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.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.

[Application of hepatocellular carcinoma targeted multifunctional nanocarriers].

OBJECTIVE: To synthesize the RGD-modified magnetic resonance imaging (MRI)-visible gene transfer nanocarrier and assess its gene delivery ability and MRI visibility for hepatocellular carcinoma. METHODS: The multifunctional nanocarrier RGD-PEG-PEI-SPION was constructed. And the degree of binding between nanocarrier and siRNA was determined by agarose gel electrophoresis. The zeta potential and particle size of cationic polymer vectors were measured with a Zeta-Plus instrument. Immunocytochemical assay was performed for detecting the expression of α(v)ß(3) in Bel-7402 cells. The active targeting ability of nanocarrier to Bel-7402 cells was evaluated by flow cytometry and laser confocal microcopy. The MRI visibility of nanocarrier to Bel-7402 cells was assessed. RESULTS: RGD-PEG-PEI-SPION could condense siRNA entirely at a N/P ratio of 2.8; the membranes of Bel-7402 cells possessed an enrichment of α(v)ß(3) receptors. At a nitrogen/phosphate ratio of 10, the particle size of RGD-PEG-PEI-SPION/siRNA attained a constant size of 85.2 ± 5.6 nm, the zeta potential reached +12.4 ± 1.2 mV, the gene transfection efficiency of nanocarrier to Bel-7402 cells attained 71.2% ± 2.1% and the cells showed significantly stronger RGD-PEG-PEI-SPION (red) and siRNA (green) fluorescence under laser confocal microcopy. The cells incubated with RGD-PEG-PEI-SPION exhibited significantly lower normalized MR T(2)(*)WI signal intensity. CONCLUSION: A RGD-modified MRI-visible gene delivery nanocarrier RGD-PEG-PEI-SPION has been successfully synthesized.It has a higher transfection efficiency of transferring siRNA into Bel-7402 cells and could sensitively detect hepatocellular carcinoma with MRI.

Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions.

The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.

The role of transarterial embolization in the management of hematuria secondary to congenital renal arteriovenous malformations.

OBJECTIVE: To evaluate the efficacy and safety of transarterial embolization (TAE) in the management of hematuria secondary to congenital renal arteriovenous malformations (AVM). PATIENTS AND METHODS: Between May 2007 and February 2012, 6 patients with congenital AVM treated with TAE were analyzed retrospectively, followed by a brief review of TAE in the treatment of congenital AVM. Clinical records with respect to general conditions, location, embolic materials, complications and overall outcome were collected from the original hospital charts and outpatient medical records. RESULTS: Three patients with AVM were confirmed by contrast-enhanced CT scans, and the other 3 patients were detected by renal angiography. TAE was performed with steel coils in 2 patients and n-butyl-2-cyanoacrylate (NBCA) in 4 patients. After a mean follow-up of 22 months, no serious adverse effects were observed in all patients. There were no complaints of hematuria at the end of the follow-up period. CONCLUSION: For unexplained massive hematuria, congenital renal AVM needs to be considered as a differential diagnosis. Selective renal angiography and embolization should be recommended as the first choice to treat massive hematuria secondary to congenital renal AVM.

[Diagnosis and treatment of carotid-cavernous fistula: analysis of 28 patients].

OBJECTIVE: To evaluate the feasibility and efficacy of endovascular treatment for different types of carotid cavernous fistula (CCF) via the approach of internal carotid artery (ICA) or inferior petrosal sinus (IPS). METHODS: From April 2005 to June 2010, 28 CCF patients underwent endovascular treatment at our institution. There were 13 males and 15 females with a mean age of 39 years (range: 21 - 71). According to the Barrow's classification, they were classified into type A (n = 21), type B (n = 2) and type D (n = 5). Patients of type A underwent detachable balloon embolization of ipsilateral cavernous sinus or stent-graft placement via the ICA approach. Patients of types B and D received detachable coil plus n-BCA (n-butyl-2-cyanoacrylate) embolization of ipsilateral cavernous sinus via the IPS approach. The technical results, complications and therapeutic outcomes were reviewed. RESULTS: Detachable balloons (number: 1 - 4) were used in 16 patients of type A. Angiography at immediate postembolization showed a complete occlusion of fistula in 15 patients and a small residual fistula (< 20%) in 1 patient. Five patients of type A received stent-graft placement. One stent was placed in 4 patients and 2 stents in 1 patient. Complete fistula closures with preserved ICA were documented on immediate angiogram in 3 patients whereas a large residual flow (> 50%) persisted in 1. The fistula was completely occluded after 3 detachable balloons were deployed in affected cavernous sinus through a gap between stent and vascular wall. Both fistula and ICA were occluded in 1 patient after stenting. No cerebral infarction was observed due to the adequate collateral blood flow from contralateral ICA. Complete closures of affected cavernous sinus were achieved in 6 patients of types B and D while residual flow (< 50%) persisted in 1. The number of detachable coils for each embolization ranged from 3 to 8 (mean: 6.0). The volume of n-BCA mixture varied from 1.0 to 2.1 ml (mean: 1.3). The mean duration of n-BCA injection was 65 s (range: 45 - 90). Clinical symptoms were completely relieved in 26 patients. During the mean follow-up period of 30 months (range: 12 - 60), no recurrence of clinical symptoms was observed. No thrombosis or stenosis was found in the lumina of stents. CONCLUSION: Detachable balloon embolization is the preferential treatment for direct CCF. Detachable coil plus n-BCA embolization of cavernous sinus via the IPS approach is an efficient and safe treatment for indirect CCF.

Dual-Sensitive PEG-Sheddable Nanodrug Hierarchically Incorporating PD-L1 Antibody and Zinc Phthalocyanine for Improved Immuno-Photodynamic Therapy.

Tumor immunotherapy like immune checkpoint blockade (ICB) shows great success nowadays but is severely limited by low response rates and immune-related adverse events (IRAEs). While photodynamic therapy (PDT) could efficiently eradicate tumor cells and further induce immune responses to promote activating of T lymphocytes. Herein a nanodrug hierarchically incorporating photosensitizer and PD-L1 antibody was developed for synergistic tumor immuno-photodynamic therapy. A pH/enzyme dual-sensitive polymeric micelle with sheddable PEG coating was designed for codelivery of PD-L1 antibody and zinc phthalocyanine (ZnPc) in the tumor. The tumor microenvironment featuring low pH and high matrix metallopeptidase 2 (MMP-2) sequentially triggered the shedding of PEG and the release of PD-L1 antibody to exert local ICB in tumor tissue, after which the remaining nanodrug with ZnPc undergoing charge reversal was readily delivered into tumor cells. With light irradiation, the photodynamic therapy effect of sAMPc induced immunogenic cell death of tumor cells and further promoted intratumor recruitment of CD8+ T cells, thus resulting in a synergistic immuno-photodynamic therapy with ICB. Moreover, the PEG-sheddable strategy endowed the nanodrug with stealth properties in blood circulation, making the IRAEs of PD-L1 antibody significantly reduced. This pH/MMP-2 dual-sensitive PEG sheddable nanodrug provids a promising strategy for well-combined ICB therapy and PDT to achieve improved anticancer immuno-photodynamic therapy with reduced adverse effects.

Transvenous embolization of cavernous sinus dural arteriovenous fistulas using detachable coils and Glubran 2 acrylic glue via the inferior petrosal sinus approach.

OBJECTIVES: To describe the technique, efficacy, and safety of transvenous embolisation (TVE) of cavernous sinus arteriovenous fistulas (CSDAVFs) via the inferior petrosal sinus (IPS) with detachable coils and acrylic glue. METHODS: Spontaneous unilateral CSDAVFs were confirmed by cerebral angiography in eight patients, with angiographic patency of the ipsilateral IPS in three and angiographic non-visualisation of the ipsilateral IPS in five. There were two patients with complete occlusion of the ipsilateral internal jugular vein (IJV). TVE with detachable coils and acrylic glue were performed through a femoral vein and an IPS approach. RESULTS: TVE viaipsilateral IPS was successfully performed in all eight patients in our group. The number of detachable coils for each patient ranged from 2 to 8 (mean, 5.0). Angiography immediately after TVE showed complete occlusion of the CSCAVFs in seven patients and nearly complete occlusion in one. Complete recovery of clinical symptoms was achieved in all eight patients. No recurrence of clinical symptoms was observed at follow-up. CONCLUSIONS: Transvenous embolisation via an IPS approach is a highly efficient and safe treatment for CSDAVFs. Embolisation with a combination of coils and acrylic glue may help to achieve complete occlusion of fistulas with fewer coils.

A reduction and pH dual-sensitive nanodrug for targeted theranostics in hepatocellular carcinoma.

Sorafenib (SF) is the first drug demonstrated to improve the survival of patients diagnosed with advanced-stage hepatocellular carcinoma (HCC). However, its clinical application is limited by the poor oral bioavailability and severe side effects. In this study, a multifunctional micellar nanodrug was developed for simultaneous HCC-targeted delivery of SF and tumor detection with magnetic resonance imaging (MRI). The micellar nanodrug incorporating SF and superparamagnetic iron oxide nanoparticles (SPIONs) was prepared from a diblock copolymer of monomethoxyl poly(ethylene glycol) and poly(N-(2-aminoethanethiol-co-2-aminoethyldiisopropylamine) aspartamide) and then decorated with anti-glypican-3 antibody (AbGPC3). Owing to the small size, weak positive charge and AbGPC3-mediated active targeting to HCC cells, the nanodrug exhibited an easy cellular uptake and enhanced tumor accumulation. The prominent reduction and pH dual-sensitivity allowed the nanodrug to rapidly release SF inside cancer cells via responding to the cytoplasmic glutathione and lysosomal acidity. The nanodrug not only significantly improved the anticancer effects of SF in hepatoma treatment but also facilitated a noninvasive tumor detection and monitoring of in vivo drug delivery by MRI, which revealed its great potential as a promising theranostic system.

Partial splenic embolization using polyvinyl alcohol particles for hypersplenism in cirrhosis: a prospective randomized study.

PURPOSE: To prospectively evaluate the efficacy and safety of partial splenic embolization (PSE) using polyvinyl alcohol (PVA) particles for hypersplenism in cirrhosis, as compared to PSE using gelfoam particles. MATERIALS AND METHODS: PSE was performed in 60 consecutive patients with hypersplenism caused by cirrhosis. The patients were randomly assigned into 2 groups: gelfoam group, 32 patients received PSE using gelfoam particles as the embolic material; PVA group, 28 patients received PSE using PVA particles. The follow-up contents included peripheral blood cell counts (leukocyte, platelet and red blood cell) and complications associated with PSE. RESULTS: Prior to PSE, there was no significant difference between the two groups in sex, age, Child-Pugh grade, the extent of embolization and peripheral blood cell counts. After PSE, no matter in which group, leukocyte and platelet counts kept significantly higher than pre-PSE during the 3-year follow-up period (P<.0001), but the post-PSE improvement of leukocyte and platelet counts was significantly better in PVA group than in gelfoam group (P<.05). Red blood cell counts showed no remarkable changes after PSE (P>.05). Severe complications occurred in 8 patients (25.0%) in gelfoam group and 6 patients (21.4%) in PVA group (P>.05), but the degree of abdominal pain was higher in the latter than in the former (P<.05). Among 17 patients who received more than 70% embolization of spleen, 10 (58.8%) developed severe complications, while among 43 patients who received 70% or less embolization of spleen, only four (9.3%) had severe complications. This difference was statistically significant (P<.05). CONCLUSION: PVA particles could be used as the embolic material in PSE; in comparison with PSE using gelfoam particles, PSE using PVA particles can achieve even better efficacy in alleviating hypersplenism, but the extent of embolization should be strictly limited to not more than 70% of splenic volume.

[Transportal variceal sclerotherapy with n-butyl-2-cyanoacrylate for gastric fundal varices].

OBJECTIVE: To evaluate the technique, safety and clinical efficacy of transportal variceal sclerotherapy with n-butyl-2-cyanoacrylate (NBCA) for gastric fundal varices. METHODS: Twenty-one patients with gastric fundal varices confirmed by endoscopy were enrolled in this study. The causes of the gastric varices were cirrhosis caused by hepatitis virus B or C (n = 16) and hepatocellular carcinoma with portal venous obstruction (n = 5). Percutaneous transhepatic or transplenic portography were performed on all 21 patients. The gastric varices were treated with NBCA-lipiodol mixture injected via a microcatheter introduced into the varices. For 8 patients who had large gastrorenal shunts (GRS), a balloon-occluded catheter was introduced into the GRS via the right femoral and left renal veins before injecting the NBCA-lipiodol. During the NBCA-lipiodol injection, the balloon was inflated to block the flow of GRS. Follow-up evaluations included findings of the laboratory liver function tests, upper intestinal endoscopies, and the occurrences of rebleeding. RESULTS: In 20 patients (95.2%), the gastric varices were successfully obliterated with 2-8 ml of NBCA-lipiodol. In one patient with a large GRS, sclerotherapy was not successfully performed because a balloon-occluded catheter was not available during the procedure. In five patients, small amounts of NBCA-lipiodol entered into the distal pulmonary artery branches. Two of them suffered from transient irritable coughs; no patient developed severe pulmonary embolism. Embolization of portal venous branches occurred in two patients, which were not treated specifically. In comparison with the findings before the treatments, the serum alanine aminotransferase levels decreased at both 3 and 6 months after treatments (P less than 0.05); serum albumin levels increased at 6 months (P less than 0.05); the prothrombin times decreased at 6 months (P less than 0.05); but no significant changes were seen in the serum bilirubin levels. Fifteen patients were followed-up endoscopically for 3 months after the treatment. Gastric varices were completely resolved in 10 patients (66.7%) and were markedly smaller in 4 patients (26.6%). Worsening of the esophageal varices occurred in 3 patients (20%). All the patients were followed-up from 1 to 30 months [(16.7+/-8.8) months]. Rebleeding was observed in 4 patients, and the cumulative rebleeding rate at 1 year was 9.52%. CONCLUSION: Transportal variceal sclerotherapy with NBCA is a safe and effective method for treating gastric varices. Microcatheter technique and occlusion of the large gastrorenal shunt with a balloon-occluded catheter are necessary to ensure obliteration of gastric varices and prevent pulmonary embolism.

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.

Nanovector for Gene Transfection and MR Imaging of Mesenchymal Stem Cells.

This study centers on the use of superparamagnetic iron oxide nanoparticles coated with polyethylene glycol-grafted polyethylenimine (PEG-g-PEI-SPION) as an MRI-visible and efficient nanovector for the gene modification and in vivo MRI tracking of rat bone marrow-derived mesenchymal stem cells (rBMSCs). PEG-g-PEI-SPION was first condensed with plasmid DNA to form nanoparticles, demonstrating low cytotoxicity and good biocompatibility for rBMSCs. Based on a reporter gene assay, PEG-g-PEI-SPION/pDNA had the highest transfection efficiency (62.6 ± 5.5%) in rBMSCs, which was significantly higher than that obtained using the cationic liposomes in lipofectamine 2000, a commercially available and worldwide used gene transfection agent, under the most optimal conditions (13.9 ± 2.6%; P < 0.05). More excitingly, the transplantation of rBMSCs modified by our MRI-visible vector complexed with a plasmid encoding human hepatocyte growth factor into fibrotic rat livers effectively restored albumin production and significantly suppressed transaminase activities. In addition, the transplanted rBMSCs displayed a sensitive signal on T2/T2*-weighted images in vitro and in vivo, which enabled effective MRI tracking of the cells for up to 14 days post-transplantation. Although mesenchymal stem cells are well-known to be refractory in most of the current nonviral gene delivery techniques, our results demonstrate that the MRI-sensitive PEG-g-PEI-SPION is a highly efficient and readily observable nanovector for gene delivery into rBMSCs.

Polymeric vector-mediated gene transfection of MSCs for dual bioluminescent and MRI tracking in vivo.

MSC's transplantation is a promising cell-based therapy for injuries in regenerative medicine, and in vivo visualization of transplanted MSCs with noninvasive technique is essential for the tracking of cell infusion and homing. A new cationic polymer, poly(ethylene glycol)-block-poly(l-aspartic acid)-grafted polyethylenimine functionalized with superparamagnetic iron oxide nanoparticles (PAI/SPION), was constructed as a magnetic resonance imaging (MRI)-visible non-viral vector for the delivery of plasmids DNA (pDNA) encoding for luciferase and red fluorescence protein (RFP) as reporter genes into MSCs. As a result, the MSCs were labeled with SPION and reporter genes. The PAI/SPION complexes exhibited high transfection efficiency in transferring pDNA into MSCs, which resulted in efficient luciferase and RFP co-expression. Furthermore, the complexes did not significantly affect the viability and multilineage differentiation capacity of MSCs. After the labeled MSCs were transplanted into the rats with acute liver injury via the superior mesenteric vein (SMV) injection, the migration behavior and organ-specific accumulation of the cells could be effectively monitored using the in vivo imaging system (IVIS) and MRI, respectively. The immunohistochemical analysis further confirmed that the transplanted MSCs were predominantly distributed in the liver parenchyma. Our results indicate that the PAI/SPION is a MRI-visible gene delivery agent which can effectively label MSCs to provide the basis for bimodal bioluminescence and MRI tracking in vivo.

An MRI-visible non-viral vector bearing GD2 single chain antibody for targeted gene delivery to human bone marrow mesenchymal stem cells.

The neural ganglioside GD2 has recently been reported to be a novel surface marker that is only expressed on human bone marrow mesenchymal stem cells within normal marrow. In this study, an MRI-visible, targeted, non-viral vector for effective gene delivery to human bone marrow mesenchymal stem cells was first synthesized by attaching a targeting ligand, the GD2 single chain antibody (scAbGD2), to the distal ends of PEG-g-PEI-SPION. The targeted vector was then used to condense plasmid DNA to form nanoparticles showing stable small size, low cytotoxicity, and good biocompatibility. Based on a reporter gene assay, the transfection efficiency of targeting complex reached the highest value at 59.6% ± 4.5% in human bone marrow mesenchymal stem cells, which was higher than those obtained using nontargeting complex and lipofectamine/pDNA (17.7% ± 2.9% and 34.9% ± 3.6%, respectively) (P<0.01). Consequently, compared with the nontargeting group, more in vivo gene expression was observed in the fibrotic rat livers of the targeting group. Furthermore, the targeting capacity of scAbGD2-PEG-g-PEI-SPION was successfully verified in vitro by confocal laser scanning microscopy, Prussian blue staining, and magnetic resonance imaging. Our results indicate that scAbGD2-PEG-g-PEI-SPION is a promising MRI-visible non-viral vector for targeted gene delivery to human bone marrow mesenchymal stem cells.

An RGD-modified MRI-visible polymeric vector for targeted siRNA delivery to hepatocellular carcinoma in nude mice.

RNA interference (RNAi) has significant therapeutic promise for the genetic treatment of hepatocellular carcinoma (HCC). Targeted vectors are able to deliver small interfering RNA (siRNA) into HCC cells with high transfection efficiency and stability. The tripeptide arginine glycine aspartic acid (RGD)-modified non-viral vector, polyethylene glycol-grafted polyethylenimine functionalized with superparamagnetic iron oxide nanoparticles (RGD-PEG-g-PEI-SPION), was constructed as a magnetic resonance imaging (MRI)-visible nanocarrier for the delivery of Survivin siRNA targeting the human HCC cell line Bel-7402. The biophysical characterization of the RGD-PEG-g-PEI-SPION was performed. The RGD-modified complexes exhibited a higher transfection efficiency in transferring Survivin siRNA into Bel-7402 cells compared with a non-targeted delivery system, which resulted in more significant gene suppression at both the Survivin mRNA and protein expression levels. Then, the level of caspase-3 activation was significantly elevated, and a remarkable level of tumor cell apoptosis was induced. As a result, the tumor growth in the nude mice Bel-7402 hepatoma model was significantly inhibited. The targeting ability of the RGD-PEG-g-PEI-SPION was successfully imaged by MRI scans performed in vitro and in vivo. Our results strongly indicated that the RGD-PEG-g-PEI-SPION can potentially be used as a targeted non-viral vector for altering gene expression in the treatment of hepatocellular carcinoma and for detecting the tumor in vivo as an effective MRI probe.

Enhanced apoptosis of ovarian cancer cells via nanocarrier-mediated codelivery of siRNA and doxorubicin.

A folate conjugated ternary copolymer, FA-PEG-PEI-PCL, of poly(ethylene glycol) (PEG), poly(ethylene imine) (PEI), and poly(ɛ-caprolactone) (PCL) was synthesized. The copolymer self-assembled into cationic micelles capable of co-delivering siRNA and the anticancer drug doxorubicin (DOX). This dual functional nanocarrier demonstrated low cytotoxicity and high performance in drug/siRNA delivery. Upon the codelivery of siRNA, targeting the Bcl-2 gene, and DOX, using the folate-targeted nanocarrier, DOX-induced apoptosis in the skov-3 cells overexpressing folate receptor was significantly enhanced through a mechanism of downregulating the antiapoptotic protein Bcl-2, while simultaneously upregulating the proapoptotic protein Bax. This work suggested that the combination of Bcl-2 siRNA and DOX therapies is feasible, based on our dual functional nanocarrier, which set up a good basis for a future in vivo test.

An MRI-visible non-viral vector for targeted Bcl-2 siRNA delivery to neuroblastoma.

Polyethylene glycol-grafted polyethylenimine (PEG-g-PEI) which was functionalized with a neuroblastoma cell-specific ligand, the GD2 single chain antibody (scAb(GD2)), was synthesized in order to effectively deliver Bcl-2 siRNA into neuroblastoma cells. This polymer was complexed first with superparamagnetic iron oxide nanoparticle (SPION) to get a MRI-visible targeted non-viral vector (scAb(GD2)-PEG-g-PEI-SPION) and then with Bcl-2 siRNA to form nanoparticles showing low cytotoxicity. The targeting capacity of scAb(GD2)-PEG-g-PEI-SPION was successfully verified in vivo and in vitro by magnetic resonance imaging. The single chain antibody encoded targeted polyplex was more effective in transferring Bcl-2 siRNA than the nontargeting one in SK-N-SH cells, a human neuroblastoma cell line, resulting in a 46.34% inhibition in the expression of Bcl-2 mRNA. Consequently, a high level of cell apoptosis up to 50.76% and a significant suppression of tumor growth were achieved, which indicates that scAb(GD2)-PEG-g-PEI-SPION is a promising magnetic resonance imaging-visible non-viral vector for targeted neuroblastoma siRNA therapy and diagnosis.