Tumor Targeting and Lipid Rafts Disrupting Hyaluronic Acid-Cyclodextrin-Based Nanoassembled Structure for Cancer Therapy.

CD44 receptor targeting and lipid rafts destroying nanoassembly (NA) was developed for breast cancer therapy. Methyl-ß-cyclodextrin (MbCD), as a cholesterol depletion moiety, was conjugated to hyaluronic acid-ceramide (HACE) structure via an ester linkage. HACE-MbCD NA with 198 nm hydrodynamic size, unimodal size distribution, and spherical shape was fabricated by self-assembly strategy. By filipin III staining, it was identified that HACE-MbCD NA extracted cholesterol from the cellular membrane of MDA-MB-231 (human breast adenocarcinoma) cells more efficiently rather than MbCD and HACE NA. Efficient lipid rafts disruption of HACE-MbCD NA compared to MbCD and HACE NA groups seems to lead to the increment in apoptosis and antiproliferation efficiencies in MDA-MB-231 cells. Improvement in tumor targeting efficiency of HACE-MbCD NA compared to HACE NA in MDA-MB-231 tumor-bearing mice can be explained by the extraction process of cellular cholesterol by MbCD. Following intravenous injection in MDA-MB-231 tumor-bearing mice, the most efficient suppression of tumor growth and highest apoptotic region were observed in HACE-MbCD NA group rather than MbCD group. All of these findings suggest that CD44 receptor-targetable HACE-MbCD NA retaining cholesterol depletion activity from cancer cells may be one of the remarkable nanosystems for breast cancer therapy.

Mussel-Inspired Hyaluronic Acid Derivative Nanostructures for Improved Tumor Targeting and Penetration.

An amphiphilic hyaluronic acid-ceramide-dopamine (HACE-d) conjugate was prepared, and HACE-d-based nanoparticles (NPs) including phloretin (as an inhibitor of glucose transporter (GLUT1)) were fabricated. Mussel-inspired property of d was introduced to HACE NPs, and it may improve tumor targetability and penetration in addition to passive (based on enhanced permeability and retention effect) and active (interaction between HA and CD44 receptor) tumor targeting effects. HACE-d/phloretin NPs with 279 nm mean diameter, ∼0.2 polydispersity index, and -18 mV zeta potential were successfully fabricated, and a sustained drug release pattern was observed. HACE-d/phloretin NPs exhibited enhanced cellular accumulation efficiency and antiproliferation property, compared with HACE/phloretin NPs, in MDA-MB-231 cells (GLUT1 and CD44 receptor-expressed human breast adenocarcinoma cells). In a MDA-MB-231 spheroid model, HACE-d NPs group showed better tumor penetration efficiency and spheroid growth inhibitory effect rather than HACE NPs group. According to the optical imaging test in MDA-MB-231 tumor-xenografted mouse, HACE-d NPs group exhibited more selective distribution in tumor region and deeper infiltration into the inner part of tumor compared with HACE NPs group. After intravenous injection, HACE-d/phloretin NPs group also exhibited improved antitumor efficacies rather than the other experimental groups in MDA-MB-231 tumor-xenografted mouse. All these findings suggested that HACE-d/phloretin NP may be a promising tumor targetable and penetrable nanosystem for the therapy and imaging of GLUT1 and CD44 receptor-expressed cancers.

Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

(3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface of HACE-AMPB/MB NPs (in the aqueous milieu) may react with the sialic acid over-expressed in cancer cells and intramolecular B‒O bond can be formed. This phenylboronic acid-sialic acid interaction may provide additional tumor targeting and penetration potentials together with an enhanced permeability and retention (EPR) effect (passive tumor targeting) and HA-CD44 receptor interaction (active tumor targeting). Developed HACE-AMPB NP may be one of promising nanocarriers for the imaging and therapy of CD44 receptor-expressed cancers.

Grip Strength on the Unaffected Side as an Independent Predictor of Functional Improvement After Stroke.

OBJECTIVE: The aim of this study was to investigate the association between grip strength on the unaffected side and post-stroke functional improvement. DESIGN: A total of 127 patients with unilateral stroke were included in this study. Demographic data, clinical data on initial grip strength, initial National Institutes of Health Stroke Scale, admission and discharge Modified Barthel Index (MBI), and stroke profiles were retrospectively reviewed. RESULTS: Univariate and multiple linear regression analyses were carried out to evaluate the predictive values of each variable. In the model for discharge MBI, age, initial National Institutes of Health Stroke Scale, grip strength on the unaffected side, lesion side, and admission MBI were shown to be independent predictors. Meanwhile, grip strength on the unaffected side, lesion side, and admission MBI had significant predictive values in the model for difference between admission and discharge MBI. CONCLUSION: The current study suggests for the first time that grip strength on the unaffected side is an independent predictor for short-term functional gain and outcome after stroke. This result may change post-stroke rehabilitation strategies to emphasize exercises to prevent loss of muscle strength. In addition, this implies the possibility of a relationship between sarcopenia and post-stroke function. Further research is needed to reveal the effect of sarcopenia on stroke patients and its mechanism.

Dual CD44 and folate receptor-targeted nanoparticles for cancer diagnosis and anticancer drug delivery.

Dual CD44 and folate receptor targetable nanoparticles (NPs) based on hyaluronic acid-ceramide-folic acid (HACE-FA) were fabricated for improving tumor targetability. HACE-FA was synthesized via esterification between the carboxylic group of FA and hydroxyl group of HA. Doxorubicin (DOX)-loaded HACE-FA NPs, with a mean diameter of 120-130nm, narrow size distribution, and negative zeta potential, were prepared. The drug release from HACE-FA NPs were significantly increased in acidic pH (pH5.5) compared with physiological pH (7.4) (p<0.05). The cellular accumulation of the drug in HACE-FA NPs group was higher than that of HACE NPs group in SKOV-3 cells (human ovarian cancer cells; CD44 and folate receptor (FR)-positive cells). Dual targetability of HACE-FA NPs, compared to HACE NPs, was also verified in the SKOV-3 tumor-xenografted mouse model by near-infrared fluorescence (NIRF) imaging. Twenty-four hours after injection, HACE-FA NPs were accumulated mainly in tumor regions and their fluorescence intensity was 4.82-fold higher than that of HACE NPs (p<0.05). These findings suggest successful application of HACE-FA NPs for the accurate delivery of anticancer drugs to ovarian cancer.

Electrosprayed nanocomposites based on hyaluronic acid derivative and Soluplus for tumor-targeted drug delivery.

Nanocomposite (NC) based on hyaluronic acid-ceramide (HACE) and Soluplus (SP) was fabricated by electrospraying for the tumor-targeted delivery of resveratrol (RSV). Amphiphilic property of both HACE and SP has been used to entrap RSV in the internal cavity of NC. Electrospraying with established experimental conditions produced HACE/SP/RSV NC with 230nm mean diameter, narrow size distribution, negative zeta potential, and >80% drug entrapment efficiency. Sustained and pH-dependent drug release profiles were observed in drug release test. Cellular uptake efficiency of HACE/SP NC was higher than that of SP NC, mainly based on HA-CD44 receptor interaction, in MDA-MB-231 (CD44 receptor-positive human breast cancer) cells. Selective tumor targetability of HACE/SP NC, compared to SP NC, was also confirmed in MDA-MB-231 tumor-xenograted mouse model using a near-infrared fluorescence (NIRF) imaging. According to the results of pharmacokinetic study in rats, decreased in vivo clearance and increased half-life of RSV in NC group, compared to drug solution group, were shown. Given that these experimental results, developed HACE/SP NC can be a promising theranostic nanosystem for CD44 receptor-expressed cancers.

Efficacy of Slimming Cream Containing 3.5% Water-Soluble Caffeine and Xanthenes for the Treatment of Cellulite: Clinical Study and Literature Review.

BACKGROUND: Cellulite is a 'cottage cheese-like' cutaneous change caused by subcutaneous fat bulging into the dermis that usually leads to cosmetic problems. Slimming cream containing 3.5% water-soluble caffeine and xanthenes exhibits a lipolytic effect with penetration into the dermis. OBJECTIVE: To evaluate the efficacy and safety of slimming cream for the treatment of cellulite. METHODS: Fifteen subjects with cellulite applied slimming cream to the thighs and inner side of the upper arms twice daily for 6 weeks. Efficacy was assessed using a standard visual scale, changes in the circumferences of the thighs and upper arms, and patient satisfaction by a questionnaire at baseline, week 3, and week 6. Safety was assessed by inquiring about adverse events through questionnaires. RESULTS: The standard visual scale score improved significantly by 0.49 points (19.8%) at week 6. Thigh and upper-arm circumferences decreased by 0.7 cm (1.7%) and 0.8 cm (2.3%), respectively, at week 6. Slight itching and transient flushing were commonly reported, but no serious adverse event occurred. CONCLUSION: The slimming cream tested appears to be effective for the treatment of cellulitis without serious adverse effects. However, additional large clinical trials are required to confirm the efficacy and safety of slimming cream for the treatment of cellulitis.

Ulnar Neuropathy After Extracorporeal Shockwave Therapy: A Case Report.

Currently, extracorporeal shockwave therapy (ESWT) is widely used for treatment of various musculoskeletal disorders. We report a case of ulnar neuropathy secondary to the application of ESWT. A 48-year-old man was diagnosed with medial epicondylitis and underwent 2 sessions of ESWT. Immediately after the second session, he experienced paresthesia and weakness in the right hand. On physical examination, atrophy of the first dorsal interosseus and weakness of the abductor digiti minimi were observed. Electrophysiologic study demonstrated ulnar neuropathy at the elbow with severe partial axonotmesis. Our case report demonstrates that ESWT might cause or contribute to peripheral nerve injury at the site of application.

Development of poly(lactic-co-glycolic) acid nanoparticles-embedded hyaluronic acid-ceramide-based nanostructure for tumor-targeted drug delivery.

A hyaluronic acid-ceramide (HACE) nanostructure embedded with docetaxel (DCT)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) was fabricated for tumor-targeted drug delivery. NPs with a narrow size distribution and negative zeta potential were prepared by embedding DCT-loaded PLGA NPs into a HACE nanostructure (DCT/PLGA/HACE). DCT-loaded PLGA and DCT/PLGA/HACE NPs were characterized by solid-state techniques, including Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). A sustained drug release pattern from the NPs developed was observed and negligible cytotoxicity was seen in NIH3T3 cells (normal fibroblast, CD44 receptor negative) and MDA-MB-231 cells (breast cancer cells, CD44 receptor positive). PLGA/HACE NPs containing coumarin 6, used as a fluorescent dye, exhibited improved cellular uptake efficiency, based on the HA-CD44 receptor interaction, compared to plain PLGA NPs. Cyanine 5.5 (Cy5.5)-labeled PLGA/HACE NPs were injected intravenously into a MDA-MB-231 tumor xenograft mouse model and demonstrated enhanced tumor targetability, compared with Cy5.5-PLGA NPs, according to a near-infrared fluorescence (NIRF) imaging study. Considering these experimental results, the DCT/PLGA/HACE NPs developed may be useful as a tumor-targeted drug delivery system.

Nanocomplexes based on amphiphilic hyaluronic acid derivative and polyethylene glycol-lipid for ginsenoside rg3 delivery.

Hybrid nanocomplex formulations, based on amphiphilic hyaluronic acid-ceramide (HACE) and lipids, were fabricated for the delivery of 20(S)-ginsenoside Rg 3 [(S)-Rg3]. Nanocomplexes with less than 200 nm mean diameter, narrow size distribution, spherical shape, and negative zeta potential were prepared. The maintenance of the structural stability of the hybrid nanocomplexes in the blood stream was demonstrated by measuring their particle size in serum. Nanocomplexes based on HACE, phosphatidylcholine (PC), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) showed a sustained drug release profile compared with other formulations. Blank nanocomplexes exhibited negligible cytotoxicity within the tested concentration range in A549 human lung adenocarcinoma cells. The cellular uptake efficiency of hybrid nanocomplexes was improved compared with the HACE-based nanoparticles probably because of interactions between lipids and the cellular membrane. The results of a pharmacokinetic study in rats revealed decreased in vivo clearance of (S)-Rg3, especially in the HACE/PC/DSPE-PEG-based hybrid nanocomplex (F3) group. The hybrid nanostructure and the outer PEG chain likely contributed to improve in vivo performance of the F3 group. Thus, these developed hybrid nanocomplexes could serve as good candidates for tumor-targeted delivery of anticancer agents.

Interconnected hyaluronic acid derivative-based nanoparticles for anticancer drug delivery.

Doxorubicin (DOX)-loaded nanoparticles (NPs) based on interconnected hyaluronic acid-ceramide (HACE) structure were fabricated and their anti-tumor efficacy was evaluated in vitro. Interconnected HACE was synthesized by cross-linking HACE with adipic acid dihydrazide (ADH) and its synthesis was identified by (1)H NMR analysis. DOX-loaded NPs with <200nm mean diameter, negative zeta potential, and spherical shape were prepared. Interconnected HACE-based NPs increased drug-loading capacity and in vitro drug release, compared to HACE-based NPs. DOX release was dependent on the environmental pH, implying the feasibility of enhancing drug release in tumor region and endosomal compartments. Synthesized interconnected HACE did not show cytotoxic effect up to 1000µg/ml concentration in NIH3T3 and MDA-MB-231 cells. In cellular uptake studies using confocal laser scanning microscopy (CLSM) and flow cytometry in MDA-MB-231 cells, higher uptake of DOX was observed in the interconnected HACE-based NPs than HACE NPs. In vitro anti-tumor efficacy was assessed by MTS-based assay, in which cytotoxic effect of DOX-loaded interconnected HACE NPs was higher than that of DOX-loaded HACE NPs. Thus, these results suggest the feasibility of interconnected HACE-based NPs to be used for efficient tumor-targeted delivery of anticancer drugs.

Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery.

Nanohybrid liposomes coated with amphiphilic hyaluronic acid-ceramide (HACE) was fabricated for targeted delivery of anticancer drug and in vivo cancer imaging. Nanohybrid liposomes including doxorubicin (DOX) and Magnevist, a contrast agent for magnetic resonance (MR) imaging, with 120-130nm mean diameter and a narrow size distribution were developed. DOX release from the developed formulation was improved at acidic pH (pH5.5 and 6.8) versus physiological pH (pH7.4). Cytotoxicity induced by the blank plain liposome was reduced by coating the outer surface of the nanohybrid liposome with HACE. Cellular uptake of DOX from the nanohybrid liposome was enhanced by HA and CD44 receptor interaction, versus the plain liposome. In vivo contrast-enhancing effects revealed that the nanohybrid liposome can be used as a tumor targeting MR imaging probe for cancer diagnosis. In a pharmacokinetic study in rats, in vivo clearance of DOX was decreased in the order DOX solution, plain liposome (F2), and nanohybrid liposome (F3), indicating prolonged circulation of the drug in the blood stream and improved therapeutic efficacy of the nanohybrid liposome (F3). Based on these findings, the nanohybrid liposomal system may be a useful candidate for real-time cancer diagnosis and therapy.

Factors associated with compliance with viscosity-modified diet among dysphagic patients.

OBJECTIVE: To investigate compliance with a viscosity-modified diet among Korean dysphagic patients and to determine which factors are associated with compliance. METHODS: We retrospectively reviewed medical records of patients who had been recommended to use thickeners in the previous videofluoroscopic swallowing study (VFSS). Among 68 patients, 6 were excluded because tube feeding was required due to deterioration in their medical condition. Finally, 62 patients were included in the study. Patient compliance was assessed using their medical records by checking whether he or she had maintained thickener use until the next VFSS. To determine which factors affect compliance, the relationship between thickener use and patient characteristics, such as sex, age, inpatient/outpatient status, severity of dysphagia, aspiration symptoms, follow-up interval of VFSS, and current swallowing therapy status were assessed. For noncompliers, reasons for not using thickeners were investigated by telephone interview. RESULTS: Among 62 patients, 35 (56.5%) were compliers, and 27 (43.5%) were noncompliers. Eighteen (90%) of 20 inpatients had followed previous recommendations; however, only 17 (40.5%) of 42 outpatients had been using thickeners. Of patient characteristics, only admission status was significantly correlated with compliance. When asked about the reason why they had not used thickeners, noncompliers complained about dissatisfaction with texture and taste, greater difficulty in swallowing, and inconvenience of preparing meals. CONCLUSION: Among Korean dysphagic patients, compliance with a viscosity-modified liquid diet was only about 50%. Betterments of texture and taste along with patient education might be necessary to improve compliance with thickener use.

Prevalence of the rotator cuff tear increases with weakness in hemiplegic shoulder.

OBJECTIVE: To investigate the relationship between the rotator cuff tear (RCT) and the muscle strength in hemiplegic side, and the effects of paralysis on the affected shoulders in hemiplegic patients. METHODS: A cross-sectional observational study performed in a university hospital was presented. The study enrolled 55 participants with hemiplegia of diverse degree of motor paresis, excluding those with bilateral lesions, history of major trauma or other co-existing musculoskeletal disorders of the shoulder. The main outcome measurements were muscle strength of the affected upper extremity (based on Medical Research Council scale), RCTs of the bilateral shoulders (by ultrasonography), and presence of shoulder pain, subluxation of the glenohumeral joint, passive range of motions, and subacromial spurs. RESULTS: Comparing each side of the shoulders, the prevalence of shoulder pain and supraspinatus muscle tear was higher (p<0.0001, p=0.007), and the range of motion was restricted (p<0.0001, p<0.0001, p<0.0001, p<0.0001) in the affected side. There was a significant trend toward higher prevalence of RCT and shoulder subluxation in the weaker shoulder (p=0.019, p<0.0001). In a multivariate analysis, Manual Muscle Test grade of less than three was an independent risk factor for RCT (p=0.025). CONCLUSION: RCT in hemiplegia had a linear trend with muscle weakness in the affected side and the degree of weakness was an independent risk factor for the occurrence of RCT. In addition, shoulder pain, limitation of range of motions, and RCT were more frequent on the hemiplegic side of the shoulders. It is the first study to reveal a linear trend between RCT and upper extremity weakness and will provide physicians an insight to the management of RCTs in hemiplegic patients.

Hyaluronic acid derivative-based self-assembled nanoparticles for the treatment of melanoma.

PURPOSE: Hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs) were developed for the targeted delivery of doxorubicin (DOX), and their antitumor efficacy for melanoma was evaluated. METHODS: DOX-loaded HACE-based self-assembled NPs were prepared and their physicochemical properties were characterized. The in vitro cytotoxicity of HACE was measured using an MTS-based assay. The cellular uptake efficiency of DOX into mouse melanoma B16F10 cells was assessed by confocal laser scanning microscopy and flow cytometry. Tumor growth and body weight were monitored after the intratumoral and intravenous injection of DOX-loaded NPs into a B16F10 tumor-bearing mouse model. RESULTS: DOX-loaded NPs, with a mean diameter of ~110 nm, a narrow size distribution, and high drug entrapment efficiency, were prepared. A sustained DOX release pattern was shown, and drug release was enhanced at pH 5.5 compared with pH 7.4. The cytotoxicity of HACE to B16F10 cells was negligible. It was assumed that DOX was taken up into the B16F10 cells through receptor-mediated endocytosis. A significant inhibitory effect was observed on tumor growth, without any serious changes in body weight, after the injection of DOX-loaded NPs into the B16F10 tumor-bearing mouse model. CONCLUSIONS: DOX-loaded HACE-based NPs were successfully developed and their antitumor efficacy against B16F10 tumors was demonstrated.

Hyaluronic acid-ceramide-based optical/MR dual imaging nanoprobe for cancer diagnosis.

Hyaluronic acid-ceramide (HACE)-based nanoprobes for magnetic resonance (MR) and optical imaging were developed for cancer diagnosis. Diethylenetriaminepentaacetic dianhydride (DTPA) was conjugated to HACE for the chelation of gadolinium (Gd) as an MR contrast agent. Cy5.5 was also conjugated to the HACE backbone as a near-infrared fluorescence (NIRF) imaging dye. The self-assembled HACE-based nanoprobe, Cy5.5-HACE-DTPA-Gd, exhibited a uniformly distributed particle size and morphological shape. The HACE-based nanoprobe did not induce serious cytotoxicity in U87-MG (low expression of CD44 receptor) and SCC7 (high expression of CD44 receptor) cells. The cellular uptake efficiency of the HACE-based nanoprobe was higher in SCC7 cells than in U87-MG cells, indicating an HA-CD44 receptor interaction. In vitro MR signal enhancement of the HACE-based nanoprobe was confirmed compared with a commercial formulation (Magnevist). Moreover, in vivo MR contrast enhancement of the HACE-based nanoprobe in the tumor region was verified in an SCC7 tumor xenograft mouse model. The tumor targetability of the developed nanoprobe was monitored by an NIRF imaging study, and improved accumulation of the nanoprobe in the tumor region was observed. Therefore, this HACE-based dual-imaging nanoprobe can be used to make a more accurate diagnosis of cancer based on its passive and active tumor targeting strategies.

Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin.

Polyethylene glycol (PEG)-conjugated hyaluronic acid-ceramide (HACE) was synthesized for the preparation of doxorubicin (DOX)-loaded HACE-PEG-based nanoparticles, 160 nm in mean diameter with a negative surface charge. Greater uptake of DOX from these HACE-PEG-based nanoparticles was observed in the CD44 receptor highly expressed SCC7 cell line, compared to results from the CD44-negative cell line, NIH3T3. A strong fluorescent signal was detected in the tumor region upon intravenous injection of cyanine 5.5-labeled nanoparticles into the SCC7 tumor xenograft mice; the extended circulation time of the HACE-PEG-based nanoparticle was also observed. Pharmacokinetic study in rats showed a 73.0% reduction of the in vivo clearance of DOX compared to the control group. The antitumor efficacy of the DOX-loaded HACE-PEG-based nanoparticles was also verified in a tumor xenograft mouse model. DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction and by passive targeting due to its small mean diameter (<200 nm). Moreover, PEGylation resulted in prolonged nanoparticle circulation and reduced DOX clearance rate in an in vivo model. These results therefore indicate that PEGylated HACE nanoparticles represent a promising anticancer drug delivery system for cancer diagnosis and therapy.

Self-assembled nanoparticles based on hyaluronic acid-ceramide (HA-CE) and Pluronic® for tumor-targeted delivery of docetaxel.

Hyaluronic acid-ceramide (HA-CE)-based self-assembled nanoparticles were developed for intravenous docetaxel (DCT) delivery. In this study, physicochemical properties, cellular uptake efficiency, and in vivo targeting capability of the nanoparticles developed were investigated. DCT-loaded nanoparticles composed of HA-CE and Pluronic 85 (P85) with a mean diameter of 110-140 nm were prepared and their morphological shapes were assessed using transmission electron microscopy (TEM). DCT release from nanoparticle was enhanced with increasing P85 concentrations in our in vitro model. Blank nanoparticles exhibited low cytotoxicity in U87-MG, MCF-7 and MCF-7/ADR cell lines. From cellular uptake studies, the nanoparticles developed enhanced the intracellular DCT uptake in the CD44-overexpressing cell line (MCF-7). The nanoparticles were shown to be taken up by the HA-CD44 interaction according to DCT and coumarin 6 (C6) cellular uptake studies. The multidrug resistance (MDR)-overcoming effects of DCT-loaded HA-CE/P85-based nanoparticles were also observed in cytotoxicity tests in MCF-7/ADR cells. Following the intravenous injection of DCT-loaded cyanine 5.5 (Cy5.5)-conjugated nanoparticles in MCF-7/ADR tumor-bearing mice, its in vivo targeting for CD44-overexpressing tumors was identified by non-invasive near-infrared (NIR) fluorescence imaging. These results indicate that the HA-CE-based nanoparticles prepared may be a promising anti-cancer drug delivery system through passive and active tumor targeting.