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Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer

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Bioactive Materials 2023年第5期23卷 1-15页

作者： Wen Chen Kun Shi Jie Liu Peipei Yang ruxia han Meng Pan Liping Yuan Chao Fang Yongyang Yu Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan University and Collaborative Innovation CenterChengdu610041PR China Department of Gastrointestinal Surgery West China HospitalSichuan UniversityChengdu610041PR China

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide,posing a severe threat to human health.Surgical resection remains the most preferred option for gastric cancer treatment.However,for advanced gastric cancer,the curative effect of surgical resection is usually limited by the local recurrence,peritoneal carcinomatosis,or distal metastasis.Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection.Here,we designed a 5-fluorouracil(5-FU)and cis-platinum(DDP)co-delivery system based on a biodegradable temperature-sensitive hydrogel(PDLLA-PEG-PDLLA,PLEL)for intraoperative adjuvant combination chemotherapy of gastric cancer.This 5-FU+DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo.A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU+DDP/PLEL were observed against gastric cancer MKN45-luc cells.After intraperitoneal injection,the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model.The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well.What’s more,we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer,in which the intraoperative administration of 5-FU+DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors,resulting in an extended lifetime.Hence,this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer,that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

关键词： Thermo-sensitive hydrogel Localized drug delivery Sustained release Intraoperative chemotherapy Gastric cancer

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Review of a new bone tumor therapy strategy based on bifunctional biomaterials

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Bone Research 2021年第2期9卷 153-165页

作者： Jinfeng Liao ruxia han Yongzhi Wu Zhiyong Qian State Key Laboratory of Oral Diseases National Clinical Research Centre for Oral DiseasesState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan UniversityChengduSichuanP.R.China

Bone tumors,especially those in osteosarcoma,usually occur in adolescents.The standard clinical treatment includes chemotherapy,surgical therapy,and radiation therapy.Unfortunately,surgical resection often fails to completely remove the tumor,which is the main cause of postoperative recurrence and metastasis,resulting in a high mortality rate.Moreover,bone tumors often invade large areas of bone,which cannot repair itself,and causes a serious effect on the quality of life of patients.Thus,bone tumor therapy and bone regeneration are challenging in the clinic.Herein,this review presents the recent developments in bifunctional biomaterials to achieve a new strategy for bone tumor therapy.The selected bifunctional materials include 3D-printed scaffolds,nano/microparticle-containing scaffolds,hydrogels,and bone-targeting nanomaterials.Numerous related studies on bifunctional biomaterials combining tumor photothermal therapy with enhanced bone regeneration were reviewed.Finally,a perspective on the future development of biomaterials for tumor therapy and bone tissue engineering is discussed.This review will provide a useful reference for bone tumor-related disease and the field of complex diseases to combine tumor therapy and tissue engineering.

关键词： biomaterials chemotherapy mortality

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Ag2S nanoparticles as an emerging single-component theranostic agent

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Chinese Chemical Letters 2020年第7期31卷 1717-1728页

作者： ruxia han Jinrong Peng Yao Xiao Ying Hao Yanpeng Jia Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China Medical SchoolSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu 610041China

Last two decades,with the rapid changes and development of nanotechnology and biological materials,diverse multi-functional nanomaterials emerging,which offers a novel way to treat and diagnose diseases,and therefore spawned the new biomedical technology of theranostics,which integrates the treatment and diagnosis or monitoring of diseases into one.Ag2S as a bio-nanomaterial with low biotoxicity has attracted more and more attention due to its good photoluminescence properties and fluorescence imaging of small animals in the second near-infrared region(NIR-Ⅱ).Meanwhile,Ag2S has the ability to absorb near-infrared light strongly because of its local surface plasma resonance(LSPR)effect and had become a kind of photothermal conve rters with good photothermal conve rsion efficiency.More interestingly,both photothermal effect and fluorescence characteristics of Ag2S nanoparticles(NPs)are closely related to their particle sizes.However,the relationship between photothermal effect and fluorescence characteristics of Ag2S NPs and their sizes has not been reviewed so far.Herein,the synthesis methods and influencing factors of synthesize Ag2S NPs with different sizes were compared firstly,and then the photothermal effect and fluorescence characte ristics of Ag2S NPs with different sizes were summarized.Finally,the possibilities and challenges of using Ag2S NPs to construct theranostic agent were discussed in the end.

关键词： Ag2S nanoparticle Different sizes Photothermal effect Fluorescence characteristics Theranostics

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Intracellular aggregation of peptide-reprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy

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Acta Pharmaceutica Sinica B 2021年第4期11卷 1069-1082页

作者： Jinrong Peng Yao Xiao Qian Yang Qingya Liu Yu Chen Kun Shi Ying Hao ruxia han Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityAnd Collaborative Innovation Center of BiotherapyChengdu 610065China

The intracellular retention of nanotherapeutics is essential for their therapeutic activity.The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors.However,strategies for the intracellular immobilization of nanoparticles are limited.Herein,a cisplatin prodrug was synthesized and utilized as a glutathione(GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly.The nanoassembly has been reprogrammed with peptidecontaining moieties for tumor-targeting and PD-1/PD-L1 blockade.The aggregation of the nanoassemblies is dependent on GSH concentration.Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species(ROS)generation and immunogenic cell death.Moreover,the nanoassemblies reinvigorate the immunocytes,especially the systemic immunocytes,and thereby alleviate pulmonary metastasis,even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics.This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.

关键词： Nanoassembly Glutathione response Intracellular aggregation Chemotherapy Combinational immunotherapy

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Near-infrared responsive 5-fluorouracil and indocyanine green loaded MPEG-PCL nanoparticle integrated with dissolvable microneedle for skin cancer therapy

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Bioactive Materials 2020年第3期5卷 542-552页

作者： Ying Hao YuWen Chen XinLong He Fan Yang ruxia han ChengLi Yang Wei Li ZhiYong Qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041PR China Department of Dermatovenereology West China HospitalSichuan UniversityChengdu610041PR China

The prevalence of skin cancer is rising along with the rapid population aging in recent years.Traditional therapies,such as surgical treatment,radiotherapy,chemotherapy,photodynamic therapy,and immunotherapy,may accompany serious side effects,limiting their clinical benefits.According to the biological characteristics of skin cancer,we have already established two kinds of synergetic systems of photothermal therapy(microneedle)and chemotherapy,containing gold nanorods(GNR).Although the microneedle system exhibited great potential for skin cancer treatment,the system could be still improved further.So,we designed a near-infrared lightresponsive 5-fluorouracil(5-Fu)and indocyanine green(ICG)loaded monomethoxy-poly(ethylene glycol)-polycaprolactone(MPEG-PCL)nanoparticle(5-Fu-ICG-MPEG-PCL),and then 5-Fu-ICG-MPEG-PCL was integrated with a hyaluronic acid dissolvable microneedle system(HA MN)to get 5-Fu-ICG-MPEG-PCL loaded HA MN for treating skin cancers,including human epidermoid cancer and melanoma.In this system,hyaluronic acid,the microneedle carrier,possesses good skin penetration ability and is approved by FDA as a pharmaceutical adjuvant;5-Fu is recommended by FDA for skin cancer treatment;ICG,a photothermal agent,possesses a strong photothermal ability and is approved by FDA for its use in the human body.We hypothesized that 5-Fu-ICG-MPEG-PCL could be delivered by the dissolvable microneedle through the skin,and the release behavior of the drug in the nanoparticle could be controlled by near-infrared light for achieving a single-dose cure of skin cancer,improving the cure rate of skin cancer and providing a new idea and possibility for the clinical treatment of skin cancer.

关键词： 5-Fluorouracil(5-Fu) Indocyanine green(ICG) Monomethoxy-poly(ethylene glycol)- polycaprolactone(MPEG-PCL) Hyaluronic acid dissolvable microneedle(HA MN) Skin cancer

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Adhesive chitosan-based hydrogel assisted with photothermal antibacterial property to prompt mice infected skin wound healing

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Chinese Chemical Letters 2023年第12期34卷 415-423页

作者： Shuang Cheng Meng Pan Danrong Hu ruxia han Lang Li Zhongwu Bei Yicong Li Ao Sun Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu610041China Rehabilitation Medicine Center and Institute of Rehabilitation Medicine Key Laboratory of Rehabilitation Medicine in Sichuan Province West China HospitalSichuan UniversityChengdu610041China Department of Pediatric Surgery West China HospitalSichuan UniversityChengdu 610041China

Bacterial infection of wounds is an escalating medical problem,issuing threats to both global public health and personal health.Photothermal antibacterial technology as a novel sterilization strategy has outstanding sterilization efficiency,high safety and low risk of emergence of drug-resistant bacteria.By combining inherent antibacterial activity and light-assisted antibacterial treatment,developing novel multifunctional dressings with synergistic high-efficiency antibacterial effects and also promoting wound healing possesses attractive advantages in the field of treating bacterial wound infections in clinical care.Herein,a multifunctional hydrogel formed by in situ photo-cross linking was designed and prepared by first grafting methacrylic anhydride as a photosensitizer onto chitosan,and then introducing oxidatively synthesized polydopamine(PDA).The physicochemical characterizations of the synthesized hydrogels demonstrated their tunability certainly associated with PDA concentration,including pore size,water swelling,rheological properties and in vitro degradability.In addition,the composite hydrogels exhibited good adhesion,anti-oxidation and photothermal properties due to the existence of PDA.Within 10min upon exposure to 808 nm near-infrared(NIR)light irradiation,this hydrogel system displayed outstanding antibacterial activity against Staphylococcus aureus with almost 100%killing efficiency,of which rapid efficient sterilization plays a significant role in wound healing.Moreover,the hydrogel is capable of cytocompatibility and has low toxicity to murine fibroblasts(L929 and NIH/3T3).In the full-thickness wound defect infection model in mice,the wound closure ratio,inflammatory response,fibroblasts,neovascularization and epithelialization were measured.Animal experiments also reveal that the hydrogel assisted with NIR laser irradiation can inhibit effectively infection at an early stage and accelerate the wound healing process.In summary,this novel multifunctional injectable hydrogel exhibits excellent sw

关键词： Hydrogel Adhesion Photothermal therapy Antibacterial Wound infection

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Sustained co-delivery of gemcitabine and cis-platinum via biodegradable thermo-sensitive hydrogel for synergistic combination therapy of pancreatic cancer

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Nano Research 2019年第6期12卷 1389-1399页

作者： Kun Shi Bingxin Xue Yanpeng Jia Liping Yuan ruxia han Fan Yang Jinrong Peng Zhiyong Qian State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan University and Collaborative Innovation CenterChengdu 610041China

Pancreatic cancer is one of the most devastating cancers with poor prognosis and no significant change in the survival rate over the past decades.Localized targeted drug delivery through interventional endoscopic ultrasonography-guided fine-needle injection (EUS-FNI) is an attractive and minimally invasive strategy for inoperable pancreatic cancer.An injectable in-situ formed long-lasting drug delivery system is a promising alternative for the localized treatment of pancreatic cancer via EUS-FNI.Here,a biodegradable thermo-sensitive copolymer hydrogel for the co-delivery of anticancer agents gemcitabine (GEM) and cis-platinum (DDP) was developed.This hydrogel is a free flowable liquid at room temperature that changes into a semi-solid hydrogel following injection in response to the physiological temperature.Both in vitro and in vivo drug release behaviors indicate sustained drug release of this delivery system.Synergistic cellular proliferation inhibition and desirable apoptosis promotion have been found when pancreatic cancer Bxpc-3 cells were co-cultured with this GEM-DDP/hydrogel system.After a single intratumoral injection,the dual-drug loaded hydrogel formulation exhibited superior anti-tumor efficacy and minimized systemic side effect on pancreatic cancer xenograft mouse model in comparison to the intravenously injected free GEM and DDP combination.In addition,a strong synergistic therapeutic effect of the GEM-DDP/hydrogel system against pancreatic cancer has been found in vitro and in vivo compared to the single-drug loaded hydrogel composites.The obtained findings suggest this developed thermo-sensitive copolymer hydrogel system as a potential universal carrier for the localized targeted delivery of multi-drugs,for use in a variety of inoperable solid tumors.

关键词： localized drug delivery sustained release thermo-sensitive hydrogel combination therapy pancreatic cancer

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Erratum to “Near-infrared responsive 5-fluorouracil and indocyanine green loaded MPEG-PCL nanoparticle integrated with dissolvable microneedle for skin cancer therapy” [Bioact. Mater. 5 (2020) 542–552]

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Bioactive Materials 2021年第1期6卷 297-298页

This is an erratum to our published paper,the scale bar in Fig.6A was wrong[1].In the paper mentioned above,the scale bar in Fig.6A was wrong[1].We missed a decimal point of the scale bar.The correct scale bar of 5-Fu... 详细信息

关键词： needle loaded mentioned

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非线性三阶三点边值问题的拟上下解方法

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数学理论与应用 2016年第2期36卷 33-39页

作者：韩如霞河北工业大学理学院天津300401

通过构造拟上下解的单调迭代过程,在拟解对之间利用Sadvoskii不动点定理获得了Banach空间非线性三阶三点边值问题解的存在性.

关键词：拟上下解对非紧性测度凝聚映射 Sadvoskii不动点定理

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深州蜜桃一次晚霜冻害统计分析

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绿色科技 2023年第6期25卷 62-66页

作者：徐建芬韩建广李韬位璞路儒侠衡水市气象局河北衡水053000 饶阳国家气候观象台河北饶阳053900 河北省深州市气象局河北深州053800

采用深州蜜桃种植区和邻近国家气象站气温数据,分析了2020年4月21~23日深州蜜桃幼果期晚霜冻害天气的气温特征及春季晚霜冻的多年气候与气候变化特征。结果表明:①晚霜冻害过程中,种植区最低气温连续2 d低于桃幼果冻害温度;中心地带气... 详细信息

采用深州蜜桃种植区和邻近国家气象站气温数据,分析了2020年4月21~23日深州蜜桃幼果期晚霜冻害天气的气温特征及春季晚霜冻的多年气候与气候变化特征。结果表明:①晚霜冻害过程中,种植区最低气温连续2 d低于桃幼果冻害温度;中心地带气温最低、冻害温度维持时间最长,其次分别是林间道路旁、种植区边缘;②种植区最低气温明显低于城镇区和其他野外开阔区;③具有区域气候代表性的国家气候观象台近66 a春季最低气温<0℃终日数据表明,晚霜冻害多出现在3月下旬~4月上旬;1957~2012年,春季最低气温<0℃终日为显著提前的趋势;2013~2022年则进入终日日期剧烈波动期,极端偏晚和偏早日期频繁出现,春季晚霜冻害风险加大。

关键词：深州蜜桃春季晚霜冻气温气候变化

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