the relative bioavailability of alginate beads was enhanced by approximately 2.52-fold compared with that of the commercial tablet. Therefore, our study illustrated the potential use of floating alginate beads combined with the solid dispersion technique for the delivery of acid-soluble compounds, such as dipyridamole.

Hyaluronic acid-based multifunctional nanoplatform for glucose deprivation-enhanced chemodynamic/photothermal synergistic cancer therapy.

We present a hyaluronic acid (HA)-based nanoplatform (CMGH) integrating starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for targeted cancer treatment. CMGH fabrication involved the encapsulation of glucose oxidase (GOx) within a copper-based metal-organic framework (CM) followed by surface modification with HA. CMGH exerts its antitumor effects by catalyzing glucose depletion at tumor sites, leading to tumor cell starvation and the concomitant generation of glucuronic acid and H2O2. The decreased pH and elevated H2O2 promote the Fenton-like reaction of Cu ions, leading to hydroxyl radical production. HA modification enables targeted accumulation of CMGH at tumor sites via the CD44 receptor. Under near-infrared light irradiation, CM exhibits photothermal conversion capability, enhancing the antitumor effects of CMGH. In vitro and in vivo studies demonstrate the effective inhibition of tumor growth by CMGH. This study highlights the potential of CMGH as a targeted cancer therapeutic platform.

Effect of preparation conditions on the size and encapsulation properties of mPEG-PLGA nanoparticles simultaneously loaded with vincristine sulfate and curcumin.

This study prepared monomethoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA) nanoparticles simultaneously loaded with vincristine sulfate (Vin) and curcumin (Cur) via O/W emulsion solvent evaporation. Five independent processing parameters were systematically evaluated to enhance the entrapment of dual agents with different properties (i.e. Vin and Cur, which are the hydrophilic and hydrophobic, respectively) into mPEG-PLGA nanoparticles and to control the particle size. The approaches used to investigate the enhancement of drug entrapment efficiencies and control over the particle size included mPEG-PLGA concentration, polyvinyl alcohol (PVA) concentration, initial Vin/Cur content, dichloromethane-to-acetone volume ratio, and aqueous-to-organic phase volume ratio. The nanoparticles produced using the optimum formulation conditions had a particle size of 131.5 nm with a low polydispersity index of 0.047. The entrapment efficiencies were 63.52 ± 2.36% for Vin and 54.60 ± 2.46% for Cur (n = 3). The drug loadings were 1.06 ± 0.04% for Vin and 3.64 ± 0.16% for Cur (n = 3).

Palladium-based multifunctional nanoparticles for combined chemodynamic/photothermal and calcium overload therapy of tumors.

Due to the high mortality and incidence rates associated with tumors and the specificity of the tumor microenvironment (TME), it is difficult to achieve a complete cure for tumors using a single therapy. In this study, calcium carbonate-modified palladium hydride nanoparticles (PdH@CaCO3) were prepared and utilized for the combined treatment of tumors through chemodynamic therapy (CDT)/photothermal therapy (PTT) and calcium overload therapy. After entering tumor cells, PdH@CaCO3 releases calcium ions (Ca2+) and PdH once it reaches the TME due to the pH reactivity of the calcium carbonate coating. The mitochondrial membrane potential is lowered by the Ca2+, leading to irreversible cell damage. Meanwhile, PdH reacts with excessive hydrogen peroxide (H2O2) in the TME via the Fenton reaction, generating hydroxyl radicals (·OH). Moreover, PdH is an excellent photothermal agent that can kill tumor cells under laser irradiation, leading to significant anti-tumor effects. In vitro and in vivo studies have demonstrated that PdH@CaCO3 could combine CDT/PTT and calcium overload therapy, exhibiting great clinical potential in the treatment of tumors.

Dual-Oxygenation/Dual-Fenton Synergistic Photothermal/Chemodynamic/Starvation Therapy for Tumor Treatment.

Due to the complexity of tumor pathogenesis and the heterogeneity of the tumor microenvironment (TME), it is difficult to obtain satisfactory efficacy with a single therapy. In this study, a hyaluronic acid (HA)-modified ruthenium nanoaggregate (RuNA) and glucose oxidase (GOD) -loaded manganese dioxide (MnO2) nanoflowers (MRG@HA) have been prepared. RuNA and MnO2 nanoflowers can generate O2 in TME, alleviating tumor tissue hypoxia. RuNA is a good photothermal agent for high-temperature ablation of solid tumors under infrared laser irradiation. GOD consumes glucose in the presence of O2 and converts it into glucuronic acid and hydrogen peroxide, reducing tumor nutrient supply while promoting Fenton-like reactions of MnO2 nanoflowers and RuNA to produce cytotoxic hydroxyl radicals. MRG@HA can also actively target tumor cells through the affinity of HA and CD44 receptor to improve the antitumor effect. In vitro and in vivo studies have confirmed the synergistic effect of MRG@HA with tumor photothermal/chemodynamic/starvation therapy, showing its great potential for clinical application in tumor therapy.

Design and evaluation of an economic taste-masked dispersible tablet of pyridostigmine bromide, a highly soluble drug with an extremely bitter taste.

Pyridostigmine bromide (PTB) is a highly soluble and extremely bitter drug. Here, an economic complexation technology combined with direct tablet compression method has been developed to meet the requirements of a patient friendly dosage known as taste-masked dispersible tablets loaded PTB (TPDPTs): (1) TPDPTs should have optimal disintegration and good physical resistance (hardness); (2) a low-cost, simple but practical preparation method suitable for industrial production is preferred from a cost perspective. Physicochemical properties of the inclusion complex of PTB with beta-cyclodextrin were investigated by Fourier transformed infrared spectroscopy, differential scanning calorimetry and UV spectroscopy. An orthogonal design was chosen to properly formulate TPDPTs. All volunteers regarded acceptable bitterness of TPDPTs. The properties including disintegration time, weight variation, friability, hardness, dispersible uniformity and drug content of TPDPTs were evaluated. The dissolution profile of TPDPTs in distilled water exhibited a fast rate. Pharmacokinetic results demonstrated that TPDPTs and the commercial tablets were bioequivalent.

Ferrocene-based multifunctional nanoparticles for combined chemo/chemodynamic/photothermal therapy.

Ferrocene and its derivatives have great potential for biomedical applications, but few related studies have been reported. In this study, copper ions and ferrocene derivatives were used for the first time to construct the ferrocene-based nanoparticles (Cu-Fc) with a hydrated particle size of approximately 220 nm. Their good photothermal conversion properties were verified in vitro and in vivo for the first time, indicating that they could be used as a novel photothermal agent for tumor treatment. In addition, the nanoparticles exhibited efficient Fenton effect under weakly acidic conditions, indicating that they can generate hydroxyl radicals (OH) to kill tumors in the weakly acidic environment of the tumor-specific microenvironment. More importantly, the nanoparticles can deplete glutathione (GSH), thus further enhancing Fenton effect-mediated chemodynamic therapy (CDT). Multifunctional ferrocene-based nanoparticles (DOX@Cu-Fc) were obtained after loading the chemotherapeutic drug doxorubicin hydrochloride (DOX). The results of in vitro and in vivo experiments showed that DOX@Cu-Fc could enhance tumor treatment by the combination of chemo/CDT/photothermal therapy (PTT).

Facile preparation of a novel hyaluronic acid-modified metal-polyphenol photothermal nanoformulation for tumor therapy.

Photothermal therapy (PTT) is a potentially effective and non-invasive tumor therapy that has attracted the attention of many researchers. This study systematically investigated the formation of metal-polyphenol nanoparticles and their photothermal properties. A simple physical self-assembly method was used to embed hyaluronic acid (HA) into metal-polyphenol nanoparticles, and a novel type of HA-modified ferrous baicalein nanoparticle (HFBNP) was successfully prepared for the first time. Unlike most current methods that utilize positive and negative charge attraction or chemical bonding, the method proposed in this study is to embed HA into nanostructures to reduce the risk of HA shedding in the circulation, thereby improving the tumor targeting efficiency while avoiding the use of other chemical reagents. HFBNP had a suitable size distribution and good biosafety meanwhile efficiently converting near-infrared (NIR) laser energy into thermal energy. The active targeting capability mediated by HA significantly increased the uptake of nanoparticles by tumor cells, and HFBNP exhibited a strong growth inhibitory effect on tumor cells under NIR laser irradiation. With the combination of PTT and chemotherapy, HFBNP significantly inhibited tumor growth in tumor-bearing mice. In conclusion, the nanosystem prepared in this study provides a new strategy for tumor therapy.

[Preparation and in vitro release characteristics of curcumin in nanosuspensions].

OBJECTIVE: To prepare curcumin albumin nanosuspensions and study its release characteristics in vitro. METHOD: Curcumin albumin nanosuspensions were prepared by solvent evaporation method. The nanosuspensions were characterized in terms of morphology, size, encapsulation efficiency and in vitro drug release. RESULT: The mean size of albumin nanosuspensions before lyophilization was 245.2 nm and 240.3 nm after reconstitution. The distribution of particle size was uniform. The encapsulation efficiency was (42.39 +/- 0.91)%. In vitro release study revealed that the 72 h accumulative release percentage reached 96%. CONCLUSION: The method described to prepare curcumin albumin nanosuspensions is simple. It might be a novel vehicle potentially for nanoparticle drug delivery system of curcumin.

[Study on intra-gastric floating beads of naringenin].

OBJECTIVE: To prepare calcium alginate-chitosan intra-gastric floating beads of naringenin combining with the solid dispersion method and investigate the in vitro floating characteristics, entrapment efficiency and drug release property of the beads. METHODS: The solid dispersion of naringenin was prepared by the Eudragit RLPO. Sodium alginate solution mixed with the powder of the solid dispersion of naringenin and frother was slowly dripped into chitosan-calcium chloride solution added with acetic acid. Calcium alginatechitosan intra-gastric floating beads of naringenin were obtained after drying. The effects of solid dispersion on in vitro release of naringenin were investigated. RESULTS: Intra-gastric floating beads of naringenin were acquired successfully. More than 70% of the beads kept floating in artificial gastric juice in 9 h, the release ratio of naringenin during 9 h was 65%-70% and the entrapment efficiency was about 70%-80%. CONCLUSION: The sustained release of naringenin in the calcium alginate-chitosan intra-gastric floating beads could be achieved by using the solid dispersion method and it provides some ideas of intra-gastric floating preparations.

A novel self-coated polydopamine nanoparticle for synergistic photothermal-chemotherapy.

The combination of photothermal therapy (PTT) and chemotherapy is a promising strategy to overcome the shortcomings of monotherapy. For the first time, we designed a self-coated nanoparticle formed by mesoporous polydopamine (MPDA) core and polydopamine (PDA) shell, which was used to load docetaxel and modified with hyaluronic acid (HA). The obtained nanoparticle can achieve targeted drug delivery and further exert the synergistic effect of PTT and chemotherapy. The MPDA core has high drug loading due to mesopores, and the PDA shell can prevent the drug from releasing in the non-target-site because of the pH-sensitivity of the PDA. Compared with other PDA coated nanoparticle, self-coated nanoparticle has a simpler composition and can avoid the potential toxicity caused by the introduction of other materials. Experimental results showed that it had good photothermal conversion ability both in vivo and in vitro, and could be actively targeted into tumor cells through HA-mediated targeting. Under laser irradiation, it ablated the tumors. Simple ingredient and preparation, good compatibility and obvious therapeutic effect make it have a broad application prospect in tumor therapy.

[Study on novel colon position pulsatile capsule and its release in vitro].

OBJECTIVE: To develop a colon position pulsatile capsule drug delivery system of which the lag-time is controlled by a plug tablet mainly made of konjac glucomannan and evaluate its release profile in vitro. METHOD: Impermeable capsule body was prepared by filling method, the plug tablet was pressed by direct compression, and the rapid-disintegrable drug tablets was made by wet granulation. The pulsatile capsules were prepared by putting the drug tablet into the impermeable body and sealed it with the plug tablet The factors affecting the lag-time were investigated by dissolution testing. RESULT: The formulation of the rapid-disintegrable drug tablets influenced the pulsatile release of the drug, the composition of the plug tablet significantly influenced the lag-time; the lag-time was extended with the higher viscosity of HPMC and the increased proportion of konjac glucomannan. CONCLUSION: The pulsatile capsule with a suitable lag-time and colon position characteristics can be achieved by adjusting the composition of the plug tablet.

Facile preparation of hyaluronic acid-based quercetin nanoformulation for targeted tumor therapy.

In this study, a novel hyaluronic acid-based quercetin nanoformulation (QUT/HA-NF) was constructed for targeted tumor therapy. QUT/HA-NFs have the advantages of simple operation steps, low production cost and good industrialization prospects. Moreover, surfactants, solvents and chemicals are not involved in the preparation process, which avoid the cumbersome extraction of surfactants and the side effects caused by residual solvents or chemicals. The QUT/HA-NFs we prepared have small particle size and high drug loading. In vitro studies have shown that QUT/HA-NFs can significantly enhance tumor cell uptake and tumor cell killing through CD44 receptor mediation. In a xenograft mouse model of 4T1 tumor, QUT/HA-NFs showed stronger inhibition of tumor growth compared with quercetin alone. The QUT/HA-NFs proposed in this study are expected to provide a potential candidate for the treatment of tumors.

Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells.

Acute liver injury and its terminal phase, hepatic failure, trigger a series of complications, including hepatic encephalopathy, systematic inflammatory response syndrome, and multiorgan failure, with relatively high morbidity and mortality. Liver transplantation is the ultimate intervention, but the shortage of donor organs has limited clinical success. Mangiferin (MF), a xanthone glucoside, has been reported to have excellent anti-inflammatory efficacy. Here, a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury mouse model was established to investigate the protective role of MF and the underlying mechanisms of action. Pretreatment with MF improved survival, decreased serum aminotransferase activities, and inhibited hepatic TNF-α production in LPS/D-GalN-challenged mice. Through Kupffer cell (KC) deletion by GdCl3 and KC adoptive transfer, KCs were confirmed to be involved in these beneficial effects of MF. MF reduced LPS-mediated TNF-α production via the suppression of the TLR4/NF-κB signaling pathway in vitro. MF promoted HO-1 expression, but the knockdown of HO-1 prevented TNF-α inhibition, suggesting that the damage-resistance effects of HO-1 occurred via the suppression of TNF-α synthesis. When HO-1-silenced KCs were transferred to the liver with KC deletion, the protective effect of MF against LPS/D-GalN-induced acute liver injury was reduced, illustrating the role of KC-derived HO-1 in the anti-injury effects of MF. Collectively, MF attenuated acute liver injury induced by LPS/D-GalN via the inhibition of TNF-α production by promoting KCs to upregulate HO-1 expression.

In vitro and in vivo evaluation of liposomes modified with polypeptides and red cell membrane as a novel drug delivery system for myocardium targeting.

Ischemic cardiac disease (ICD) is a cardiovascular disease with high morbidity and mortality. In this study, a novel myocardial targeted drug delivery system was developed represented by co-modified liposomes consisting of red cell membrane (RCM), and the peptides TAT and PCM. Liposomes were prepared using a membrane dispersion-ultrasonic method; the prepared 1% TAT and 3% PCM micelles were mixed with liposomes and under overnight stirring to form polypeptid-modified liposomes. RCM was isolated from mice blood, and the mechanical force facilitated RCM adhesion to the lipid bilayer. The characteristics of liposomes such as the morphology, particle size, zeta-potential, and RCM-conjugation to lipsomes were evaluated. Uptake efficiency and cellular toxicity of liposomes were evaluated in vitro on myocardial cells (MCs). As regard the experiments in vivo, liposomes were intravenously injected into mice, and the blood and organs were collectedat different times to analyze the pharmacokinetics profile of liposomes. The cellular uptake and intracellular distribution of liposomes of different composition into MCs demonstrated that RCM-modified liposomes had the best delivery capability. The pharmacokinetics study further demonstrated that RCM-modified liposomes had prolonged mean residence time (MRT) and more accumulation in the heart. This study indicated that RCM can be used to modify liposomes in combination with polypeptides, because such modification increases the myocardial targeting of liposomes. Therefore, this system constructed in this study might be a potentially effective myocardial drug delivery system.

Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice.

As a natural flavonoid compound, baicalin(BA)has been reported to exhibit hepatoprotective and anti-inflammatory properties. However, the characteristic of poor solubility and low bioavailability greatly limits its application. In addition, the effects and underlying mechanisms of BA in nonalcoholic fatty liver disease (NAFLD) remain elusive. In this study, Methionine and choline deficient diet (MCD)-induced NAFLD mice were treated with baicalin or baicalin-loaded nanoliposomes (BA-NL), then hepatic histopathological changes, biochemical parameters and inflammatory molecules were observed. We found that mice in MCD group showed significant increases in plasma transaminase, hepatocyte apoptosis, hepatic lipid accumulation, liver fibrosis, and infiltration of neutrophils and macrophages compared with control group, however, BA and BA-NL markedly attenuated MCD-induced the above changes. Besides, further analysis indicated that BA and BA-NL also inhibited the up-regulation of toll-like receptor 4 (TLR4) signal and the production of inflammatory mediators in MCD mice. Importantly, BA-NL was found to be more effective than baicalin on MCD-induced NAFLD in mice. These data suggested that BA and its nanoliposomes BA-NL could effectively protect mice against MCD-induced NAFLD, which might be mediated through inhibiting TLR4 signaling cascade.

[Preparation and in vitro release characteristics of curcumin loaded biodegradable microspheres].

OBJECTIVE: To prepare curcumin-loaded poly-(D,L-lactide-co-glycolide) microspheres and study its release characteristics in vitro. METHOD: Curcumin-loaded poly-(D,L-lactide-co-glycolide) microspheres were prepared by W/O/W emulsification solvent-evaporation process. The microspheres were characterized in terms of morphology, size, encapsulation efficiency, the rate of drug loading and in vitro drug release. RESULT: The formed microspheres were spherical with smooth surfaces. The distribution of particle size was uniform and average size was 1 151 nm. The rate of drug loading was (1.98 +/- 0.14)% and the encapsulation efficiency was (59.44 +/- 4.05)%. In vitro release study revealed that the 71-hour accumulative release percentage reached 77%. CONCLUSION: Curcumin loaded poly-(D,L-lactide-co-glycolide) microspheres are prepared successfully and show good sustained-release characteristics.

[Study on the swelling and release properties of pectinate gel beads crosslinked with different metal ions].

This study was aimed to reveal how the swelling properties and release behavior of a model drug from pectin gel beads were influenced by its crosslinking with different metal ions. Coomassie Brilliant Blue G-250 was chosen as the model drug. Pectinate beads were prepared by the dropping method and crosslinked with Ca2+, Fe3+, Zn2+, Ba2+, respectively. The release behavior and swelling properties were investigated. The results showed that there were significant differences between the pectinate beads that were crosslinked with different ions. Pectinate gel beads, as a potential cell microencapsulation and drug vehicle, could be acquired for different release profile by crosslinking with different ions.

A novel NIR-controlled NO release of sodium nitroprusside-doped Prussian blue nanoparticle for synergistic tumor treatment.

Nitric oxide (NO) has shown positive effects in tumor treatment. However, controlling NO release in specific targets is still a crucial challenge for antitumor therapy. Considering that sodium nitroprusside (SNP) and potassium ferricyanide have similar chemical structures, a near infrared (NIR) laser-controlled NO release nanoplatform has been fabricated by allowing SNP to participate in mesoporous Prussian blue (m-PB) nanoparticle formation. The resulting SNP-doped m-PB (m-PB-NO) exhibited a good NIR-controlled NO release behavior, and the amount of NO released can be controlled by adjusting the laser intensity and irradiation time. Given that m-PB-NO still has strong absorption in NIR region, it exhibited an excellent photothermal effect in vitro and in vivo. After carrying antitumor drug, docetaxel (DTX)-loaded m-PB-NO (DTX@m-PB-NO) can simultaneously achieve NIR-controlled NO release, good photothermotherapy, and chemotherapy. The combination therapy of DTX@m-PB-NO showed a significant synergistic effect compared with each monotherapy and can significantly improve the therapeutic effect. Combination therapy also significantly inhibited the lung metastasis of 4T1 breast cancer cells in tumor-bearing mice by ablating primary tumors.