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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Polypyrrole-coated phase-change liquid perfluorocarbon nanoparticles for the visualized photothermal-chemotherapy of breast cancer.

A theranostic nanoplatform (DTX/PFH@PPy-FA) for multi-modal imaging-guided photothermal-chemotherapy has been constructed. Lipid-perfluorohexane (PFH) nanodroplet loaded with docetaxel (DTX) was coated with a polypyrrole (PPy) shell. Then the folic acid (FA) molecule with active tumor-targeting function was modified on the surface of PPy shell. Due to the good photothermal conversion performance, PPy shell can raise the temperature under the near infrared laser irradiation, which not only produces photothermal effect to kill tumor cells, but also promotes liquid-gas phase change of PFH, and produces ultrasound imaging effect. The results of photothermal experiment and imaging experiment confirmed that the obtained DTX/PFH@PPy-FA possessed good photothermal, photoacoustic imaging and ultrasound imaging effects in vitro and in vivo. The results of in vitro cell experiments showed that DTX/PFH@PPy-FA had a active targeting ability to tumor cells, and its photothermal-chemotherapy synergistically inhibited the proliferation of tumor cells. In vivo study on 4T1-bearing BALB/c mice indicated that the photothermal-chemotherapy of DTX/PFH@PPy-FA not only effectively inhibited the growth of 4T1 breast cancer, but also inhibited lung metastasis. This multifunctional nanoparticle is expected to become a new nanoplatform for the visualized photothermal-chemotherapy of cancer. STATEMENT OF SIGNIFICANCE: In this work, we presented a multi-modal imaging-guided photothermal-chemotherapy theranostic nanoplatform (DTX/PFH@PPy-FA) for visualized treatment of breast cancer. The docetaxel (DTX) loaded perfluorohexane (PFH) nanodroplets (DTX/PFH@SPC) were firstly prepared and then coated with polypyrrole shell (PPy). Then, PEGylated folic acid was covalently modified to obtain the folate-targeted multifunctional nanoparticle (DTX/PFH@PPy-FA). Due to the good photothermal conversion performance, PPy shell can raise the temperature under the near infrared laser irradiation, which not only produces photothermal effect to kill tumor cells, but also promotes liquid-gas phase change of PFH, and produces good ultrasound imaging effect. The PPy shell also imparts photoacoustic imaging characteristics to the nanoparticles. Experimental results show that our prepared DTX/PFH@PPy-FA possesses folic acid-mediated tumor targeting ability, ultrasound and photoacoustic imaging, and photothermal-chemotherapy synergistic effect. This multi-functional nanoparticle is expected to become a new platform for the visualized photothermal-chemotherapy of breast cancer.

Novel hyaluronic acid-modified temperature-sensitive nanoparticles for synergistic chemo-photothermal therapy.

This study has developed a versatile nano-system with the combined advantages of photothermal effect, active tumor-targeting, temperature-sensitive drug release, and photoacoustic imaging. The nano-system consists of the core of the phase change material (PCM), the outer polypyrrole (PPY) shell and the hyaluronic acid (HA) modified in the PPY shell. The obtained composite nanoparticles (denoted as DTX/PPN@PPY@HA) were spherical with a mean diameter of about 232.7 nm. In vivo and in vitro photoacoustic imaging experiments show that DTX/PPN@PPY@HA is an effective photoacoustic contrast agent, which can be used for accurate localization of tumor region and real-time guidance of photothermal chemotherapy. DTX/PPN@PPY@HA shows good photothermal effects and temperature-sensitive drug release. In addition, cellular experiments showed that DTX/PPN@PPY@HA could be efficiently internalized into tumor cells and produce significant cytotoxicity with the help of near-infrared (NIR) laser. Furthermore, the remarkable inhibition of DTX/PPN@PPY@HA against tumor growth was achieved in 4T1 tumor-bearing mice model.

Multifunctional Polypyrrole-Coated Mesoporous TiO2 Nanocomposites for Photothermal, Sonodynamic, and Chemotherapeutic Treatments and Dual-Modal Ultrasound/Photoacoustic Imaging of Tumors.

TiO2 nanoparticles have emerged as satisfactory sonosensitizers in sonodynamic therapy over the years, but shortcomings such as poor drug loading capability and inadequate techniques to construct suitable TiO2 nanoparticles, limit their broader applications. Hence, in this paper, versatile nanocomposites that combine mesoporous TiO2 nanoparticles (mTiO2 s) with the promising photothermal material, polypyrrole (PPY) to exert synergistic therapeutic effects on tumors are fabricated. The PPY-coated mesoporous TiO2 nanocomposites (mTiO2 @PPYs) act as drug delivery vehicles and ultrasonically activated sonosensitizers as well as photothermal agents. Besides, mTiO2 @PPY may have potential as an ultrasound/photoacoustic (US/PA) imaging contrast agent. The mTiO2 @PPY shows a favorable drug loading and good photothermal conversion ability. Moreover, intracellular reactive oxygen species generation is verified. The in vitro cell experiments on HepG2 and 4T1 cells demonstrate that honokiol (HNK)-loaded mTiO2 @PPY has satisfactory cytotoxicity under laser and US irradiation, and the results are further validated by animal experiments. The ability of mTiO2 @PPY as a contrast agent for US and PA imaging is investigated both in vitro and in vivo. The results indicate that mTiO2 @PPY-HNK has multitherapeutic effects and bimodal imaging property, which shows great prospect as a novel nanosystem in antitumor applications.

Hyaluronic acid and polydopamine functionalized phase change nanoparticles for ultrasound imaging-guided photothermal-chemotherapy.

In this study, we successfully prepared polydopamine (PD) and hyaluronic acid (HA) coated liquid perfluorocarbon nanoparticles, which integrated the good photothermal conversion effect of PD, the ultrasound imaging properties of the liquid fluorocarbon and active tumor-targeting of HA. Liquid perfluorocarbon nanodroplets significantly improved in terms of their physical stability after being coated with PD and HA as the shell. Photothermal and ultrasound imaging experiments showed that PD could effectively convert near-infrared (NIR) laser energy into heat for photothermal therapy, which could induce a phase change of the liquid perfluorocarbon, thereby generating microbubbles, enhancing ultrasound imaging signals and promoting drug release. In vitro cellular experiments showed that HA on the surface of the nanoparticles could actively target 4T1 breast cancer cells by CD44 receptor-mediated endocytosis. Furthermore, the novel nanosystem has shown effective inhibition of tumor growth by synergistic photothermal-chemotherapy in tumor-bearing mice. In conclusion, the novel nanosystem we prepared in this study is expected to provide a new strategy for the diagnosis and treatment of cancer.

Development of a Chitosan-based Nanoparticle Formulation for Ophthalmic Delivery of Honokiol.

BACKGROUND: Retinal neovascularization (NV) is the leading cause of blindness in the majority of ocular diseases. Several treatment approaches have been developed for retinal NV; of these methods, instillation of nanoparticles into the conjunctival sac has shown potential for retinal NV treatment because it does not cause physical damage and is easy to operate. METHODS: In this study, honokiol-loaded chitosan/sulfobutylether-ß-cyclodextrin nanoparticles (HKCS- NPs) were prepared for ophthalmic drug delivery systems. An inclusion complex of honokiol and sulfobutylether-ß-cyclodextrin was used to incorporated insoluble honokiol into chitosan nanoparticles, which were prepared through ionotropic gelation. RESULTS: HK-CS-NPs featured a spherical surface with a narrow size distribution of polydispersity index less than 0.250, a mean size range of 373-523 nm, a positive surface charge of +19.9 to +24.2 mV, and an entrapment efficiency of 84.92%. In vitro release studies showed an initial burst release phase and a sustained release phase of nanoparticles. Moreover, in vivo study showed that HK-CS-NPs exhibited good ocular tolerability and could improve ophthalmic bioavailability of honokiol. In particular, the maximum concentration of honokiol after administration of HK-CS-NPs was enhanced by 1.65 times compared with that after instillation of the honokiol suspension alone. CONCLUSION: This study proposes HK-CS-NPs as a potential ophthalmic delivery system.

Facile Synthesis of Lipid-Perfluorocarbon Nanoemulsion Coated with Silica Shell as an Ultrasound Imaging Agent.

A novel organic/inorganic hybrid nanovesicle as an ultrasound imaging agent is synthesized via facile emulsion and silica deposition methods. This nanovesicle, hyaluronate (HA)-docetaxel (DTX)/perfluoro-n-pentane (PFP)@SNC, consists of an encapsulated liquid PFP core, loaded DTX, and an HA-decorated silica shell. The HA-DTX/PFP@SNC has a narrow size distribution of 274.5 ± 3.25 nm, a negative zeta potential of -11.6 ± 0.47 mV, and an entrapment efficiency of 86.70% ± 1.42%. HA-DTX/PFP@SNC possesses an ultrasound (US)-triggered drug release and a temperature-dependent size change behavior. Compared with DTX/PFP@soybean phosphatidylcholine (SPC), which has no silica shell, the HA-DTX/PFP@SNC is more stable under various conditions. The MTT assay indicates that the blank HA-PFP@SNC vehicle has no cytotoxicity to A549 cells. Furthermore, due to the HA-mediated tumor-targeting ability, the HA-DTX/PFP@SNC shows obvious cytotoxicity to A549 cells. In vitro and in vivo US imaging results indicate that HA-DTX/PFP@SNC has a stronger and more durable echo signal than DTX/PFP@SPC. Moreover, the in vivo echo signal of HA-DTX/PFP@SNC is stronger than that of DTX/PFP@SNC due to the HA-mediated tumor targeting. Therefore, this novel organic/inorganic hybrid vesicle is a US contrast agent candidate.

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.

Novel apigenin-loaded sodium hyaluronate nano-assemblies for targeting tumor cells.

We aimed to construct a novel nano-assembly carrying apigenin (APG), a hydrophobic drug, and to evaluate its in vitro targeting ability for A549 cells overexpressing CD44 receptors. The apigenin-loaded sodium hyaluronate nano-assemblies (APG/SH-NAs) were assembled by multiple non-covalent interactions between sodium hyaluronate (SH) and APG. The prepared APG/SH-NAs exhibited a small average size and narrow particle size distribution. In addition, satisfactory encapsulation efficiency and drug loading were obtained. The drug release curves indicated that APG/SH-NAs achieved a sustainable drug-release effect due to the presence of hydrophilic materials. The in vitro cytotoxicity of APG/SH-NAs against A549 cells and HepG2 cells was evaluated, and the results indicated that the prepared APG/SH-NA showed higher cytotoxicity compared to apigenin suspensions. When CD44 receptors on the surface of A549 cells were blocked by the addition of excess SH, the cytotoxicity of APG/SH-NA was significantly reduced. However, similar phenomena were not observed in HepG2 cells with relatively low CD44 receptor expression. The resulting APG/SH-NAs could efficiently facilitate the internalization of APG into A549 cells, which might be due to their high affinity for CD44 receptors. Moreover, the apoptotic rate of APG/SH-NAs through receptor-mediated endocytosis mechanism was higher than that of the other groups in A549 cells. Thus, such nano-assemblies were considered to be an effective transport system with excellent affinity for CD44 receptors to allow the SH-mediated targeted delivery of APG.

Ultrasound-Triggered Destruction of Folate-Functionalized Mesoporous Silica Nanoparticle-Loaded Microbubble for Targeted Tumor Therapy.

A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound-guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN-FA) to enhance cell membrane translocation. MSN-FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN-FA-TAN-MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN-FA-TAN-MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN-FA-TAN-MB are conducted on A549 and HeLa tumor cells. FA-facilitated MSN-FA-TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA-receptor-mediated endocytosis mechanism. The ultrasound response property of MSN-FA-TAN-MB is also verified. MSN-FA-TAN-MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy.