Sialic acid-modified doxorubicin liposomes target tumor-related immune cells to relieve multiple inhibitions of CD8+ T cells.

In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.

Sialic acid-modified docetaxel cationic liposomes: double targeting of tumor-associated macrophages and tumor endothelial cells.

Taxane drugs are clinically used for the treatment of many types of cancers due to their excellent antitumor effects. However, the surfactants contained in the injections currently used in the clinic may have serious toxic side effects on the organism, making it necessary to develop new dosage forms. Cationic liposomes have been widely used in antitumor research because of their advantage of preferentially targeting tumor neovascularization, but antitumor by targeting tumor vasculature alone does not necessarily provide good results. Malignant tumors represent complex ecosystems, tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) in the tumor microenvironment play crucial roles in tumor growth. Therefore, given the ability to achieve active targeting of TAMs and TECs by using sialic acid (SA) as a targeting material, the potential of cationic nanoformulations to preferentially target neovascularization at the tumor site, and the excellent antitumor effects of the taxane drugs docetaxel (DOC), in the present study, sialic acid-cholesterol coupling (SA-CH) was selected as a targeting material to prepare a DOC cationic liposome (DOC-SAL) for tumor therapy. The results of the study showed that DOC-SAL had the strongest drug accumulation in tumor tissues compared with the common DOC formulations, and was able to effectively reduce the colonization of TAMs, inhibit the proliferation of tumor cells, and have the best tumor-suppressing effect. In addition, DOC-SAL was able to improve the internal microenvironment of tumors by modulating cytokines. In summary, this drug delivery system has good anti-tumor effects and provides a new option for tumor therapy.

Phosphatidylserine and/or Sialic Acid Modified Liposomes Increase Uptake by Tumor-associated Macrophages and Enhance the Anti-tumor Effect.

DOX liposomes have better therapeutic effects and lower toxic side effects. The targeting ability of liposomes is one of the key factors affecting the therapeutic effect of DOX liposomes. This study developed two types of targeted liposomes. Sialic acid (SA)-modified liposomes were designed to target the highly expressed Siglec-1 receptor on tumor-associated macrophages surface. Phosphatidylserine (PS)-modified liposomes were designed to promote phagocytosis by monocyte-derived macrophages through PS apoptotic signaling. In order to assess and compare the therapeutic potential of different targeted pathways in the context of anti-tumor treatment, we compared four phosphatidylserine membrane materials (DOPS, DSPS, DPPS and DMPS) and found that liposomes prepared using DOPS as material could significantly improve the uptake ability of RAW264.7 cells for DOX liposomes. On this basis, normal DOX liposomes (CL-DOX) and SA-modified DOX liposomes (SAL-DOX), PS-modified DOX liposomes (PS-CL-DOX), SA and PS co-modified DOX liposomes (PS-SAL-DOX) were prepared. The anti-tumor cells function of each liposome on S180 and RAW264.7 in vitro was investigated, and it was found that SA on the surface of liposomes can increase the inhibitory effect. In vivo efficacy results exhibited that SAL-DOX and PS-CL-DOX were superior to other groups in terms of ability to inhibit tumor growth and tumor inhibition index, among which SAL-DOX had the best anti-tumor effect. Moreover, SAL-DOX group mice had high expression of IFN-γ as well as IL-12 factors, which could significantly inhibit mice tumor growth, improve the immune microenvironment of the tumor site, and have excellent targeted delivery potential.

Helical Anatase Titanium Nanotubes through a Protected Crystallization Strategy for Enhanced Photocatalytic Performance.

Helical structure in catalysts has attracted attention and been recently investigated for various catalytic reactions. However, helical transition metal oxides suffer from uncontrollable crystallization processes at high temperatures when being transformed from an amorphous phase into a crystalline structure. Herein, we report a helical anatase TiO2 nanotube for the first time, which has been prepared using a protected crystallization strategy in the confined space of silica. A single chirality of helical TiO2 has been used to track the ordering of the twisted structure. The twisted structure in helical anatase TiO2 nanotube is maintained after a vigorous crystallization process. Helical anatase TiO2 nanotubes possess more accessible active sites and abundant defects of oxygen vacancy and Ti3+ species owing to the twisted structure. The obtained helical anatase TiO2 nanotube exhibits superior photocatalytic activity for hydrogen production without adding any co-catalysts. This work provides new insights into the role of helical structure in transition metal-based catalysts.

Targeting Ibrutinib to Tumor-Infiltrating T Cells with a Sialic Acid Conjugate-Modified Phospholipid Complex for Improved Tumor Immunotherapy.

Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses. SA-GA-OCT@PC-mediated combination therapy with PD-L1 blockade agents dramatically suppressed tumor growth and inhibited tumor relapse in B16F10 melanoma mouse models. Overall, the combination of the SA-modified nanocomplex platform and PD-L1 blockade offers a treatment opportunity for IBR in solid tumors, providing novel insights for tumor immunotherapy.

Electrocatalytic oxygen reduction with cobalt corroles bearing cationic substituents.

Recent decades have seen increasing interest in developing highly active and selective electrocatalysts for the oxygen reduction reaction (ORR). The active site environment of cytochrome c oxidases (CcOs), including electrostatic and hydrogen-bonding interactions, plays an important role in promoting the selective conversion of dioxygen to water. Herein, we report the synthesis of three CoIII corroles, namely 1 (with a 10-phenyl ortho-trimethylammonium cationic group), 2 (with a 10-phenyl ortho-dimethylamine group) and 3 (with a 10-phenyl para-trimethylammonium cationic group) as well as their electrocatalytic ORR activities in both acidic and neutral solutions. We discovered that 1 is much more active and selective than 2 and 3 for the electrocatalytic four-electron ORR. Importantly, 1 showed ORR activities with half-wave potentials at E1/2 = 0.75 V versus RHE in 0.5 M H2SO4 solutions and at E1/2 = 0.70 V versus RHE in neutral 0.1 M phosphate buffer solutions. This work is significant for outlining a strategy to increase both the activity and selectivity of metal corroles for the electrocatalytic ORR by introducing cationic units.

Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin.

Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system. Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.

Rapid sensing and imaging of methylglyoxal in living cells enabled by a near-infrared fluorescent probe.

A novel near-infrared fluorescent probe (SWJT-2) has been designed and synthesized for the detection of methylglyoxal (MGO). It showed a low detection limit (0.32 µM), high selectivity and the fastest detection (15 min) over various reactive carbonyl compounds in aqueous solution. SWJT-2 had been successfully applied to bioimaging in HeLa cells to detect exogenous and endogenous MGO.

Polysialic Acid Self-assembled Nanocomplexes for Neutrophil-Based Immunotherapy to Suppress Lung Metastasis of Breast Cancer.

The role of neutrophils in tumor metastasis has recently attracted widespread interest. Neutrophils are the most abundant immune cells in human peripheral blood, and large numbers can spontaneously migrate to metastatic sites, where they form an immunosuppressive microenvironment. Polysialic acid (PSA) can target peripheral blood neutrophils (PBNs) mediated by L-selectin, and abemaciclib (ABE) and mitoxantrone (MIT) can treat immunosuppressive microenvironments. Here, we aimed to inhibit lung metastasis of breast cancer and improve chemoimmunotherapy by designing a PSA-modified ABE and MIT co-delivery system (AM-polyion complex (PIC)) to target PBNs in mice with metastatic tumors. We found that through electrostatic interactions between the strong negative charge of PSA and the positive charge of the drug can form stable nanocomplexes and that spontaneous migration of neutrophils can mediate the aggregation of these complexes in the lungs, induce antimetastatic immune responses, enhance the effectiveness of cytotoxic T lymphocytes (CTLs), and inhibit regulatory T cell (Treg) proliferation in vivo and in vitro. Pharmacodynamic results suggested that neutrophil-mediated AM-PIC chemoimmunotherapy inhibited tumor metastasis in mice with lung metastasis of 4T1 breast cancer. Overall, PSA-modified nanocomplexes offer promising neutrophil-mediated, targeted drug delivery systems to treat lung metastasis of breast cancer.

An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid-Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis.

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis. Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.

Antitumor Immunotherapy of Sialic Acid and/or GM1 Modified Coenzyme Q10 Submicron Emulsion.

Immunotherapy is a novel therapeutic approach for controlling and killing tumor cells by stimulating or reconstituting the immune system, among which T cells serve as immune targets. Herein, we used coenzyme Q10 (CoQ10), which has both immune activation and avoids adverse reactions, as a model drug and developed four CoQ10 submicron emulsions modified with sialic acid (SA) and/or monosialotetrahexosyl ganglioside (GM1). On the one hand, SA interacts with L-selectins on the surface of T cells after entering the circulatory system, leading to activation of T cells and enhancement of antitumor immune responses. On the other hand, owing to its immune camouflage, GM1 can prolong the circulation time of the preparation in the body, thereby increasing the accumulation of the drug at the tumor site. In vitro and in vivo experiments showed that SA-modified preparations exhibited stronger immune activation and inhibition of tumor proliferation. Pharmacokinetic experiments showed that GM1-modified preparations have longer circulation times in vivo. However, SA and GM1 co-modification did not produce a synergistic effect on the preparation. In conclusion, the SA-modified CoQ10 submicron emulsion (Q10-SE) showed optimal antitumor efficacy when administered at a medium dose (6 mg CoQ10 kg-1). In this study, the submicron emulsion model was used as a carrier, and the tumor-bearing mice were used as animal models. In addition, CoQ10 submicron emulsion was modified with SA-CH with active targeting function and/or GM1 with long-circulation function to explore the antitumor effects of different doses of CoQ10 submicron emulsion, and to screen the best tumor immunotherapy formulations of CoQ10.

Intragastric Administration of Casein Leads to Nigrostriatal Disease Progressed Accompanied with Persistent Nigrostriatal-Intestinal Inflammation Activited and Intestinal Microbiota-Metabolic Disorders Induced in MPTP Mouse Model of Parkinson's Disease.

Gut microbial dysbiosis and alteration of gut microbiota composition in Parkinson's disease (PD) have been increasingly reported, no recognized therapies are available to halt or slow progression of PD and more evidence is still needed to illustrate its causative impact on gut microbiota and PD and mechanisms for targeted mitigation. Epidemiological evidence supported an association between milk intake and a higher incidence of Parkinson's disease (PD), questions have been raised about prospective associations between dietary factors and the incidence of PD. Here, we investigated the significance of casein in the development of PD. The mice were given casein (6.75 g/kg i.g.) for 21 days after MPTP (25 mg/kg i.p. × 5 days) treatment, the motor function, dopaminergic neurons, inflammation, gut microbiota and fecal metabolites were observed. The experimental results revealed that the mice with casein gavage after MPTP treatment showed a persisted dyskinesia, the content of dopamine in striatum and the expression of TH in midbrain and ileum were decreased, the expression of Iba-1, CD4, IL-22 in midbrain and ileum increased continuously with persisted intestinal histopathology and intestinal barrier injury. Decreased intestinal bile secretion in addition with abnormal digestion and metabolism of carbohydrate, lipids and proteins were found, whereas these pathological status for the MPTP mice without casein intake had recovered after 24 days, no significant differences were observed with regard to only treated with casein. Our study demonstrates that intestinal pathologic injury, intestinal dysbacteriosis and metabolism changes promoted by casein in MPTP mice ultimately exacerbated the lesions to dopaminergic neurons.

Evaluation of the Antitumor Effect and Immune Response of Micelles Modified with a Polysialic Acid-D-α-Tocopheryl Polyethylene Glycol 1000 Succinate Conjugate.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has shown potential applications in cancer therapy owing to its attractive properties, including reversal of multi-drug resistance and synergistic effects with antitumor drugs. However, its associated shortcomings cannot be underestimated, including activation of the body's immune response and acceleration of blood clearance of polyethylene glycolylated preparations. Polysialic acid (PSA) is a polysaccharide homopolymer, with the dual function of immune camouflage and tumor targeting. PSA and TPGS conjugates (PSA-TPGS) were synthesized to weaken the immune risks of TPGS. We developed PSA-TPGS and TPGS self-assembled mixed micelles and encapsulated the classical antineoplastic, docetaxel. The particle size of docetaxel-loaded mixed micelles was 16.3 ± 2.0 nm, with entrapment efficiency of 99.0 ± 0.9% and drug-loading efficiency of 3.20 ± 0.03%. Antitumor activity studies revealed that the mixed micelles showed better tumor inhibition than Tween 80 and TPGS micelles. Detection of the accelerated blood clearance (ABC) phenomenon demonstrated that insertion of PSA-TPGS into the micelles weakened the ABC phenomenon induced by TPGS. In summary, PSA-TPGS could be a potential nanocarrier to improve antitumor activity and weaken immune responses.

Influence of Dose on Neutrophil-Mediated Delivery of Nanoparticles for Tumor-Targeting Therapy Strategies.

It is well known that neutrophil-mediated delivery of therapeutic agents is a promising method for treating tumors. However, owing to the limited number and limited uptake ability of neutrophils, determining a reasonable dose has become an urgent problem to be solved. Furthermore, the number of nanoparticles is far greater than the number of neutrophils at normal doses, which causes excessive nanoparticles to reach nontargeted organs or tissues, leading to serious adverse effects. To address these problems, a neutrophil-targeting delivery system (DiR-DADGC-L) based on DiR-labeled and butanedioic acid (DA)-linked 5-amino-3,5-dideoxy-D-Glycerol-D-galactonanulose-cholesterol conjugate (DADGC) was designed to improve the efficiency of hitchhiking neutrophils through the specific binding of sialic acid (SA) to L-selectin (SA-binding receptor, expressed on neutrophils). DiR-DADGC-L was prepared with favorable particle size and encapsulation efficiency (%EE) to deliver DiR into neutrophils. Subsequently, diverse doses of DiR-DADGC-L were injected intravenously into S180 tumor-bearing and cyclophosphamide-depleted (CTX-D) S180 tumor-bearing mice to evaluate the in vivo behavior of liposomes. The results verified the following: a) The content of DiR-DADGC-L in neutrophils accounts for approximately 14.5% of the content of DiR-DADGC-L in plasma, and the uptake capacity of neutrophils remains unchanged under different doses, and b) both neutrophils and the enhanced permeability and retention (EPR) effect might exert significant roles in tumor treatment. As for the neutrophil-mediated delivery system, higher doses are not necessarily appropriate, and a lower dose may achieve an unexpected effect. It will be wise to determine an optimum dose to improve delivery efficiency.

Sialic Acid Conjugate-Modified Liposomal Dexamethasone Palmitate Targeting Neutrophils for Rheumatoid Arthritis Therapy: Influence of Particle Size.

Many anti-inflammatory therapies targeting neutrophils have been developed so far. A sialic acid (SA)-modified liposomal (SAL) formulation, based on the high expression of L-selectin in peripheral blood neutrophils (PBNs) and SA as its targeting ligand, has proved to be an effective neutrophil-mediated drug delivery system targeting rheumatoid arthritis (RA). The objective of this study was to investigate the influence of particle size of drug-carrying SALs transported and delivered by neutrophils on their anti-RA effect. Dexamethasone palmitate-loaded SALs (DP-SALs) of different particle sizes (300.2 ± 5.5 nm, 150.3 ± 4.3 nm, and 75.0 ± 3.9 nm) were prepared with DP as a model drug. Our study indicated that DP-SALs could efficiently target PBNs, with larger liposomes leading to higher drug accumulation in cells. However, a high intake of large DP-SALs by PBNs inhibited their migration ability and capacity to release the payload at the target site. In contrast, small DP-SALs (75.0 ± 3.9 nm) could maintain the drug delivery potential of PBNs, leading to their efficient accumulation at the inflammatory site, where PBNs would be excessively activated to form neutrophil extracellular traps along with efficient payload release (small DP-SALs) and finally to induce excellent anti-RA effect.

Accelerated Blood Clearance of Nanoemulsions Modified with PEG-Cholesterol and PEG-Phospholipid Derivatives in Rats: The Effect of PEG-Lipid Linkages and PEG Molecular Weights.

Various types of nanocarriers modified with poly(ethylene glycol) (PEG) exhibit the accelerated blood clearance (ABC) phenomenon, resulting in reduced circulation time and abnormal increase in hepatic and splenic accumulations. Based on the abundance of esterases in the serum of rats, we developed cleavable methoxy PEG-cholesteryl methyl carbonate (mPEG-CHMC) with a carbonate linkage and noncleavable N-(carbonyl-methoxy PEG-n)-1,2-distearoyl-sn-glycero-3-phos-phoethanolamine (mPEG-DSPE) with a carbamate linkage on the surface of the nanoemulsions (CHMCE and PE, respectively). Both PEG derivatives possessed PEG with six different molecular weights (n = 350, 550, 750, 1000, 2000, and 5000). The pharmacokinetic behaviors and biodistributions of single and repeated injection of the two types of PEGylated nanoemulsions were determined to investigate the influence of cleavable linkages and PEG molecular weights on the ABC phenomenon in an attempt to find a potential strategy to eliminate the ABC phenomenon. CHMCEns (n = 1000, 2000, and 5000) exhibited the same pharmacokinetic behaviors as PE550 and PE750 and only alleviated the ABC phenomenon to a certain extent at the expense of shortened cycle time, indicating that the cleavable carbonate linkage was not an ideal strategy to eliminate the ABC phenomenon. As the molecular weights of PEG increased, the ABC phenomenon became more severe. Surprisingly, PE5000 induced a lower anti-PEG IgM level and a weaker ABC phenomenon compared with PE2000 while possessing a similar long circulation time. The results suggested that increasing the molecular weight of PEG in the PEG derivatives could be a potential strategy for eliminating the ABC phenomenon while simultaneously guaranteeing longer circulation time.

Effects of Uncleavable and Cleavable PEG-Lipids with Different Molecular Weights on Accelerated Blood Clearance of PEGylated Emulsions in Beagle Dogs.

To investigate the effect of polyethylene glycol (PEG) molecular weights on circulation time of PEGylated emulsions and the second injection of injected PEGylated emulsions, we studied the effect of molecular weights on the pharmacokinetic behavior of PEG-DSPE (modified emulsions with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethyleneglycol)]) and PEG-CHMC (modified emulsions with poly(ethyleneglycol)-cholesteryl carbonate) emulsions in beagle dogs. The "accelerated blood clearance" (ABC) phenomenon was induced. Through this study, the contribution of PEG molecular weights on the ABC phenomenon was further clarified, and the results provided guidance for lessening or eliminating the ABC phenomenon. We injected different PEG-modified emulsions with 10% PEG-modified density into beagle dogs at 2 µmol phospholipids kg-1 and the blood samples were drawn after 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, 240 min, 360 min, 600 min, and 24 h. Then, concentrations of the drug were assayed using high-performance liquid chromatography (HPLC). The results showed that the circulation times of PEG-DSPE-modified emulsions were significantly different because of the difference in molecular weights, whereas those of the PEG-CHMC modified emulsions were not. The spatial conformation of PEG with small molecular weights (PEG400, PEG600, and PEG800) was more likely to induce a strong ABC phenomenon. The results of our work suggest the interaction of circulation time and PEG molecular weights on the ABC phenomenon, implying that the spatial conformation of PEG has advantages that alleviate the ABC phenomenon. Importantly, the results have implications for the choice of molecular weights of PEG for PEGylated formulations.

Neutrophil-Mediated Delivery of Dexamethasone Palmitate-Loaded Liposomes Decorated with a Sialic Acid Conjugate for Rheumatoid Arthritis Treatment.

PURPOSE: The aim of this research was to design dexamethasone palmitate (DP) loaded sialic acid modified liposomes, with the eventual goal of using peripheral blood neutrophils (PBNs) that carried drug-loaded liposomes to improve the therapeutic capacity for rheumatoid arthritis (RA). METHODS: A sialic acid - cholesterol conjugate (SA-CH) was synthesized and anchored on the surface of liposomal dexamethasone palmitate (DP-SAL). The physicochemical characteristics and in vitro cytotoxicity of liposomes were evaluated. Flow cytometry and confocal laser scanning microscopy were utilized to investigate the accumulation of liposomes in PBNs. The adjuvant-induced arthritis was adopted to investigate the targeting ability and anti-inflammatory effect of DP loaded liposomes. RESULTS: Both DP-CL and DP-SAL existed an average size less than 200 nm with remarkably high encapsulation efficiencies more than 90%. In vitro and in vivo experiments manifested SA-modified liposomes provided a reinforced accumulation of DP in PBNs. As well, DP-SAL displayed a greater degree of accumulation in the joints and a stronger anti-inflammatory effect in terms of RA suppression. CONCLUSIONS: SA-modified liposomal DP was a promising candidate for RA-targeting treatment through the neutrophil-mediated drug delivery system.

Dual-Ligand Modification of PEGylated Liposomes Used for Targeted Doxorubicin Delivery to Enhance Anticancer Efficacy.

Mannose receptor (CD206) and E-selectin are selectively expressed in M2-like tumor-associated macrophages (M2-TAMs) and activated endothelial cells of vessels surrounding tumor tissues. With the knowledge that D-mannose is the natural ligand of mannose receptors and L-fucose is the key calcium chelator for tumor-associated carbohydrate antigens (TACAs) binding to E-selectin, herein, we firstly reported D-mannose polyethylene glycol (PEG) conjugates (Man-PEG) and L-fucose PEG conjugates (Fuc-PEG) co-modified liposomal doxorubicin (DOX-MFPL) to improve tumor-targeting ability. The dual-ligand modified PEGylated liposomes (DOX-MFPL) were assessed by both in vitro and in vivo trials. Compared with the single-ligand D-mannose- or L-fucose-modified liposomes (DOX-MPL or DOX-FPL), DOX-MFPL achieved an increased distribution of DOX in tumor tissues. The antitumor study based on S180 tumor-bearing mice was conducted and the superior tumor inhibitory rate was shown with DOX-MFPL, probably owing to the superior tumor-targeting effect of DOX-MFPL and the modulation of the tumor microenvironment with the exhaustion of TAMs. In general, the dual-ligand drug delivery systems are expected to be promising in the development of specific and efficient methods for tumor treatment.

Intestinal Pathology and Gut Microbiota Alterations in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Mouse Model of Parkinson's Disease.

Patients with Parkinson's disease (PD) often have non-motor symptoms related to gastrointestinal (GI) dysfunction, such as constipation and delayed gastric emptying, which manifest prior to the motor symptoms of PD. Increasing evidence indicates that changes in the composition of the gut microbiota may be related to the pathogenesis of PD. However, it is unclear how GI dysfunction occurs and how gut microbial dysbiosis is caused. We investigated whether a neurotoxin model of PD induced by chronic low doses of MPTP is capable of reproducing the clinical intestinal pathology of PD, as well as whether gut microbial dysbiosis accompanies this pathology. C57BL/6 male mice were administered 18 mg/kg MPTP twice per week for 5 weeks via intraperitoneal injection. GI function was assessed by measuring the 1-h stool frequency and fecal water content; motor function was assessed by pole tests; and tyrosine hydroxylase and alpha-synuclein expression were analyzed. Furthermore, the inflammation, intestinal barrier and composition of the gut microbiota were measured. We found that MPTP caused GI dysfunction and intestinal pathology prior to motor dysfunction. The composition of the gut microbiota was changed; in particular, the change in the abundance of Lachnospiraceae, Erysipelotrichaceae, Prevotellaceae, Clostridiales, Erysipelotrichales and Proteobacteria was significant. These results indicate that a chronic low-dose MPTP model can be used to evaluate the progression of intestinal pathology and gut microbiota dysbiosis in the early stage of PD, which may provide new insights into the pathogenesis of PD.