Paclitaxel/hydroxypropyl-ß-cyclodextrin complex-loaded liposomes for overcoming multidrug resistance in cancer chemotherapy.

Multidrug resistance (MDR) is the largest obstacle to the success of chemotherapy. The development of innovative strategies and safe sensitizers is required to overcome MDR. Paclitaxel (PTX) is a widely used chemotherapeutic drug, the application of which has been learn to understand MDR. However, the application and use are severely restricted because of this MDR. Cyclodextrins (CDs) of many carriers, additionally have shown anti-cancer capability in MDR cancer cells. In this study, novel paclitaxel/hydroxypropyl-ß-cyclodextrin complex-loaded liposomes (PTXCDL) have been developed in an attempt to overcome MDR in a PTX-resistant human lung adenocarcinoma (A549/T) cell line. The in vitro application of PTXCDL exhibited pH-sensitive PTX release, potent cytotoxicity, and enhanced intracellular accumulation. In comparison to in vivo, PTXCDL also show a stronger inhibition of tumor growth. In comparison, these findings suggest that the PTXCDL provide a novel strategy for effective therapy of resistant cancers by overcoming the drug resistance.

Polysialic-Acid-Based Micelles Promote Neural Regeneration in Spinal Cord Injury Therapy.

Spinal cord injury (SCI) routinely causes the immediate loss and disruption of neurons followed by complicated secondary injuries, including inflammation, oxidative stress, and dense glial scar formation. Inhibitory factors in the lesion scar and poor intrinsic neural regeneration capacity restrict functional recovery after injury. Minocycline, which has neuroprotective activity, can alleviate secondary injury, but the long-term administration of this drug may cause toxicity. Polysialic acid (PSA) is a large cell-surface carbohydrate that is critical for central nervous system development and is capable of promoting precursor cell migration, axon path finding, and synaptic remodeling; thus, PSA plays a vital role in tissue repair and regeneration. Here, we developed a PSA-based minocycline-loaded nanodrug delivery system (PSM) for the synergistic therapy of spinal cord injury. The prepared PSM exerted marked anti-inflammatory and neuroprotective activities both in vitro and in vivo. The administration of PSM could significantly protect neurons and myelin sheaths from damage, reduce the formation of glial scar, recruit endogenous neural stem cells to the lesion site, and promote the regeneration of neurons and the extension of long axons throughout the glial scar, thereby largely improving the locomotor function of SCI rats and exerting a superior therapeutic effect. The findings might provide a novel strategy for SCI synergistic therapy and the utilization of PSA in other central nervous system diseases.

Highly Integrated Nanoplatform Based on an E-Selectin-Targeting Strategy for Metastatic Breast Cancer Treatment.

Therapeutic goals for metastatic breast cancer, including shrinkage of established metastasis and suppression of movement of tumor cells, are often hard to achieve and remain the main obstacles restricting the antimetastatic efficacy of targeted drug delivery systems (TDDSs). Herein, we proposed an E-selectin-targeting nanoplatform for the systemic treatment of metastatic breast cancer. Versatile functions, including killing the circulating tumor cells, shrinking the established lesions, as well as inhibiting the movement of tumor cells, were integrated into doxorubicin-loaded sialic acid-dextran-octadecanoic acid (SDO) micelles (SDD). The prepared SDD micelles could not only inhibit lung and liver metastasis in the orthotopic 4T1 tumors model, but also decrease the metastatic lesions in the metastatic 4T1 cell model, resulting in 27.33% reduced number of metastatic nodules when compared to those without sialic acid modification. It was found that the good antimetastatic effect of SDD was only partially attributed to its ability on removing metastatic cells and metastases. Most importantly, the blank SDO micelles left in the lesion could further inhibit the cell migration and cell-cell binding. These results suggest that SA-driven TDDS has the potential for specific targeting and effective treatment of cancer metastasis.

Correction: An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury.

Correction for 'An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury' by Jing-Bo Hu et al., Biomater. Sci., 2018, 6, 3397-3409, https://doi.org/10.1039/C8BM00813B.

[Farnesoid-X-receptor blockade reduces myocardial reperfusion injury in cholesterol-fed apolipoprotein E knockout mice].

OBJECTIVE: To investigate the effect of farnesoid-X-receptor (FXR) antagonist Z-guggulsterone in an in vivo high-fat fed apolipoprotein E knockout (ApoE(-/-)) mice model of myocardial ischemia/reperfusion (I/R). METHODS: Male ApoE(-/-) mice were randomly divided into three groups: standard ApoE(-/-) group (fed with standard mouse diet for 12 weeks before myocardial I/R procedure, n = 18), high-fat ApoE(-/-) group (fed with high-fat mouse diet for 12 weeks before myocardial I/R procedure, n = 22), and high-fat ApoE(-/-) + FXR antagonist group(fed with high-fat mouse diet for 12 weeks and received FXR antagonist Z-Guggulsterone 30 minutes before myocardial I/R procedure, n = 17). The expression of FXR was detected by real-time quantitative-PCR. Myocardial infarct size was determined by Evans blue/TTC double staining methods. Myocardial apoptosis was determined by in situ TUNEL technique. Markers of the mitochondrial-mediated apoptotic pathway (cytochrome c release, caspase-9 activity, and BAX and BCL-2 levels), endoplasmic reticulum stress apoptotic pathway (caspase-12 activity and CHOP level), and death receptor apoptotic pathway (caspase-8 activity, and Fas and FasL levels) were also measured. RESULT: FXR expression (3.7-fold higher, P < 0.01), myocardial infarct size [(62.1 ± 7.0)% vs. (33.8 ± 5.8)%, P < 0.01] and myocardial apoptosis index[ (36.8 ± 5.7)% vs. (17.2 ± 3.8)%, P < 0.01]were all significantly higher in high-fat ApoE(-/-) group than those in standard ApoE(-/-) group. Compared with high-fat ApoE(-/-) group, myocardial infarct size [(24.4 ± 4.7)% vs. (62.1 ± 7.0)%, P < 0.01] and myocardial apoptosis index [(13.8 ± 2.7)% vs. (36.8 ± 5.7)%, P < 0.01] were significantly reduced in high-fat ApoE(-/-) + FXR antagonist group. Moreover, levels of mitochondrial-mediated apoptotic pathway markers (cytochrome c release, caspase-9 activity, and BAX/BCL-2 levels) and endoplasmic reticulum stress apoptotic pathway markers (caspase-12 activity and CHOP level) were significantly lower in high-fat ApoE(-/-) + FXR antagonist group than those in high-fat ApoE(-/-) group (all P < 0.01). Levels of death receptor apoptotic pathway markers (caspase-8 activity, and Fas and FasL levels) were similar between high-fat ApoE(-/-) group and high-fat ApoE(-/-) + FXR antagonist group. CONCLUSION: FXR antagonist alleviates myocardial reperfusion injury in cholesterol-fed ApoE(-/-) mice via inhibition of the mitochondrial-mediated and endoplasmic-reticulum stress pathway.

Lipid Profile Features and Their Associations With Disease Severity and Mortality in Patients With COVID-19.

Background: Emerging studies have described and analyzed epidemiological, clinical, laboratory, and radiological features of COVID-19 patients. Yet, scarce information is available regarding the association of lipid profile features and disease severity and mortality. Methods: We conducted a prospective observational cohort study to investigate lipid profile features in patients with COVID-19. From 9 February to 4 April 2020, a total of 99 patients (31 critically ill and 20 severely ill) with confirmed COVID-19 were included in the study. Dynamic alterations in lipid profiles were recorded and tracked. Outcomes were followed up until 4 April 2020. Results: We found that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apoA-1) levels were significantly lower in the severe disease group, with mortality cases showing the lowest levels (p < 0.0001). Furthermore, HDL-C and apoA-1 levels were independently associated with disease severity (apoA-1: odds ratio (OR): 0.651, 95% confidence interval (CI): 0.456-0.929, p = 0.018; HDL-C: OR: 0.643, 95% CI: 0.456-0.906, p = 0.012). For predicting disease severity, the areas under the receiver operating characteristic curves (AUCs) of HDL-C and apoA-1 levels at admission were 0.78 (95% CI, 0.70-0.85) and 0.85 (95% CI, 0.76-0.91), respectively. For in-hospital deaths, HDL-C and apoA-1 levels demonstrated similar discrimination ability, with AUCs of 0.75 (95% CI, 0.61-0.88) and 0.74 (95% CI, 0.61-0.88), respectively. Moreover, patients with lower serum concentrations of apoA-1 (<0.95 g/L) or HDL-C (<0.84 mmol/l) had higher mortality rates during hospitalization (log-rank p < 0.001). Notably, levels of apoA-1 and HDL-C were inversely proportional to disease severity. The survivors of severe cases showed significant recovery of apoA-1 levels at the end of hospitalization (vs. midterm apoA-1 levels, p = 0.02), whereas the mortality cases demonstrated continuously lower apoA-1 levels throughout hospitalization. Correlation analysis revealed that apoA-1 and HDL-C levels were negatively correlated with both admission levels and highest concentrations of C-reactive protein and interleukin-6. Conclusions: Severely ill COVID-19 patients featured low HDL-C and apoA-1 levels, which were strongly correlated with inflammatory states. Thus, low apoA-1 and HDL-C levels may be promising predictors for severe disease and in-hospital mortality in patients suffering from COVID-19.

Sialic acid-modified chitosan oligosaccharide-based biphasic calcium phosphate promote synergetic bone formation in rheumatoid arthritis therapy.

Therapeutic goals for rheumatoid arthritis (RA) consist of inhibiting the inflammatory response and repairing the damaged bone/cartilage. Tissue engineering could achieve both goals, however, it was hindered due to the lack of biologically relevant tissue complexity, limitation in covering the entire polyarthritis lesions and requirement of extra surgical implantation. Integrating nanotechnologies into clinically sized implants represents a major opportunity to overcome these problems. Herein, we designed a sialic acid (SA)-modified chitosan oligosaccharide-based biphasic calcium phosphate (BCP), a biomimetic nanoplatform that could load with methotrexate. We found that SA modification could not only improve the accumulation of the designed organic-inorganic nanoplatform in arthritic paws (34.38% higher than those without SA modification at 48 h), but also cooperate with BCP to exert synergetic mineralization of calcium phosphate, allowing more osteoblasts to attach, proliferate and differentiate. The more differentiated osteoblasts produced 4.46-fold type I collagen and 2.60-fold osteoprotegerin compared to the control group. Besides, the disassembled nanorods released chitosan oligosaccharide-based micelles, revealing a cartilage-protective effect by reducing the loss of glycosaminoglycan. All these improvements contributed to the light inflammatory response and reduced destruction on cartilage/bone. The findings provide a novel strategy for RA therapy via nanometer-scale dimension mimicking the natural tissues.

Stimuli-responsive Drug Delivery Systems as an Emerging Platform for Treatment of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a systemic autoimmune disease accompanied by chronic inflammation. Due to the long-term infiltration in inflammatory sites, joints get steadily deteriorated, eventually resulting in functional incapacitation and disability. Despite the considerable effect, RA sufferers treated with current drug therapeutic efficacy are exposed to severe side effects. Application of Drug Delivery Systems (DDS) has improved these situations while the problem of limited drug exposure remains untackled. Stimuli-responsive DDS that are responsive to a variety of endogenous and exogenous stimuli, such as pH, redox status, and temperature, have emerged as a promising therapeutic strategy to optimize the drug release. Herein, we discussed the therapeutic regimes and serious side effects of current RA therapy, as well as focused on some of the potential stimuliresponsive DDS utilized in RA therapy. Besides, the prospective room in designing DDS for RA treatment has also been discussed.

Mechanism investigation of ethosomes transdermal permeation.

Ethosomes are widely used to promote transdermal permeation of both lipophilic and hydrophilic drugs, but the mechanism of interaction between the ethosomes and the skin remains unclear. In this work, it was exploded with several technologies and facilities. Firstly, physical techniques such as attenuated total reflectance fourier-transform infrared and laser confocal Raman were used and the results indicated that the phospholipids configuration of stratum corneum changes from steady state to unstable state with the treatment of ethosomes. Differential scanning calorimetry reflected the thermodynamics change in stratum corneum after treatment with ethosomes. The results revealed that the skin of Bama mini-pigs, which is similar to human skin, treated by ethosomes had a relatively low Tm and enthalpy. Scanning electron microscopy and transmission electron microscopy showed that the microstructure and ultrastructure of stratum corneum was not damaged by ethosomes treatment. Furthermore, confocal laser scanning microscopy revealed that lipid labeled ethosomes could penetrate the skin via stratum corneum mainly through intercellular route, while during the process of penetration, phospholipids were retained in the upper epidermis. Cell experiments confirmed that ethosomes were distributed mainly on the cell membrane. Further study showed that only the drug-loaded ethosomes increased the amount of permeated drug. The current study, for the first time, elucidated the mechanistic behavior of ethosomes in transdermal application from molecular configuration, thermodynamic properties, ultrastructure, fluorescent labeling and cellular study. It is anticipated that the approaches and results described in the present study will benefit for better design of drug-loaded ethosomes.

Preparation of Ethyl Cellulose Microspheres for Sustained Release of Sodium Bicarbonate.

Sustained release of thermal-instable and water-soluble drugs with low molecule weight is a challenge. In this study, sodium bicarbonate was encapsulated in ethyl cellulose microspheres by a novel solid-in-oil-in-oil (S/O/O) emulsification method using acetonitrile/soybean oil as new solvent pairs. Properties of the microspheres such as size, recovery rate, morphology, drug content, and drug release behavior were evaluated to investigate the suitable preparation techniques. In the case of that the ratio of the internal and external oil phase was 1: 9, Tween 80 as a stabilizer resulted in the highest drug content (2.68%) and a good spherical shape of microspheres. After the ratio increased to 1: 4, the microspheres using Tween 80 as the stabilizer also had high drug content (1.96%) and exhibited a sustained release behavior, with 70% of drug released within 12 h and a sustained release of more than 40 h. Otherwise, different emulsification temperatures at which acetonitrile was evaporated could influence the drug release behaviour of microspheres obtained. This novel method is a potential and effective method to achieve the encapsulation and the sustained release of thermal-instable and water-soluble drugs with low molecule weight.

Combinational protective therapy for spinal cord injury medicated by sialic acid-driven and polyethylene glycol based micelles.

Spinal cord injury (SCI) leads to immediate disruption of neuronal membranes and loss of neurons, followed by extensive secondary injury process. Treatment of SCI still remains a tremendous challenge clinically. Minocycline could target comprehensive secondary injury via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms. Polyethylene glycol (PEG), a known sealing agent, is able to seal the damaged cell membranes and reduce calcium influx, thereby exerting neuroprotective capacity. Here, an E-selectin-targeting sialic acid - polyethylene glycol - poly (lactic-co-glycolic acid) (SAPP) copolymer was designed for delivering hydrophobic minocycline to achieve combinational therapy of SCI. The obtained SAPP copolymer could self-assemble into micelles with critical micelle concentration being of 13.40 µg/mL, and effectively encapsulate hydrophobic minocycline. The prepared drug-loaded micelles (SAPPM) displayed sustained drug release over 72 h, which could stop microglia activation and exhibited excellent neuroprotective capacity in vitro. The SAPP micelles were efficiently accumulated in the lesion site of SCI rats via the specific binding between sialic acid and E-selectin. Due to the targeting distribution and combinational effect between PEG and minocycline, SAPPM could obviously reduce the area of lesion cavity, and realize more survival of axons and myelin sheaths from the injury, thus distinctly improving hindlimb functional recovery of SCI rats and conferring superior therapeutic effect in coparison with other groups. Our work presented an effective and safe strategy for SCI targeting therapy. Besides, neuroprotective capacity of PEG deserves further investigation on other central nervous system diseases.

Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system.

In this study, water-in-oil (W/O) miniemulsion was used as nanoreactor to prepare solid lipid nanoparticles (SLN) by solvent diffusion method. n-Hexane, Tween 80 and Span 80 were used as the oil phase and surfactant combination for preparation of W/O miniemulsion, respectively. The stable miniemulsion with the particle size of 27.1+/-7.6 nm was obtained when the composition of water/Tween 80/Span 80/n-hexane was 1 ml/18 mg/200 mg/10 ml. Clobetasol propionate (CP) was used as a model drug. The physicochemical properties of the SLN, such as particle size, zeta potential, surface morphology, drug entrapment efficiency, drug loading capacity and in vitro drug release behaviors were investigated, comparing with those of SLN prepared by conventional aqueoethod. The SLN prepared by the novel method displayed smaller particles size and higher dus solvent diffusion mrug entrapment efficiency than those of SLN prepared by the conventional method. The drug entrapment efficiency decreased with increasing of charged amount of drug, and 15.9% of drug loading was achieved as the charged amount of drug was 20%. The in vitro drug release tests indicated that the drug release rate was faster than that of SLN prepared by the conventional method, and the drug content in SLN did not affect the in vitro drug release profile.

Preparation and characterization of modified lipid nanoparticles for doxorubicin controlled release.

Low drug encapsulation efficiency and burst release are the main drawbacks of lipid nanoparticles. To solve these problems, lipid nanoparticles containing a cross-linked lipid network were prepared in this study. Monostearin (MS) and octadecylamine (ODA) were used as the solid lipids, and oleic acid (OA) was used as liquid lipid. The use of a small amount of ODA was to form cross-linked network by glutaraldehyde in the presence of OA. Using doxorubicin (DOX) as a model drug, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and glutaraldehyde cross-linked NLC were prepared. The physicochemical properties of these lipid nanoparticles such as average diameter, drug loading, drug encapsulation efficiency and in vitro drug release were investigated. The drug loading capacities and encapsulation efficiency were improved by mixing OA with the solid lipids to produce the nanoparticle matrix, and were further increased by the cross-linking of glutaraldehyde. The faster drug release was obtained when the NLC with higher OA content. After cross-linking by glutaraldehyde, the burst release of DOX from NLC could be reduced, in comparison to both SLN and non cross-linked NLC. The results indicated the NLC with cross-linked network are a potential drug delivery system with improved drug encapsulation and controlled drug release.

[Determination of progesterone concentration in plasma after oral administration of progesterone-loaded lipid nanoparticles in rats].

OBJECTIVE: To establish a RP-HPLC method for determination of plasma progesterone and to apply the method for pharmacokinetics study of progesterone-loaded lipid nanoparticles after oral administration in rats. METHODS: The plasma samples were collected from castrated rat after oral administration of progesterone-loaded lipid nanoparticles and extracted by acetic ether. The determination was performed on a Hypersil C18 column (150 mm X 3.9 mm , 5 microm) with a mobile phase consisting of methanol and water (60:40) at a flow-rate of 0.6 ml/min. The UV detector was at 240 nm and danazol was used as internal standard. RESULT: Good linearity was obtained over the range of 0.02-2 microg/ml progesterone in plasma(r=0.9999, n=3). The quantification limit was (0.02 +/-0.004) microg/ml(n=3) and the limit of detection was 0.005 microg.mL(-1)(S/N = or >3). The inter-and intra-day RSDs were all less than 10% for quality control samples at high-, medium- and low-concentrations. The average absolute recovery rate was 90.5 % and the average method recovery was in the range of 93.4 %-107.5%. The plasma concentration-time curves indicated that tmax was delayed after administration of progesterone-loaded lipid nanoparticles, and the bioavailability was increased significantly, compared with contrast solution. CONCLUSION: The method developed is stable, simple, rapid, accurate, sensitive and applicable for determining plasma concentrations of progesterone of progesterone-loaded lipid nanoparticles in pharmacokinetic studies.

An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury.

Based on the overproduction of matrix metalloproteinase-2 (MMP-2) in renal tissue during acute kidney injury (AKI) occurrence, we developed a MMP-2 enzyme-triggered polymeric prodrug with sialic acid (SA) as the targeting group to the inflamed vascular endothelial cells for enhanced therapeutic outcomes. An MMP-2-responsive peptide, PVGLIG, was used to endow the polymeric prodrug with the ability to rapidly release the anti-inflammatory drug, curcumin (CUR), after the targeted site is reached and to improve the drug concentration in the target tissue. The sialic acid-dextran-PVGLIG-curcumin (SA-DEX-PVGLIG-CUR) polymeric prodrug was successfully synthesized via multi-step chemical reactions and characterized by 1H NMR. The water solubility of CUR was significantly increased in the polymeric prodrug and was approximately 23-fold higher than that of free CUR. The in vitro drug release results showed that the release rate of SA-DEX-PVGLIG-CUR was significantly enhanced compared to that of SA-DEX-CUR in a dissolving medium containing the MMP-2 enzyme, suggesting that SA-DEX-PVGLIG-CUR had rapid drug release characteristics in an inflammatory environment. A cellular uptake test confirmed that SA-DEX-PVGLIG-CUR was effectively internalized by inflamed vascular endothelial cells in comparison with that by normal cells, and the mechanism was associated with the specific interaction between SA and E-selectin receptors specifically expressed on inflamed vascular endothelial cells. Bio-distribution results further demonstrated the rapid and increased renal accumulation of SA-DEX-PVGLIG-CUR in AKI mice. Benefiting from the rapid drug release in renal tissue, SA-DEX-PVGLIG-CUR effectively ameliorated the pathological progression of AKI compared with free CUR and SA-DEX-CUR, as reflected by the improved renal functions, histopathological changes, pro-inflammatory cytokine production, oxidative stress and expression of apoptosis related proteins. Altogether, this study provided a new therapeutic strategy for the treatment of AKI.

Polycaprolactone/polysialic acid hybrid, multifunctional nanofiber scaffolds for treatment of spinal cord injury.

Scaffold-based tissue engineering is widely used for spinal cord injury (SCI) treatment by creating supporting and guiding neuronal tissue regeneration. However, how to enhance the axonal regeneration capacity following SCI still remains a challenge. Polysialic acid (PSA), a natural, biodegradable polysaccharide, has been increasingly explored for controlling central nervous system (CNS) development by regulating cell adhesive properties and promoting axonal growth. Here, a polycaprolactone (PCL)/PSA hybrid nanofiber scaffold encapsulating glucocorticoid methylprednisolone (MP) is developed for SCI treatment. Rat models with spinal cord transection is established and the PCL/PSA/MP scaffold is transplanted into lesion area. PCL/PSA/MP scaffold decreases tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release by inhibiting ionized calcium-binding adapter molecule 1 (Iba1) positive microglia/macrophage activation and reduces apoptosis-associated Caspase-3 protein expression. In addition, the PCL/PSA/MP scaffold inhibits axonal demyelination and glial fibrillary acidic protein (GFAP) expression, increases neurofilament 200 (NF-200) expression and improves functional outcome by Basso, Beattie and Bresnahan (BBB) test. These results demonstrate the therapeutic potential of PSA hybrid nanofiber scaffold in promoting axonal growth and enhancing the functional recovery following SCI. STATEMENT OF SIGNIFICANCE: Scaffold-based tissue engineering is widely used for spinal cord injury (SCI) treatment by creating supporting and guiding neuronal tissue regeneration. And how to enhance the axonal regeneration capacity following SCI still remains a challenge. Polysialic acid (PSA), a natural, biodegradable polysaccharide, has been increasingly explored for controlling central nervous system (CNS) development by regulating cell adhesive properties and promoting axonal growth. However, in vivo therapeutic effect of PSA scaffolds towards SCI is still lack of evidence and needs to be further explored. In this study, a novel electrospun polycaprolactone/PSA scaffold loaded with methylprednisolone (MP) was developed to achieve efficient therapeutic effects towards SCI. And we believe that it broadens the application of PSA for SCI treatment.

Endogenous sialic acid-engineered micelles: a multifunctional platform for on-demand methotrexate delivery and bone repair of rheumatoid arthritis.

Rheumatoid arthritis (RA) patients have suffered from the current drug therapeutic regimen because of its high toxicity and the absence of bone regeneration for existing erosion, seriously affecting the quality of life. Herein, a sialic acid-dextran-octadecanoic acid (SA-Dex-OA) conjugate was synthesized to form micelles with a 55.06 µg mL-1 critical micelle concentration. The obtained micelles can encapsulate a disease-modifying anti-rheumatic drug, methotrexate (MTX), with 4.28% (w/w) drug content, featuring sustained drug release behavior over 48 h. In vitro and in vivo studies showed that SA-Dex-OA micelles significantly improved accumulation and transportation through a combination of SA and E-selectin receptors in inflamed cells and arthritic paws highly expressing E-selectin. MTX-loaded SA-Dex-OA micelles not only significantly inhibited the inflammatory response, but also diminished the adverse effects of MTX, as reflected by the reduced alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen levels. Most importantly, the bone mineral density in rats treated with MTX-loaded SA-Dex-OA micelles was significantly higher as compared to in those treated with free MTX and Dex-OA/MTX micelles (increasing from 391.4 to 417.4 to 492.7 mg cc-1), benefiting from the effects of endogenous sialic acid in promoting MC3T3-E1 cell differentiation and mineralization. It is anticipated that SA-based micelles with bone repair activities have great potential for RA treatment and other metabolic bone diseases with serious bone erosion.

CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage.

Based on the abnormally increased expression of CD44 receptors on renal tubule epithelial cells during ischemia/reperfusion-induced acute kidney injury (AKI), we developed a hyaluronic acid-curcumin (HA-CUR) polymeric prodrug targeting to epithelial cells and then relieving oxidative stress damages. The water solubility of HA-CUR was significantly enhanced and approximately 27-fold higher than that of CUR. Cellular uptake test showed HA-CUR was preferably internalized by H2O2-pretreated tubular epithelial (HK-2) cells compared with free CUR benefiting from the specific binding between HA and CD44 receptors. Biodistribution results further demonstrated the increased accumulation of HA-CUR in kidneys with 13.9-fold higher than that of free CUR. Pharmacodynamic studies indicated HA-CUR effectively ameliorated AKI, and the exact mechanism was that HA-CUR protected renal tubule epithelial cells from oxidative stress damage via inhibiting PtdIns3K-AKT-mTOR signaling pathway. Taken together, this study provides a new therapeutic strategy for the treatment of AKI based on the pathogenesis of the disease.