Curcumin-loaded pH-sensitive carboxymethyl chitosan nanoparticles for the treatment of liver cancer.

In this study, the pH-responsive API-CMCS-SA (ACS) polymeric nanoparticles (NPs) based on 1-(3-amino-propyl) imidazole (API), stearic acid (SA), and carboxymethyl chitosan (CMCS) were fabricated for the effective transport of curcumin (CUR) in liver cancer. CUR-ACS-NPs with various degrees of substitution (DS) were employed to prepare through ultrasonic dispersion method. The effect of different DS on NPs formation was discussed. The obtained CUR-ACS-NPs (DSSA=12.4%) had high encapsulation rate (more than 85%) and uniform particle size (186.2 ± 1.42 nm). The CUR-ACS-NPs showed better stability than the other groups. Drug release from the CUR-ACS-NPs was pH-dependent, and more than 90% or 65% of CUR was released in 48 h in weakly acid medium (pH 5.0 or 6.0, respectively). Additionally, the CUR-ACS-NPs increased the intracellular accumulation of CUR and demonstrated high anticancer effect on HepG2 cells compared with the other groups. CUR-ACS-NPs prolonged the retention time of the drug, and the area under the curve (AUC) increased significantly in vivo. The in vivo antitumor study further revealed that the CUR-ACS-NPs exhibited the capability of inhibiting tumor growth and lower systemic toxicity. Meanwhile, CUR, CUR-CS-NPs, and CUR-ACS-NPs could be detected in the evaluated organs, including tumor, liver, spleen, lung, heart, and kidney in distribution studies. Among them, CUR-ACS-NPs reached the maximum concentration at the tumor site, indicating the tumor-targeting properties. In short, the results suggested that CUR-ACS-NPs could act a prospective drug transport system for effective delivery of CUR in cancer treatment.

Anxiety and depression are associated with poor outcomes in open elbow arthrolysis.

BACKGROUND: Open elbow arthrolysis (OEA) is an established treatment for posttraumatic elbow stiffness (PTES); however, its efficacy is debatable for some patients. Poor surgical outcomes have been associated with anxiety and depression in other orthopedic conditions, but no studies have examined this association in OEA. In this study, we aimed to determine whether a high preoperative anxiety and depression score is associated with a worse functional outcome in OEA for PTES. METHODS: A retrospective review of prospectively collected data was carried out in patients undergoing OEA between April 2021 and March 2022. Mental state evaluated by Hospital Anxiety and Depression Scale (HADS), subjective elbow function valued by Disabilities of the Arm, Shoulder, and Hand (DASH) score, objective elbow function valued by Mayo Elbow Performance Score (MEPS), pain score measured by visual analog scale (VAS) and the flexion-extension range of motion (ROM) of the affected elbow were collected before and after surgery in outpatient clinic follow-up at 3 months and 6 months. Patient satisfaction was only recorded 6 months postoperatively. All patients were divided into 2 groups based on the preoperative HADS score for analysis: Group A was the nonanxiety-depression group, and Group B was the anxiety-depression group. RESULTS: A total of 49 patients were included. Both groups improved in DASH, MEPS and ROM at 3 months and at 6 months. The HADS score in Group B decreased significantly at 6 months, showing that the mental state of patients in Group B improved after surgery. Group A had a lower DASH at 3 months and 6 months, larger 6-month ROM and higher satisfaction rate than Group B. Comparing the differences between preoperative and postoperative measurements, Group A improved more in ROM at 6 months. There was no significant difference in other outcome measures between the two groups. CONCLUSIONS: OEA is a safe and effective treatment for PTES, and can achieve good clinical outcomes in the short-term follow-up, regardless of whether the patients suffer from anxiety or depression. Patients with a HADS score ≥11 before OEA, however, have worse outcomes than those with a HADS score <11. LEVEL OF EVIDENCE: Level II; Retrospective Design; Prognosis Study.

Research on preparation and antitumor activity of redox-responsive polymer micelles co-loaded with sorafenib and curcumin.

A novel redox-responsive mPEG-SS-PLA (PSP) polymeric micelle was synthesized and prepared for the delivery of sorafenib (SAF) and curcumin (CUR). And a series of validations were conducted to confirm the structure of the synthesized polymer carriers. Using the Chou-Talalay approach, the combination indexes (CI) of SAF and CUR were determined, and explore the inhibitory effects of the two drugs on HepG2R cells at different ratios. SAF/CUR-PSP polymeric micelles were prepared by thin film hydration method, and the physicochemical properties of nanomicelles were evaluated. The biocompatibility, cell uptake, cell migration, and cytotoxicity assays were assessed in HepG2R cells. The expression of the phosphoinositol-3 kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway was detected by Western blot assay. Additionally, the tumor suppressive effect of SAF/CUR-PSP micelles was clearly superior to free drug monotherapy or their physical combination in HepG2 cell-induced tumor xenografts. The current study revealed that mPEG-SS-PLA polymer micelles loaded with SAF and CUR showed the enhanced therapeutic effects against hepatocellular carcinoma in vitro and in vivo models. It has promising applications for cancer therapy.

Glucosamine-Modified Reduction-Responsive Polymeric Micelles for Liver Cancer Therapy.

In this work, glucose transporter-1 (GLUT-1) and glutathione (GSH) over-expression in liver cancer was utilized to design a reduction-responsive and active targeting drug delivery system AG-PEG-SS-PCL (APSP) for the delivery of sorafenib (SF). The SF-APSP micelles were prepared using the thin film hydration method and characterized by various techniques. In vitro release experiments showed that the cumulative release of SF-APSP micelles in the simulated tumor microenvironment (pH 7.4 with GSH) reached 94.76 ± 1.78% at 48 h, while it was only 20.32 ± 1.67% in the normal physiological environment (pH 7.4 without GSH). The in vitro study revealed that glucosamine (AG) enhanced the antitumor effects of SF, and SF-APSP micelles inhibited proliferation by targeting HepG2 cells and suppressing cyclin D1 expression. The in vivo antitumor efficacy study further confirmed that the SF-APSP micelles had excellent antitumor effects and better tolerance against nude mouse with HepG2 cells than other treatment groups. All in all, these results indicated that SF-APSP micelles could be a promising drug delivery system for anti-hepatoma treatment.

Relationship between measurements of ipsilateral capitellum and prosthetic radial head size.

BACKGROUND: Selecting the correct size of head component is challenging in radial head arthroplasty, particularly in comminuted fractures. This study aimed to investigate the relationship between measurements of the ipsilateral capitellum and the prosthetic radial head size, which may be used to predict the size of the radial head prosthesis preoperatively. METHODS: Our study enrolled all patients who underwent radial head arthroplasty at Beijing Jishuitan Hospital. Demographic, injury-related and radiographic data were collected. The prosthetic radial head size was recorded from the surgical notes. Three-dimensional models of preoperative CT scans were reconstructed, on which the lateral capitellar diameter, the capitellar width and the width between the capitellum and trochlea were measured. The correlations between measurements of the ipsilateral capitellum and the prosthetic radial head size were evaluated, and linear regression equations were established. RESULTS: The study enrolled 37 patients, with an average age of 42.8 ± 11.5 years and a male-female ratio of 20:17. The median diameter of the radial head prostheses was 22 (20, 22) mm. The average lateral capitellar diameter was 20.71 ± 1.93 mm, the mean capitellar width was 14.90 ± 1.40 mm, and the mean width between the capitellum and trochlea was 19.29 ± 1.78 mm. The lateral capitellar diameter (R = 0.820, P < 0.001), the capitellar width (R = 0.726, P < 0.001) and the width between the capitellum and trochlea (R = 0.626, P < 0.001) were significantly positively correlated with the size of the radial head prosthesis. The linear regression equation between the lateral capitellar diameter and the size of the radial head prosthesis was calculated and defined as follows: D = 7.44 + 0.67*d (D: diameter of radial head prosthesis; d: lateral capitellar diameter; and adjusted R2 = 0.719, P < 0.001). CONCLUSIONS: There are positive correlations between the anatomical parameters of the ipsilateral capitellum and the prosthetic radial head size. The lateral capitellar diameter can be measured on three-dimensional CT preoperatively to predict the size of the radial head prosthesis intraoperatively.

Perioperative Protocol of Ankle Fracture and Distal Radius Fracture Based on Enhanced Recovery after Surgery Program: A Multicenter Prospective Clinical Controlled study.

Background: The enhanced recovery after surgery (ERAS) program is aimed to shorten patients' recovery process and improve clinical outcomes. This study aimed to compare the outcomes between the ERAS program and the traditional pathway among patients with ankle fracture and distal radius fracture. Methods: This is a multicenter prospective clinical controlled study consisting of 323 consecutive adults with ankle fracture from 12 centers and 323 consecutive adults with distal radial fracture from 13 centers scheduled for open reduction and internal fixation between January 2017 and December 2018. According to the perioperative protocol, patients were divided into two groups: the ERAS group and the traditional group. The primary outcome was the patients' satisfaction of the whole treatment on discharge and at 6 months postoperatively. The secondary outcomes include delapsed time between admission and surgery, length of hospital stay, postoperative complications, functional score, and the MOS item short form health survey-36. Results: Data describing 772 patients with ankle fracture and 658 patients with distal radius fracture were collected, of which 323 patients with ankle fracture and 323 patients with distal radial fracture were included for analysis. The patients in the ERAS group showed higher satisfaction levels on discharge and at 6 months postoperatively than in the traditional group (P < 0.001). In the subgroup analysis, patients with distal radial fracture in the ERAS group were more satisfied with the treatment (P=0.001). Furthermore, patients with ankle fracture had less time in bed (P < 0.001) and shorter hospital stay (P < 0.001) and patients with distal radial fracture received surgery quickly after being admitted into the ward in the ERAS group than in the traditional group (P=0.001). Conclusions: Perioperative protocol based on the ERAS program was associated with high satisfaction levels, less time in bed, and short hospital stay without increased complication rate and decreased functional outcomes.

Lateral minimal approach to the terrible triad of the elbow: a treatment protocol in Beijing Jishuitan Hospital.

BACKGROUND: This study aimed to report the surgical techniques and results of treating coronoid process and radial head fracture combined with dislocation of the elbow (terrible triad of the elbow) using a single lateral incision, known as the extensor digitorum communis (EDC) split approach. METHODS: A retrospective analysis was performed of 109 patients with terrible triad of the elbow who had been treated by the authors from January 2013 to December 2019. The participants included 67 males and 42 females, with a mean age of 42.2 years (14-71 years). All participants were treated via a single lateral approach. The coronoid process was fixated with Kirschner wires combined with anterior capsule suture lasso fixation. For the radial head fracture, 58 cases were fixated by AO headless cannulated screw (AO HCS) and 51 cases by acumed radial head replacement. In repair of the lateral collateral ligament (LCL) complex and the common extensor tendon, 28 cases used ETHIBOND suture through bone holes at the humeral lateral epicondyle, and the other 81 cases used suture anchors. No medial collateral ligament was repaired. A total of 46 participants were fixated with a Stryker dynamic joint distractor (DJD) II hinged external fixator to protect the bone and soft tissue. RESULTS: All participants were followed up from 6 to 60 months (mean, 36.1 months). Their elbow range of flexion and extension averaged 123.4°±20.7°, forearm rotation 151.0°±25.6°, and Mayo elbow performance score (MEPS) 92.3±8.8. There were 22 participants (19.5%) with ulnar nerve symptoms, 16 (14.7%) who had elbow stiffness, and 7 underwent secondary surgery, including 6 removals of internal fixation, 5 arthrolyses of the elbow, and 2 ulnar neurolyses. CONCLUSIONS: Coronoid fractures, radial head fractures, and LCL injuries of the terrible triad of the elbow can be treated satisfactorily through a lateral minimal incision, combined with a hinged external fixation if necessary.

Changes in bone mineral density after parathyroidectomy in patients with moderate to severe primary hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is relatively common in China and results in severe damage to the skeletal system. This study aimed to investigate changes in bone mineral density (BMD) over 2 years in patients with PHPT after parathyroidectomy. METHODS: This retrospective cohort study included patients with PHPT who underwent parathyroidectomy between January 2010 and December 2015. BMD and T-scores and Z-scores of the lumbar spine (L1, L2, L3, and L4) and total hip (femoral neck, great trochanter, and Ward's triangle) at baseline and 2 years after surgery were measured by dual-energy X-ray absorptiometry. RESULTS: Thirty patients with moderate to severe PHPT (17 men and 13 women) aged 38.90±15.48 years were included. BMD, and T-score and Z-score values at the lumbar spine and total hip at 6 months, 1 year, and 2 years after parathyroidectomy were significantly improved compared with preoperative values. Improvement in BMD was largest at L4 (46.7%) and smallest at L1 (37.4%) in the lumbar spine 2 years after parathyroidectomy. For the total hip, the increase in BMD was largest at Ward's triangle (42.6%) and smallest at the femoral neck (37.5%). CONCLUSIONS: BMD of the lumbar spine and total hip is improved after parathyroidectomy in patients with PHPT.

Correlation between modified trochleocapitellar index and post-traumatic elbow stiffness in type C2-3 distal humeral fractures among adults.

BACKGROUND: The purpose of this study was to propose the modified trochleocapitellar index (mTCI), assess its reliability, and evaluate its correlation with post-traumatic elbow stiffness in type C2-3 distal humeral fractures among adults. METHODS: From January 2013 to June 2017, a total of 141 patients with type C2-3 distal humeral fractures were included. The mTCI was calculated as the ratio between the modified trochlear and capitellar angles relative to the humeral axis (mTCI-HA), lateral humeral line (mTCI-LHL), and medial humeral line (mTCI-MHL) from anteroposterior radiographs taken immediately after the operation. The patients were divided into group A (with elbow stiffness) and group B (without elbow stiffness) based on follow-up results. To determine risk factors for elbow stiffness, univariate and logistic regression analyses were performed on each radiographic parameter separately, together with other clinical variables. Interrater reliability was assessed for all measurements. RESULTS: Specific optimal ranges of value were identified for mTCI-HA (0.750-0.875), mTCI-LHL (0.640-1.060), and mTCI-MHL (0.740-0.900), beyond which the likelihood of elbow stiffness significantly increased (P < .001). By multivariate analysis, mTCI-HA (odds ratio [OR] 26.22, 95% confidence interval [CI] 3.39-203.07, P = .002), mTCI-LHL (OR 5.37, 95% CI 2.17-13.28, P < .001), and mTCI-MHL (OR 5.95, 95% CI 1.91-18.56, P = .002) values beyond the optimal ranges were identified as the independent risk factors for elbow stiffness. The interrater reliability of mTCI-HA, mTCI-LHL, and mTCI-MHL was 0.986, 0.983, and 0.987, respectively. CONCLUSION: The mTCI measurement method is reliable. Either too small or too large mTCI values were associated with post-traumatic elbow stiffness among adult patients with type C2-3 distal humeral fractures. The mTCI-HA showed a better predictive value than mTCI-LHL and mTCI-MHL.

Effect of nano yam polysaccharide on the blood glucose and blood lipid in rats.

Chinese yam is the dry rhizome of dioscoreaceae plant. Polysaccharide in yam is one of significant functional components, its pharmacological effects include glucose-lowering, lipid-lowering, anti-tumor, anti-oxidation and enhancing the immune. The effects of nano yam polysaccharide on the metabolism of blood glucose and blood lipid in model rats were systematically investigated in this study. The results showed that the diabetic rat model can been successfully induced by the peritoneal injection of 200mg/kg alloxan. The rats were fed with the high-fat diet for 30d, which could induce a model of hyperlipidemia rat successfully. After the model rats were fed with nano yam polysaccharide of 50mg/ml and 100mg/ml per day for 12d and 30d, respectively. For each nano yam polysaccharide group, the blood glucose level was significantly reduced, the glucose tolerance, glycogen and the content of C-peptide were improved in alloxan rats. Moreover, the symptom of one little and three more in diabetic rats was ameliorated and the contents of TC, TG and LDL-C in the serum for the high fat rats were significantly decreased.

I6P7 peptide modified superparamagnetic iron oxide nanoparticles for magnetic resonance imaging detection of low-grade brain gliomas.

Glioma, the most severe primary brain malignancy, has very low survival rates and a high level of recurrence. Nowadays, conventional treatments for these patients are suffering a similar plight owing to the distinctive features of the malignant gliomas, for example chemotherapy is limited by the blood-brain barrier while surgery and radiation therapy are affected by the unclear boundaries of tumor from normal tissue. In the present study, a novel superparamagnetic iron oxide (SPIO) nanoprobe for enhanced T2-weighted magnetic resonance imaging (MRI) was developed. A frequently used MRI probe, SPIO nanoparticles, was coated with a silica outer layer and for the first time was covalently modified with interleukin-6 receptor targeting peptides (I6P7) to promote transportation through the blood-brain barrier and recognition of low-grade gliomas. The efficiency of transcytosis across the blood-brain barrier was examined in vitro using a transwell invasion model and in vivo in nude mice with orthotopic low-grade gliomas. The targeting nanoprobe showed significant MRI enhancement and has potential for use in the diagnosis of low-grade gliomas.

Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis.

BACKGROUND: Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity. MATERIALS AND METHODS: Liposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE-/-) mice. RESULTS: Targeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity. CONCLUSION: Both in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone.

MRI-visible and pH-sensitive micelles loaded with doxorubicin for hepatoma treatment.

Emerging pH-sensitive polymeric nanocarriers carrying therapeutic drugs are bringing about new opportunities for the effective treatment of cancer. A big challenge remains though to develop pH-sensitive polymers, which is hard to achieve via introducing only one kind of pH-sensitive chemical structure with a specific pKa. Consequently, in this study, an amphiphilic block copolymer, poly(ethylene glycol)-b-poly(ß-benzyl l-aspartate) (mPEG-PBLA), was synthesized, and its PBLA block was aminolyzed by N,N-diisopropylamino ethylamine (DIP) and N,N-dibutalamino ethylamine (DBA) at different molar ratios. The copolymer mPEG-PAsp(DBA75%&DIP25%) (PPAP75%) with an appropriate pKa was screened out to form a pH-sensitive micelle, which could encapsulate a high content of the hydrophobic anticancer drug doxorubicin (DOX) and magnetic resonance imaging (MRI) contrast agent superparamagnetic iron oxide nanoparticles (SPIONs) at neutral pH, but disassemble rapidly under weak acidic conditions. The micellar nanodrug was efficiently taken up by HepG2 cells and intracellular DOX release was readily triggered inside acidic lysosomal compartments to allow migration of the free drug to the cell nucleus. In vivo fluorescence and MR bimodal imaging showed that the pegylated nanodrug with a suitable size and weak positive charge could stay longer in the blood circulation and extravasate preferentially into a tumor. The nanodrug not only exhibited high cytotoxicity in HepG2 cells but also significantly prolonged the survival time of tumor-bearing mice, thereby demonstrating the great potential of this pH-sensitive and MRI-visible micelle for the effective treatment of cancer.

Co-Delivery of Doxorubicin and Anti-BCL-2 siRNA by pH-Responsive Polymeric Vector to Overcome Drug Resistance in In Vitro and In Vivo HepG2 Hepatoma Model.

Drug resistance, developed through multiple mechanisms, is a major hindrance to successful chemotherapy of tumor. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy which may improve anticancer effect by synergistic actions. In this study, triblock copolymer of poly(ethylene glycol)- block-poly(l-lysine)- block-poly aspartyl ( N-( N', N'-diisopropylaminoethyl)) (PEG-PLL-PAsp(DIP)) was synthesized for the first time to enable the codelivery of BCL-2 siRNA and DOX. The system is supposed to not only bypass drug efflux but also down-regulate the antiapoptotic gene and consequently confronting against chemoresistance as well. Moreover, the pH responsive ability of the codelivery system can prevent drug leakage during circulation and guarantee swift drug release at tumors. The codelivered siRNA serves to suppress the expression of antiapoptotic BCL-2 and hence sensitize the cancer cells to anticancer drugs and produce improved therapeutic effect. Consequently, the codelivery of BCL-2 siRNA and anticancer drug DOX serves as a promising strategy against drug resistance in chemotherapy.

Antitumor effect of a new nano-vector with miRNA-135a on malignant glioma.

INTRODUCTION: MiR-135a is found to selectively induce apoptosis in glioma cell but not in normal neurons and glial cells. However, low transfection efficacy limits its application in vivo as other miRNAs. We prepared a new kind of nano-vector based on polyethylene glycol methyl ether (mPEG) and hyper-branched polyethylenimine (hy-PEI) in order to improve the miRNA delivery system into the glioma cells. METHODS: The mPEG-g-PEI/miR-135a was constructed and detected by 1H NMR and FTIR analyses. Transmission electron microscope was utilized for its characteristics. Stability and release efficiency was assessed by electrophoresis. Biocompatibility was observed and analyzed through co-culture with astrocytes and malignant glioma cells (C6). Transfection rate was monitored by laser confocal microscopy and flow cytometry. The antitumor effect of mPEG-g-PEI/miR-135a to C6 was confirmed in vivo by MR scanning, pathology and survival curve. RT-PCR was used to assay transfection efficiency of mPEG-g-PEI/miR-135a in vitro and in vivo. And Western blotting was used to assess the expressions of the targeted proteins of miR-135a. RESULTS: In this experiment, we found the optimal N/P ratio of mPEG-g-PEI/miR-135a was about 6 judged by Zeta potential, particle size and encapsulation ability. The stability of mPEG-g-PEI/miR-135a in serum and the release efficiency in acid(pH=5.0) of mPEG-g-PEI/miR-135a were simulated the environment in vivo and in tumor. The mPEG-g-PEI nano-vector was co-cultured with malignant glioma cell C6 and normal astrocytes in vitro and showed good biocompatibility evaluated by CCK8 assay. The cell experiments in vitro indicated that mPEG-g-PEI could significantly improve miR-135a transfection by enhancing uptake effect of both normal glial and glioma cells. Given the C6 implanted in situ model, we discovered that the mPEG-g-PEI/miR-135a could obviously increase the survival period and inhibit the growth of glioma confirmed by MRI and histochemistry. In addition, the transfection efficiency of mPEG-g-PEI was better than that of other transfection agents either in vitro or in vivo confirmed by RT-PCR. Moreover, the expressions of the targeted proteins of miR-135a were consistent with the in vitro results. CONCLUSION: These results suggest that mPEG-g-PEI is expected to provide a new effective intracellular miRNA delivery system with low toxicity for glioma therapy.

Codelivery of sorafenib and GPC3 siRNA with PEI-modified liposomes for hepatoma therapy.

Hepatocellular carcinoma (HCC) is one of the most common malignancies imposing a serious threat to human health worldwide. To date, the effect of HCC chemotherapy has been limited due to drug resistance. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy that may improve anticancer effects by synergistic actions. The current study was aimed at achieving better HCC treatment via combination therapy, in which PEI-modified liposomes prepared by a thin-film hydration method were used to codeliver sorafenib (SF) and siRNA targeting GPC3 gene (siGPC3). Under optimized experimental conditions, SF and siGPC3 were effectively loaded into liposomes (SF-PL/siGPC3). SF-PL/siGPC3 with selected sizes and zeta potentials effectively accumulated at tumor sites and entered HCC cells. The two codelivered therapeutic agents exerted good anticancer effects by jointly suppressing the expression of the anti-apoptotic GPC3 gene and the proliferative cyclin D1 gene in HCC. Consequently, the intravenous injection of SF-PL/siGPC3 into nude mice bearing subcutaneous human HepG2 xenografts effectively inhibited tumor growth and also increased the survival rates of animals. These results revealed the great potential of the PEI-modified liposomal nanomedicine carrying SF and siGPC3 to improve HCC treatment.

Release mechanism studies on TFu nanoparticles-in-microparticles system.

This study was aimed at developing a nanoparticles-in-microparticles delivery system for N(3)-O-toluyl-5-fluorouracil (TFu), a new and potential antitumor prodrug of 5-fluorouracil (5-Fu), and intended to improve the release properties, bioavailability and therapeutic efficacy. TFu nanoparticles-in-microparticles system (TFu-NiMS), was prepared by ionotropic gelation technique, and the formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency. TFu-NiMS was characterized according to particle size, zeta potential, drug entrapment efficiency, drug loading and physical stability, respectively. The effects of various factors on drug release and in vitro release characteristics of TFu from NiMS were investigated and the release mechanisms were also explored. The optimum formulation was found to be relatively uniform in size (350.5 ± 12.6 nm) with a positive zeta potential (13.4 ± 0.9 mV). The drug entrapment efficiency and loading were (75.58 ± 3.25%) and (10.19 ± 0.24%), respectively. The in vitro release behavior of TFu from NiMS followed the Weibull or Ritger-Peppas kinetic equation and could be better expressed by the following equations: lnln[1/(1-Q/100)]=0.5577 lnt-0.3377, r=0.9768 and lnQ=0.5059 lnt+3.881, r=0.9759, respectively. TFu-NiMS presented controlled release properties in comparison with TFu solutions and the release properties of TFu from NiMS were fit a combination of diffusion controlled drug release and matrix dissolution mechanism. The TFu-NiMS were valued to develop as a practical preparation for oral or i.v. administration.

Pharmacokinetics and targeting property of TFu-loaded liposomes with different sizes after intravenous and oral administration.

The purpose of the study was to develop the liposomal formulations of TFu for oral and intravenous (i.v.) administration, clarify the biodistribution characteristics and in vivo pharmacokinetic behaviors of TFu-loaded liposomes. Four TFu-loaded liposomes of different sizes were prepared and characterized. The pharmacokinetic characteristics and the biodistribution of TFu-loaded liposomes with different sizes were investigated after i.v. or oral administration to mice. The pharmacokinetic studies indicated that TFu-loaded liposomes with different sizes all resulted in higher bioavailabilities than the TFu suspension after oral administration, and the gastrointestinal absorption increased with the reduction in liposome sizes. Following i.v. administration to mice, larger TFu-loaded liposomes (530 and 400 nm) showed higher hepatic and splenic targeting properties and lower cardiac and renal accumulations, while smaller sized liposomes (180 nm) significantly enhanced drug plasma concentration, bioavailability and prolonged retention time in circulation. Therefore, it can be concluded that both the oral and the injectable TFu-loaded liposomes are promising anticancer formulations for improved bioavailability; larger sized liposomes are potential passive targeting therapeutic agents for hepatoma and splenoma through i.v. administration while smaller liposomes might be preferable for oral administration due to its enhancing oral absorption possibility. Consequently, TFu-loaded liposomes with different sizes might have different clinical applications according to different goals of treatment.

Preparation and evaluation of N(3)-O-toluyl-fluorouracil-loaded liposomes.

This study was aimed at developing a liposome delivery system for a new and potential antitumor lipophilic prodrug of 5-fluorouracil (5-Fu)-N(3)-O-toluyl-fluorouracil (TFu), intended to improve the bioavailability and therapeutic efficacy of 5-Fu by oral and intravenous administration. TFu-loaded liposomes were prepared by a modified film dispersion-homogenization technique, the formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency. TFu-loaded liposomes were characterized according to particle size, size distribution, zeta potential, drug entrapment efficiency, drug loading and physical stability, respectively. In vitro release characteristics, in vivo pharmacokinetic properties and bioavailabilities were also investigated. The formulated liposomes were found to be relatively uniform in size (400.5 +/- 9.6 nm) with a negative zeta potential (-6.4 +/- 0.8 mV). The drug entrapment efficiency and loading were (88.87 +/- 3.25%) and (8.89 +/- 0.19%), respectively. The physical stability experiments results indicated that lyophilized TFu-loaded liposomes were stable for at least 9 months at 4 degrees C. In vitro drug release profile of TFu-loaded liposomes followed the bi-exponential equation. The results of the pharmacokinetic studies in mice indicated that the bioavailability of TFu-loaded liposomes was higher than the suspension after oral administration, and was bioequivalent comparing with TFu 50% alcohol solution after intravenous (i.v.) administration. These results indicated that TFu-loaded liposomes were valued to develop as a practical preparation for oral or i.v. administration.