High energy irradiation effects on silicon photonic passive devices.

In this work, the radiation responses of silicon photonic passive devices built in silicon-on-insulator (SOI) technology are investigated through high energy neutron and 60Co γ-ray irradiation. The wavelengths of both micro-ring resonators (MRRs) and Mach-Zehnder interferometers (MZIs) exhibit blue shifts after high-energy neutron irradiation to a fluence of 1×1012 n/cm2; the blue shift is smaller in MZI devices than in MRRs due to different waveguide widths. Devices with SiO2 upper cladding layer show strong tolerance to irradiation. Neutron irradiation leads to slight changes in the crystal symmetry in the Si cores of the optical devices and accelerated oxidization for devices without SiO2 cladding. A 2-µm top cladding of SiO2 layer significantly improves the radiation tolerance of these passive photonic devices.

Combined Effect of TID Radiation and Electrical Stress on NMOSFETs.

The combined effect of total ionizing dose (TID) and electrical stress is investigated on NMOSFETs. For devices bearing both radiation and electrical stress, the threshold voltage shift is smaller than those only bearing electrical stress, indicating that the combined effect alleviates the degradation of the devices. The H bond is broken during the radiation process, which reduces the participation of H atoms in the later stage of electrical stress, thereby reducing the degradation caused by electrical stress. The positive charges of the oxide layer generated by radiation neutralize part of the tunneling electrons caused by electrical stress, and consume some of the electrons that react with the H bond, resulting in weaker degradation. In addition, the positive charges in shallow trench isolation (STI) generated by radiation create parasitic leakage paths at the interfaces of STI/Si, which increase the leakage current and reduce the positive shift of the threshold voltage. The parasitic effect generated by the positive charges of STI makes the threshold voltage of the narrow-channel device degrade more, and due to the gate edge effect, the threshold voltage of short-channel devices degrades more.

Targeted-delivery of siRNA via a polypeptide-modified liposome for the treatment of gp96 over-expressed breast cancer.

Targeted gene therapy has led to significant breakthroughs in cancer treatment. Heat shock protein gp96 is an emerging target for tumor treatment because of its transfer ability from reticulum to tumor cell surface. CDO14 is a peptide cationic liposome developed in our laboratory with higher gene transfection efficiency and lower toxicity compared with the existing cationic liposomes. In this study, gp96-targeted liposome p37-CDO14 was constructed by modifying cationic liposome CDO14 with a gp96 inhibitor, helical polypeptide p37. Liposome p37-CDO14 could specifically bind to breast cancer cells with gp96-overexpression on the cell membrane. Both liposomes CDO14 and p37-CDO14 showed high delivery efficiency for survivin siRNA (siSuvi) to SK-BR-3 and MCF-7 cells via obviously decreased survivin expression level and cell viability. P37-CDO14 significantly increased the accumulation of FAM-siRNA in tumor compared with CDO14. SiSuvi transfected by CDO14 and p37-CDO14 could inhibit the growth of xenograft in mice and the expression of survivin in tumor tissues. The anti-tumor effect of siSuvi delivered by p37-CDO14 was much higher than that delivered by CDO14. This suggests that targeted liposome p37-CDO14 is a potential gene vector for the therapy of gp96 overexpressed breast cancer.

Integrin αvß3-targeted liposomal drug delivery system for enhanced lung cancer therapy.

Conventional chemotherapy for tumor treatment remains flawed because it fails to limit cytotoxicity to a small set of selectable tissues. Active targeting techniques for the delivery of drugs to specific sites are increasingly used to enhance drug accumulation at tumor sites with the aim of reducing side effects in vivo. Liposomes, modified with different targeting ligands, are considered to be one of the most promising targeted drug carriers. Herein, novel linear and cyclic arginine-glycine-aspartate (RGD) peptide-based lipids were synthesized to develop modified liposomal drug delivery systems with active targeting and pH-sensitivity. The RGD-modified liposomes showed excellent active targeting ability for integrin αvß3 receptors, resulting in improved cellular uptake. The modified liposomes also enhanced intracellular doxorubicin (DOX) release because of their degradation in an acidic environment. Consequently, the RGD-modified, DOX-loaded liposomes exhibited significant antitumor efficacy and low toxicity in vitro and in vivo. In particular, 5% cRGD-lipid modified DOX-loaded liposome showed the greatest inhibition of tumor growth in mice among the tested formulations, and much less toxicity than free DOX. In conclusion, the DOX-loaded pH-sensitive liposome modified with 5% cRGD-lipid developed in the current study provides a potential approach for improved tumor therapy.

Co-delivery of paclitaxel and anti-VEGF siRNA by tripeptide lipid nanoparticle to enhance the anti-tumor activity for lung cancer therapy.

The combination of chemotherapeutic drug paclitaxel (PTX) and VEGF siRNA could inhibit cancer development with synergistic efficacy. However, efficient and safe delivery systems with high encapsulation efficiency of PTX and a long-time release of drugs are urgently needed. In this study, novel nanoparticles (PTX/siRNA/FALS) were constructed by using tripeptide lipid (L), sucrose laurate (S), and folate-PEG2000-DSPE (FA) to co-deliver PTX and siRNA. The cancer cell targeting nanoparticle carrier (PTX/siRNA/FALS) showed anticipated PTX encapsulation efficiency, siRNA retardation ability, improved cell uptake and sustained and controlled drug release. It led to significant anti-tumor activity in vitro and in vivo by efficient inhibition of VEGF expression and induction of cancer cell apoptosis. Importantly, the biocompatibility of the carriers and low dosage of PTX required for effective therapy greatly reduced the toxicity to mice. The targeting nanoparticles show potential as an effective co-delivery platform for RNAi and chemotherapy drugs, aiming to improve the efficacy of cancer therapy.

Stimuli-Responsive Polysaccharide Enveloped Liposome for Targeting and Penetrating Delivery of survivin-shRNA into Breast Tumor.

Silencing the inhibitor of apoptosis (IAP) by RNAi is a promising method for tumor therapy. One of the major challenges lies in how to sequentially overcome the system barriers in the course of the tumor targeting delivery, especially in the tumor accumulation and penetration. Herein we developed a novel stimuli-responsive polysaccharide enveloped liposome carrier, which was constructed by layer-by-layer depositing redox-sensitive amphiphilic chitosan (CS) and hyaluronic acid (HA) onto the liposome and then loading IAP inhibitor survivin-shRNA gene and permeation promoter hyaluronidase (HAase) sequentially. The as-prepared HA/HAase/CS/liposome/shRNA (HCLR) nanocarrier was verified to be stable in blood circulation due to the negative charged HA shield. The tumor targeting recognition and the enhanced tumor accumulation of HCLR were visualized by fluorescence resonance energy transfer (FRET) and in vivo fluorescence biodistribution. The deshielding of HA and the protonizing of CS in slightly acidic tumor extracellular pH environment (pHe, 6.8-6.5) were demonstrated by ζ potential change from -23.1 to 29.9 mV. The pHe-responsive HAase release was confirmed in the tumor extracellular mimicking environments, and the intratumoral biodistribution showed that the tumor penetration of HCLR was improved. The cell uptake of HCLR in pHe environment was significantly enhanced compared with that in physiological pH environment. The increased shRNA release of HCLR was approved in 10 mM glutathione (GSH) and tumor cells. Surprisingly, HCLR suppressed the tumor growth markedly through survivin silencing and meanwhile maintained low toxicity to mice. This study indicates that the novel polysaccharide enveloped HCLR is promising in clinical translation, thanks to the stimuli-triggered tumor accumulation, tumor penetration, cell uptake, and intracellular gene release.

Zwitterionic pH-responsive hyaluronic acid polymer micelles for delivery of doxorubicin.

As zwitterionic polymers show great promise in drug delivery, hyaluronic acid (HA) was deacetylated and grafted with dodecylamine to prepare a pH-sensitive zwitterionic polymer dHAD used as a carrier for antitumor drugs. The polymer was negatively charged at pH 7.4 and became positive at pH 6.2. In vitro delivery of DOX against MCF-7 cells showed that the blank micelle dHAD had low cytotoxicity and the dHAD-DOX micelles could greatly prohibit the growth of the MCF-7 cells. In addition, the dHAD-DOX micelles had higher cellular uptake, indicating that the micelles were rapidly internalized into the cells via CD44 receptor-mediated endocytosis. The in vivo delivery of DOX to tumor-bearing mice confirmed that the dHAD-DOX micelles greatly inhibited the tumor growth and significantly reduced systemic toxicity of DOX. These results demonstrated that biocompatible pH-responsive zwitterionic dHAD micelles are promising carriers for the delivery of DOX.

Synergistic effects of 7-O-geranylquercetin and siRNAs on the treatment of human breast cancer.

AIMS: To investigate the antitumor effect of 7-O-geranylquercetin (GQ) combining with survivin siRNA (siSuvi) or IL-10 siRNA (siIL-10) to breast cancer. MAIN METHODS: Xenograft tumor model was established by subcutaneously inoculating human breast cancer MCF-7 cells in BALB/c nude mice. Transfection efficiency of siRNA mediated by cationic liposome CDO14 in MCF-7 cells and tumor bearing mice was measured by flow cytometer and living imaging sysytem, respectively. Cell viability was detected using CCK-8 assay. Cell apoptosis was determined by Hoechst33342 staining and AV-PI staining. Tumors bearing mice were administered with GQ by gavage, and/or with liposome CDO14 mediated siRNAs via tail intravenous injection. Expression levels of proteins and cytokines were detected by western blot and ELISA, respectively. KEY FINDINGS: Liposome CDO14 could deliver siRNA to tumor effectively. Combination of GQ and siSuvi promoted the antiproliferation and pro-apoptosis effects of GQ or siSuvi to MCF-7 cells, and reduced the level of survivin and raised the level of caspase-7 in cells. GQ combining with siSuvi inhibited the growth of tumor, down-regulated the expression of survivin and up-regulated the expression of caspase-7 in tumor tissue. Similarly, GQ combining with siIL-10 inhibited the growth of tumor, decreased the level of IL-10 and increased the level of TNF-α. These results revealed that GQ enhanced the pro-apoptosis effect of siSuvi on tumor cells and the modulating effect of siIL-10 on tumor microenvironment. SIGNIFICANCES: Synergistic anti-tumor effect of GQ and siRNAs against breast cancer proved that chemical drugs combining with siRNAs is a promising antitumor strategy.

Toxicological exploration of peptide-based cationic liposomes in siRNA delivery.

The toxicology of cationic liposomes was explored to advance clinical trials of liposome-mediated gene therapy through the analysis of a peptide cationic liposome with DOTAP as a positive control. We first investigated the delivery of luciferase siRNA by several peptide liposomes in mice bearing lung cancer A549 cell xenografts. Of these, a cationic liposome (CDO14) was selected for further investigation. CDO14 efficiently mediated IGF-1R-siRNA delivery and inhibited the growth of the A549 cell xenografts. The in vivo toxicity and toxicological mechanisms of the selected liposome were evaluated to assess its potential utility for gene delivery. Specifically, the effects of CDO14 on mouse body weight, hematology, urine, serum biochemical indices, and histopathology were measured in acute toxicity and subchronic toxicity tests. CDO14 showed limited toxicological effects at low dosages although it induced pulmonary inflammation and liver injury at higher dosages. The toxicity of CDO14 was lower than that of DOTAP, and the toxicity of CDO14 did not change when complexed with siRNA. The pulmonary inflammation induced by CDO14 occurred via expressional up-regulation of the pro-inflammatory cytokines TNF-α and IL-6, and expressional down-regulation of the anti-inflammatory cytokine IL-10. Liver injury induced by CDO14 was mediated by the JAK2-STAT3 signaling pathway. Lastly, CDO14 did not affect the expression of apoptosis-related proteins in normal liver cells, suggesting that it did not induce apoptosis of normal cells. The toxicological results demonstrate that peptide-based headgroups in lipids are superior to those with quaternary ammonium headgroups that are used as gene vectors for cancer therapy.

7-O-geranylquercetin contributes to reverse P-gp-mediated adriamycin resistance in breast cancer.

AIMS: To investigate the effect of 7-O-geranylquercetin (GQ), a derivative of quercetin (Q), on reversing drug resistance in breast cancer MCF-7/ADR cells and reveal the mechanisms related to P-glycoprotein (P-gp). MAIN METHODS: Cell viability was determined by MTT assay. Accumulation of adriamycin (ADR) in cells was determined by confocal fluorescence microscope and microplate reader while that of rhodamine (Rh) was measured by flow cytometry. Expression levels of P-gp and MDR1 gene in cells were detected by western blot and Real-Time PCR, respectively. Molecular docking of GQ and Q with P-gp was conducted using AutoDock program. Xenograft model was established by inoculating MCF-7/ADR cells in BALB/c-nude mice. Tumor bearing mice were administered with ADR via tail vein injection and/or GQ (Q) by gavage. Expression levels of P-gp in tissues were detected by western blot and immunohistochemistry. KEY FINDINGS: GQ could reverse drug resistance of MCF-7/ADR cells to ADR. GQ inhibited the efflux of ADR by down-regulating the expression of P-gp protein and its encoding gene MDR1 in MCF-7/ADR cells. Molecular modeling showed that GQ matched with P-gp better than Q. GQ enhanced the antitumor effects of ADR and decreased the expression of P-gp in mice and its activities were higher than that of Q. GQ could reverse drug resistance of MCF-7/ADR cells by down-regulating the expression of P-gp in vitro and in vivo. SIGNIFICANCES: The reversal effect of GQ on P-gp-mediated drug resistance indicates its potential as a reversal agent for drug resistance in cancer chemotherapy.

Effects of sucrose ester structures on liposome-mediated gene delivery.

Sucrose esters (SEs) have great potential applications in gene delivery because of their low toxicity, excellent biocompatibility, and biodegradability. By using tripeptide-based lipid (CDO) as a model lipid and SEs as helper lipids, a series of liposomes were prepared. The SEs with hydrophilic-lipophilic balance (HLB) values of 1, 6, 11, or 16 and the fatty acids of laurate, stearate, or oleate were used in the liposomes. We investigated the effect of HLB values of SEs and fatty acid types on gene transfection efficiency and toxicity of liposomes. The results showed that transfection efficiencies of the liposomes containing SEs with HLB value of 6 were superior to other liposomes in HeLa, MCF-7, NCI-H460, and A549 tumor cells. For the same HLB value, liposomes of laurate SEs were preferable to transfect cells compared to SEs of stearate and oleate. The liposomes with SEs showed higher cellular uptake than liposome without SEs (LipoCDO). LipoL12-6/Luc-siRNA treatment on tumor-bearing mice exhibited about 60% in vivo gene silencing of luciferase, and LipoL12-6 could mediate IGF-1R siRNA to greatly inhibit tumor growth. Moreover, liposomes with SEs revealed remarkably low toxicity in vitro and in vivo. The illustration of SE structures on gene delivery will promote the use of SEs for clinical trials of liposomes. STATEMENT OF SIGNIFICANCE: This article is the first to study the effects of various chain lengths and hydrophilic-lipophilic balance (HLB) of sucrose esters (SEs) on gene transfection efficiency and safety of liposomes for gene delivery. The in vitro delivery of pDNA and siRNA by lipoplexes against HeLa, MCF-7, NCI-H460, and A549 tumor cells showed that the lipoplexes could lead to better transfection and lower cytotoxicity after the addition of SEs. SEs with shorter chain and a median HLB value could provide the liposomes with much higher gene transfection efficiency than others. The in vivo delivery of siRNA to tumor-bearing mice further confirmed that liposome containing laurate SE (LipoL12-6) could be a potential therapeutic vector, as it delivered siRNA to silence nearly 60% of the luciferase in tumors and also greatly inhibited the tumor growth. Therefore, the addition of SEs to liposomes proved to be relatively safe in vitro and in vivo. These preliminary results demonstrated that SEs show great potential for constructing controlled-release systems for gene delivery. The readers will get insights into a series of gene vectors and deepen their understanding about gene delivery.