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Bei Li,1,2,* Yuting Luo,1,2,* Geng Liu,1,2 Maling Gou,3 Lei Feng,1,2 Xiwen Ye,1,2 Jianrong Xu,1,2 Yaotian Fan,1,2 Zhen You1,2 1Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 3Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen You, Tel/Fax +86 028 85423823, Email youzhen@wchscu.cnIntroduction: Hepatocellular carcinomas (HCC) have a high morbidity and mortality rate, and is difficult to cure and prone to recurrence when it has already developed. Therefore, early detection and efficient treatment of HCC is necessary.Methods: In this study, we synthesized a novel NDI polymer with uniform size, long-term stability, and high near-infrared two-zone (NIR-II) absorption efficiency, which can greatly enhance the effect of photothermal therapy (PTT) after intravenous injection into Huh-7-tumor bearing mice.Results: The in vitro and in vivo studies showed that NDI polymer exhibited excellent NIR-guided PTT treatment, and the antitumor effect was approximately 88.5%, with obvious antimetastatic effects.Conclusion: This study developed an NDI polymer-mediated integrated diagnostic and therapeutic modality for NIR-II fluorescence imaging and photothermal therapy.Keywords: hepatocellular carcinoma, photothermal therapy, NDI polymer, NIR-II imaging

Jinlu Liu,1,* Ling Yang,1,* Xin Yuan,2,* Meimei Xiong,1 Jiao Zhu,1 Wenbi Wu,1 Min Ren,1 Jianlin Long,3 Xuewen Xu,2 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Plastic and Burn Surgery, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China; 3Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Maling GouState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaEmail goumaling@scu.edu.cnXuewen XuDepartment of Plastic and Burn Surgery, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaEmail xxw_0826@163.comIntroduction: β-lactamase (LACTB) is a tumor suppressor gene in various tumors including melanoma. However, it remains challenging to efficiently deliver the LACTB gene into melanoma. Recently, we designed a nonviral nanocarrier iRGD/DOTAP/MPEG-PDLLA (iDPP) that could deliver gene targetedly to melanoma efficiently without obvious adverse effects.Methods: In this study, the tumor-targeted nanoparticle iDPP was prepared to deliver LACTB gene to treat melanoma in vitro and in vivo. First, the expression level of LACTB in 6 clinical specimens of melanoma patients was evaluated. Subsequently, the characteristics of iDPP/LACTB nanocomplexes were studied. Afterwards, the in vitro and in vivo anti-tumor efficacy of the iDPP/LACTB nanocomplexes were explored utilizing the B16-F10 mouse melanoma cell line and the B16-F10 subcutaneous melanoma model.Results: Compared with the normal epithelium, the expression level of LACTB in melanoma tissues was significantly downregulated. In vitro B16-F10 cell tests showed iDPP/LACTB nanocomplexes could increase the mRNA levels of P21, Bid, Bax, Pidd1, and Sival genes and up-regulate the p53 signaling pathway of melanoma cells, thus promoting cell apoptosis and blocking the cell cycle. Injected intravenously, iDPP nanoparticles could deliver DNA to the subcutaneous melanoma targetedly. Based on in vivo mouse xenograft model, iDPP/LACTB nanocomplexes could effectively inhibit tumor proliferation and induce tumor apoptosis, thus significantly inhibiting melanoma growth (tumor inhibition rate is about 68%) in the subcutaneous B16-F10 melanoma model.Conclusion: The downregulated LACTB might be a potential target for melanoma therapy. The iDPP/LACTB nanocomplexes could inhibit the growth of the mouse melanoma without obvious side effects, which provide a new option for melanoma gene therapy research.Keywords: melanoma, LACTB, nanocomplexes, gene therapy

Min Sui,1,* Meimei Xiong,2,* Yuling Li,1,* Qiao Zhou,1 Xiaofei Shen,3 Da Jia,3 Maling Gou,2 Qingxiang Sun1 1Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, People’s Republic of China; 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, Division of Neurology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingxiang Sun; Maling Gou Email sunqingxiang@hotmail.com; goumaling@scu.edu.cnIntroduction: Peptides can be rationally designed as non-covalent inhibitors for molecularly targeted therapy. However, it remains challenging to efficiently deliver the peptides into the targeted cells, which often severely affects their therapeutic efficiency.Methods: Herein, we created a novel non-covalent peptide inhibitor against nuclear export factor CRM1 by a structure-guided drug design method and targetedly delivered the peptide into cancer cells by a nanoparticle-mediated gene expression system for use as a cancer therapy.Results: The nuclear export signal (NES)-optimized CRM1 peptide inhibitor colocalized with CRM1 to the nuclear envelope and inhibited nuclear export in cancer cell lines in vitro. The crystal structures of the inhibitors complexed with CRM1 were solved. In contrast to the covalent inhibitors, the peptides were similarly effective against cells harboring the CRM1 C528S mutation. Moreover, a plasmid encoding the peptides was delivered by a iRGD-modified nanoparticle to efficiently target and transfect the cancer cells in vivo after intravenous administration. The peptides could be selectively expressed in the tumor, resulting in the efficient inhibition of subcutaneous melanoma xenografts without obvious systemic toxicity.Discussion: This work provides an effective strategy to design peptide-based molecularly targeted therapeutics, which could lead to the development of future targeted therapy.Keywords: CRM1, non-covalent inhibitor, crystal structures, DNA nanocomplex, protein engineering

Qianqian Zhang,1,2,* Meimei Xiong,2,* Jinlu Liu,1,2 Shuai Wang,2 Ting Du,2 Tianyi Kang,2 Yu Liu,2 Hao Cheng,2 Meijuan Huang,1 Maling Gou21Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workBackground: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. However, whether LHPP is effective to melanoma has not been investigated. Gene therapy provides a new strategy for the treatment of melanoma. Currently, it suffers from the lack of safe and effective gene delivery systems. Methods: A CRGDKGPDC peptide (iRGD) modified hybrid monomethoxy poly(ethylene glycol)-poly(D,L-lactide) nanoparticle (iDPP) was prepared and complexed with a LHPP plasmid, forming an iDPP/LHPP nanocomplex. The iDPP/LHPP nanocomplex was characterized by particle size distribution, zeta potential, morphology, cytotoxicity, and transfection efficiency. The antitumor efficacy of the nanocomplex against melanoma was studied both in vitro and in vivo. Further, the potential epigenetic changes in melanoma induced by iDPP/LHPP nanocomplex were evaluated.Results: The iDPP/LHPP nanocomplex showed high transfection efficiency and low toxicity. Moreover, the nanocomplex displayed a neutral charge that can meet the requirement of intravenous injection for targeted gene therapy. In vitro and in vivo experiments indicated that the iDPP/LHPP nanocomplex significantly inhibited the melanoma growth without causing notable adverse effects. We also found that LHPP played an important role in epigenetics. It regulated the expression of genes related to the proliferation and apoptosis chiefly at the level of transcription.Conclusion: This work demonstrates that the iDPP nanoparticle-delivered LHPP gene has a potential application in melanoma therapy through regulation of the genes associated with epigenetics.Keywords: melanoma, LHPP, nanoparticle, gene therapy, epigenetics

Miaomiao Gou,* Yong Zhang,* Haiyan Si,* Guanghai Dai Department of Medical Oncology, Chinese People’s Liberation Army General Hospital, Beijing 100853, People’s Republic of China *These authors contributed equally to this work Objective: PD-1 inhibitors have improved efficacy in many cancers. There are currently no reports of the use of PD-1 inhibitors, such as nivolumab, for metastatic biliary tract cancer (mBTC). This study reviewed the efficacy and safety of nivolumab for mBTC with the aim of exploring ways to improve efficacy and survival. Methods: Thirty patients with mBTC were voluntarily treated with nivolumab at the PLA General Hospital. Nivolumab 3 mg/kg was administered. Progression-free survival (PFS) and overall survival were evaluated by Kaplan–Meier and univariate and multivariate analyses were carried out for clinical characteristics. Objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is four cycles. One case was complete response, 5 cases partial response, 12 cases stable, and 12 cases progression. ORR was 20%, DCR was 60%, and PFS was 3.1 months (95% CI: 2.13–4.06). The AEs of nivolumab monotherapy were fatigue (three cases), fever (two cases), hypothyroidism (one case), skin reaction (one case), and liver injury (one case). Nivolumab combined with chemotherapy related grade 1–2 hematologic toxicity were leukopenia (five cases) and thrombocytopenia (two cases), and grade 3–4 were leukopenia (three cases). Non-hematologic toxicity grade 1–2 were nausea and vomiting (four cases), fatigue (four cases), fever (three cases), peripheral neurotoxicity (three cases), and hypothyroidism (one case). Univariate analysis showed that PFS of nivolumab combined with chemotherapy was statistically significant compared with that of nivolumab monotherapy (4.1 vs 2.3 months, P=0.031). Programmed death-ligand 1 (PD-L1) expression positively has no relationship with better PFS in contrast with PD-L1 negatively (3.6 vs 3.0 months P>0.05). Multivariate analysis show nivolumab combined with chemotherapy was only the independent factor for longer PFS (HR: 0.432, P

Tianyi Kang,1 Chenyang Li,1,2 Ting Du,1 Yujiao Wu,1 Yuping Yang,1 Xuan Liu,1 Qianqian Zhang,1 Xiaoping Xu,3 Maling Gou1,4 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Shanghai Institutes for Biological Science, Chinese Academy of Science, Shanghai 200031, People’s Republic of China; 3West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China; 4Co-Innovation Center for Micro/Nano Optoelectronic Materials and Devices, Chongqing 402160, People’s Republic of China Background: Melittin, the main active peptide ingredient of bee venom, can cause severe cell membrane lysis due to its robust interaction with negatively charged phospholipids. So far, no effective anti-melittin vaccine has been developed to protect people from undesired melittin intoxication.Methods: Herein, we prepared a polydiacetylene (PDA) nanoparticle with cell membrane-mimic surface to complex melittin, forming an anti-melittin vaccine (PDA–melittin).Results: PDA nanoparticles could effectively combine with melittin and neutralize its toxicity. PDA–melittin nanocomplex is demonstrated to enhance melittin uptake by DCs and stimulate strong melittin-specific immunity. Mice immunized with PDA–melittin nanocomplex showed higher survival rate after exposion to melittin than untreated mice.Conclusion: The PDA–melittin nanocomplex can efficiently and safely generate a specific immunity against melittin to protect body from melittin intoxication, providing a new method with potential clinical application for the treatment of melittin intoxication.Keywords: PDA nanoparticles, melittin, toxoid vaccine, immunity

Luo L, Du T, Zhang J, et al. Int J Nanomedicine. 2016;11:501—513. The authors have advised due to an error at the time of figure assembly, Figure 11 on page 510 is incorrect. The correct Figure 11 is shown below. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Xun Jin,1 Peilan Zhang,1 Li Luo,1 Hao Cheng,1 Yunzu Li,1 Ting Du,1 Bingwen Zou,2 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China; 2Department of Thoracic Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of China Abstract: Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer. Keywords: bladder cancer, drug delivery, nanoparticles, intravesical therapy

Xun Jin,1,* Bingwen Zou,2,* Li Luo,1,* Chuanhong Zhong,3 Peilan Zhang,1 Hao Cheng,1 Yanfang Guo,1 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 2Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, 3Department of Neurosurgery, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan Province, People’s Republic of China *These authors contributed equally to this work Abstract: Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethylene glycol)-poly(L-lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27 nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment. Keywords: thioridazine, doxorubicin, codelivery, nanoparticles, breast cancer

Li Luo,1,* Ting Du,1,* Jiumeng Zhang,1 Wei Zhao,2 Hao Cheng,1 Yuping Yang,1 Yujiao Wu,1 Chunmei Wang,1 Ke Men,1 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, 2Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Abstract: Gene therapy has promising applications in ovarian cancer therapy. Blocking the function of the survivin protein could lead to the growth inhibition of cancer cells. Herein, we used degradable heparin–polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human survivin T34A (hs-T34A) gene to treat ovarian cancer. HPEI nanoparticles were characterized and were found to have a dynamic diameter of 66±4.5 nm and a zeta potential of 27.1±1.87 mV. The constructed hs-T34A gene expression plasmid could be effectively delivered into SKOV3 ovarian carcinoma cells by HPEI nanoparticles with low cytotoxicity. Intraperitoneal administration of HPEI/hs-T34A complexes could markedly inhibit tumor growth in a mouse xenograft model of SKOV3 human ovarian cancer. Moreover, according to our results, apparent apoptosis of cancer cells was observed both in vitro and in vivo. Taken together, the prepared HPEI/hs-T34A formulation showed potential applications in ovarian cancer gene therapy. Keywords: human survivin T34A, heparin–polyethyleneimine nanoparticles, gene therapy, ovarian cancer

Abstract Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p

The aim of the present work was to evaluate the effect of reducing nitrite content on the physicochemical, microbiological, proteolytic, and volatile properties of Cantonese sausages during fermentation and storage. The Cantonese sausages were divided into six groups based on the amount of nitrite added (0, 30, 60, 90, 120, and 150 mg/kg). Results showed that among the physicochemical parameters, moisture, weight loss, a* value, thiobarbituric acid reactive substance value, and nitrite residue levels were significantly affected (p < 0.05) along with nitrite reduction. In addition, the total viable counts and Gram-positive cocci increased with the reduction of nitrite, while lactic acid bacteria decreased. The band densities of actin (48 kDa) increased with the reduction of nitrite, while no major change in sarcoplasmic protein bands was observed. The results of volatile compounds suggested that the reduction of nitrite mainly affected compounds originating from carbohydrate fermentation, esterase activity, and lipid oxidation. [ABSTRACT FROM AUTHOR]

Abstract Recent spread of the COVID-19 forces governments around the world to temporarily close educational institutions. In this paper, we evaluated learning engagement, level of satisfaction and anxiety of e-book based remote teaching strategy on an online learning platform. The research involves 358 students at an urban junior-high school in Japan. Learning logs were analyzed to measure student engagement, whereas survey responses indicated their perception regarding the remote learning experience. Log analysis revealed that the average completion rate over 267 learning materials was 67%. We also observed a significant decrease in engagement 3 weeks after remote learning and different subjects and grades. Survey analysis showed students felt both satisfaction and anxiety about remote learning. However, there were significant differences in the level of satisfaction between different grades. The results indicated that (1) maintaining students’ motivation is a challenge to remote learning in secondary schools, and (2) we need to relieve students’ anxiety about their own progress in the class and their classes after the break. This study is the first to report trends in actual teaching–learning engagement, which were recorded during sessions of emergency remote teaching in Japanese schools. The results can inform the future implementation of remote learning in junior-high schools.

Aiming at the problem that the traditional steganography based on carrier modification has the low steganographic capacity, a steganographic scheme based on Fully Convolutional Dense Connection Network (FC-DenseNet) is proposed. Since FC-DenseNet can effectively overcome the problems of gradient dissipation and gradient explosion, and a large number of features are multiplexed, the cascaded secret image and carrier image can reconstruct good image quality after entering the network. Effectively improve steganographic capacity. First, we reset the number of input channels of the first convolution block of FC-DenseNet and the number of output channels of the last convolution block and deleted the LogSoftmax() function. On the sender side, after the concatenated secret image and carrier image pass through the hidden network FC-DenseNet, the secret image is embedded in the carrier image to obtain a stego-image. At the receiving side, the extraction network reconstructs the secret image from the stego-image. Experimental results show that our proposed steganography scheme not only has a high Peak Signal-to-Noise Ratio(PSNR) and Structural Similarity(SSIM) but also can realize large-capacity image steganography, with an average image payload capacity of 23.96 bit per pixel.

One of the advantages of cement and the cement concrete industry in sustainability is the ability to utilize large amounts of industrial solid wastes such as fly ash and ground granulated blast furnace slag. Tailings are solid wastes of the ore beneficiation process in the extractive industry and are available in huge amounts in some countries. This paper reviews the potential utilization of tailings as a replacement for fine aggregates, as supplementary cementitious materials (SCMs) in mortar or concrete, and in the production of cement clinker. It was shown in previous research that while tailings had been used as a replacement for both fine aggregate and cement, the workability of mortar or concrete reduced. Also, at a constant water to cement ratio, the compressive strength of concrete increased with the tailings as fine aggregate. However, the compressive strength of concrete decreased as the replacement content of the tailings as SCMs increased, even whentailings were ground into smaller particles. Not much research has been dedicated to the durability of concrete with tailings, but it is beneficial for heavy metals in tailings to stabilize/solidify in concrete. The clinker can be produced by using the tailings, even if the tailings have a low SiO2 content. As a result, the utilization of tailings in cement and concrete will be good for the environment both in the solid waste processing and virgin materials using in the construction industry.

Jin-Feng Qiu,1 Xiang Gao,1,2 Bi-Lan Wang,1 Xia-Wei Wei,1 Ma-Ling Gou,1 Ke Men,1 Xing-Yu Liu,1 Gang Guo,1 Zhi-Yong Qian,1 Mei-Juan Huang1 1Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Medical School, Sichuan University, Chengdu, People’s Republic of China; 2Medical School and Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, People’s Republic of China Abstract: Luteolin (Lu) is one of the flavonoids with anticancer activity, but its poor water solubility limits its use clinically. In this work, we used monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Lu by a self-assembly method, creating a water-soluble Lu/MPEG-PCL micelle. These micelles had a mean particle size of 38.6 ± 0.6 nm (polydispersity index = 0.16 ± 0.02), encapsulation efficiency of 98.32% ± 1.12%, and drug loading of 3.93% ± 0.25%. Lu/MPEG-PCL micelles could slowly release Lu in vitro. Encapsulation of Lu in MPEG-PCL micelles improved the half-life (t½; 152.25 ± 49.92 versus [vs] 7.16 ± 1.23 minutes, P = 0.007), area under the curve (0–t) (2914.05 ± 445.17 vs 502.65 ± 140.12 mg/L/minute, P = 0.001), area under the curve (0–∞) (2989.03 ± 433.22 vs 503.81 ± 141.41 mg/L/minute, P = 0.001), and peak concentration (92.70 ± 11.61 vs 38.98 ± 7.73 mg/L, P = 0.003) of Lu when the drug was intravenously administered at a dose of 30 mg/kg in rats. Also, Lu/MPEG-PCL micelles maintained the cytotoxicity of Lu on 4T1 breast cancer cells (IC50 = 6.4 ± 2.30 µg/mL) and C-26 colon carcinoma cells (IC50 = 12.62 ± 2.17 µg/mL) in vitro. These data suggested that encapsulation of Lu into MPEG-PCL micelles created an aqueous formulation of Lu with potential anticancer effect. Keywords: luteolin, micelle, MPEG-PCL, cancer therapy

Xiang Gao,1 BiLan Wang,1 XiaWei Wei,1 Wang Rao,2 Fang Ai,2 Fen Zhao,2 Ke Men,1 Bowen Yang,1 Xingyu Liu,1 Meijuan Huang,1 Maling Gou,1 ZhiYong Qian,1 Ning Huang,1 Yuquan Wei11Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China; 2Department of Surgery, First Affiliated Hospital, Xinxiang Medical School, Xinxiang, People's Republic of ChinaAbstract: Star-shaped polymer micelles have good stability against dilution with water, showing promising application in drug delivery. In this work, biodegradable micelles made from star-shaped poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymer were prepared and used to deliver doxorubicin (Dox) in vitro and in vivo. First, an acrylated monomethoxy poly (ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) diblock copolymer was synthesized, which then self-assembled into micelles, with a core-shell structure, in water. Then, the double bonds at the end of the PCL blocks were conjugated together by radical polymerization, forming star-shaped MPEG-PCL (SSMPEG-PCL) micelles. These SSMPEG-PCL micelles were monodispersed (polydispersity index = 0.11), with mean diameter of ≈25 nm, in water. Blank SSMPEG-PCL micelles had little cytotoxicity and did not induce obvious hemolysis in vitro. The critical micelle concentration of the SSMPEG-PCL micelles was five times lower than that of the MPEG-PCL micelles. Dox was directly loaded into SSMPEG-PCL micelles by a pH-induced self-assembly method. Dox loading did not significantly affect the particle size of SSMPEG-PCL micelles. Dox-loaded SSMPEG-PCL (Dox/SSMPEG-PCL) micelles slowly released Dox in vitro, and the Dox release at pH 5.5 was faster than that at pH 7.0. Also, encapsulation of Dox in SSMPEG-PCL micelles enhanced the anticancer activity of Dox in vitro. Furthermore, the therapeutic efficiency of Dox/SSMPEG-PCL on colon cancer mouse model was evaluated. Dox/SSMPEG-PCL caused a more significant inhibitory effect on tumor growth than did free Dox or controls (P < 0.05), which indicated that Dox/SSMPEG-PCL had enhanced anticolon cancer activity in vivo. Analysis with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed that Dox/SSMPEG-PCL induced more tumor cell apoptosis than free Dox or controls. These results suggested that SSMPEG-PCL micelles have promising application in doxorubicin delivery for the enhancement of anticancer effect.Keywords: drug delivery, star-shaped polymer, MPEG-PCL, CMC

Bi Lan Wang1, Xiang Gao1,2, Ke Men1, Jinfeng Qiu1, Bowen Yang3, Ma Ling Gou1, Mei Juan Huang1, Ning Huang2, Zhi Yong Qian1, Xia Zhao1, Yu Quan Wei11State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, 2Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, 3College of Life Science, Sichuan University, Chengdu, People’s Republic of ChinaAbstract: Intravesical application of an anti-inflammatory drug is an efficient strategy for acute cystitis therapy. Quercetin (QU) is a potent anti-inflammatory agent; however, its poor water solubility restricts its clinical application. In an attempt to improve water solubility of QU, biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles were used to encapsulate QU by self-assembly methods, creating QU/MPEG-PCL micelles. These QU/MPEG-PCL micelles with DL of 7% had a mean particle size of ~34 nm, and could release QU for an extended period in vitro. The in vivo study indicated that intravesical application of MPEG-PCL micelles did not induce any toxicity to the bladder, and could efficiently deliver cargo to the bladder. Moreover, the therapeutic efficiency of intravesical administration of QU/MPEG-PCL micelles on acute cystitis was evaluated in vivo. Results indicated that QU/MPEG-PCL micelle treatment efficiently reduced the edema and inflammatory cell infiltration of the bladder in an Escherichia coli-induced acute cystitis model. These data suggested that MPEG-PCL micelle was a candidate intravesical drug carrier, and QU/MPEG-PCL micelles may have potential application in acute cystitis therapy.Keywords: nanomedicine, MPEG-PCL, self-assembly

Ling Zhang1,*, Xiang Gao1,2,*, Ke Men1, BiLan Wang1, Shuang Zhang1, Jinfeng Qiu1, Meijuan Huang1, MaLing Gou1, Ning Huang2, ZhiYong Qian1, Xia Zhao1, YuQuan Wei11State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, 2Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workBackground: Gene therapy provides a novel method for the prevention and treatment of cancer, but the clinical application of gene therapy is restricted, mainly because of the absence of an efficient and safe gene delivery system. Recently, we developed a novel nonviral gene carrier, ie, heparin-polyethyleneimine (HPEI) nanoparticles for this purpose.Methods and results: HPEI nanoparticles were used to deliver plasmid-expressing mouse survivin-T34A (ms-T34A) to treat C-26 carcinoma in vitro and in vivo. According to the in vitro studies, HPEI nanoparticles could efficiently transfect the pGFP report gene into C-26 cells, with a transfection efficiency of 30.5% ± 2%. Moreover, HPEI nanoparticle-mediated ms-T34A could efficiently inhibit the proliferation of C-26 cells by induction of apoptosis in vitro. Based on the in vivo studies, HPEI nanoparticles could transfect the Lac-Z report gene into C-26 cells in vivo. Intratumoral injection of HPEI nanoparticle-mediated ms-T34A significantly inhibited growth of subcutaneous C-26 carcinoma in vivo by induction of apoptosis and inhibition of angiogenesis.Conclusion: This research suggests that HPEI nanoparticle-mediated ms-T34A may have a promising role in C-26 colon carcinoma therapy.Keywords: gene therapy, mouse survivin-T34A, colon cancer, polyethyleneimine, nanoparticles, cancer therapy