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Preparation and performance of pH-responsive 5-Fu/chitosan sustained-release microspheres based on microfluidic technology

Huidong Fang,Shiai Xu,Siyu Han,Bin Zhao,Chao Zhang,Wanji Zhou

T-shaped droplet microfluidic device was used for preparing 5-Fu-loaded chitosan microspheres. • 5-Fu-loaded chitosan microspheres exhibit pH-responsive release patterns and sustainable release characteristics for up to 60 days. • The average particle size of the microspheres is 3.90 ± 0.57 μm, and the particle size distribution is narrow. • Drug-loaded microspheres of different particle sizes have different drug release rates and cycles. Microsphere formulations are a promising drug delivery system for targeted response and prolonged sustained release. However, conventional emulsification crosslinking methods for microsphere preparation usually result in a broad particle size distribution, large particle size, poor uniformity, and consequently erratic drug release kinetics. In this investigation, chitosan microspheres encapsulating 5-Fluorouracil (5-Fu CS-MS) were fabricated using a T-type droplet microfluidic device, and the formulation was optimized by single-factor experiments. The resulting microspheres had a consistent drug release profile, a smooth surface, high monodispersity, and a uniform particle size distribution with an average particle size of 3.90 ± 0.57 μm. The polymer-drug interaction in 5-Fu CS-MS was analyzed using FTIR and XRD. The XPS and EDS results confirmed the occurrence of a Schiff base reaction between glutaraldehyde (GA) and chitosan (CS), indicating successful encapsulation. TGA results revealed that the cross-linking reaction enhanced the thermal stability of the microspheres. Biocompatibility assessments using Human umbilical vein endothelial cells (HUVEC) line demonstrated the safety and compatibility of the fabricated microspheres. More importantly, the in vitro release results illustrated a pH-responsive drug release profile and sustained release of 5-Fu CS-MS for a period up to 60 days. In summary, the CS sustained-release microspheres produced using the microfluidic technique have the potential for intelligent response, precise drug delivery, and prolonged sustained release of small-molecule drugs. Download: Download high-res image (197KB) Download: Download full-size image

Core–shell structured 5-FU@ZIF-90@ZnO as a biodegradable nanoplatform for synergistic cancer therapy

Xiao Xiao,Shuang Liang,Yajie Zhao,Dayu Huang,Bengang Xing,Ziyong Cheng,Jun Lin

High treatment efficiency and low drug toxicity are two key factors in tumor therapy. The development of multifunctional drug carrier systems is of great significance for the diagnosis and therapy of tumors. Herein, a novel biodegradable treatment system based on zeolitic imidazolate framework-90 (ZIF-90) was designed in this study. This 5-FU@ZIF-90@ZnO (FZZ) drug delivery system achieves synergistic treatment with antineoplastic 5-fluorouracil (5-FU) and zinc oxide, and also has good dispersibility in the acidic tumor microenvironment (TME), which enables the drug to achieve pH-controlled delivery in acidic organisms. Interestingly, zinc oxide nanoparticles can play a dual role here. They can prevent the premature leakage of drugs under physiological conditions. Moreover, Zn2+ produced after the decomposition of nanoparticles can act as a therapeutic agent, overcoming the tumor resistance to 5-FU and regulating a series of physiological reactions to inhibit tumor growth. It is worth noting that the porous ZIF-90 is an emerging drug carrier with a relatively high drug loading rate of 39% in this study. Synergistic 5-FU and ZnO nanoparticles have achieved tumor inhibition and have shown high therapeutic biosafety. Thus, the FZZ core–shell nanoparticles are a potential pH-controlled drug release system that can be applied to tumor treatment.

Self-assembling hydrogel loaded with 5-FU PLGA microspheres as a novel vitreous substitute for proliferative vitreoretinopathy

Zhen Yu,Shisi Ma,Mengfan Wu,Huan Cui,Rong Wu,Sizhe Chen,Chenlin Xu,Xiaohe Lu,Songfu Feng

The vitreous substitute for proliferative vitreoretinopathy (PVR) surgery remains an unmet clinical need in ophthalmology. In our study, we developed an in situ formed hydrogel by crosslinking polyvinyl alcohol (PVA) and chitosan as a potential vitreous substitute. 5-fluorouracil (5-FU) Poly (lactic-co-glycolic acid) (PLGA) microspheres were developed and loaded onto the PVA/chitosan hydrogels to treat PVR. In vitro, PVA/chitosan hydrogels at four concentrations were subjected to morphological, physical, rheological analyses, and cytotoxicity was evaluated together with the characterization of 5-FU PLGA microspheres. In vivo, pharmacologically induce PVR rabbits were performed a vitrectomy. In the PVA group, 3% PVA/chitosan hydrogel was injected into the vitreous cavity. In the PVA/MS group, 3% PVA/chitosan hydrogel and 5-FU PLGA microspheres were injected. In the Control group, phosphate-buffered saline was injected. Therapeutic efficacy was evaluated with postoperative examinations and histological analyses. This study demonstrated that the 3% PVA/chitosan hydrogel showed properties similar to those of the human vitreous and could be a novel in situ crosslinked vitreous substitute for PVR. Loading 5-FU PLGA microspheres onto this hydrogel may represent an effective strategy to improve the prognosis of PVR.

Tumor microenvironment-activated, immunomodulatory nanosheets loaded with copper(II) and 5-FU for synergistic chemodynamic therapy and chemotherapy

Yi Xia,Muge Gu,Jiayu wang,Xiangqi Zhang,Tianyi Shen,Xiaoying Shi,Wei-En Yuan

The tumor microenvironment (TME) has a redox state that differs greatly from normal tissues, as characterized by the overexpression of H 2 O 2 and glutathione (GSH). To address the GSH-related restrictions on chemodynamic therapy (CDT) efficacy, we have developed a Cu(II)-based CDT strategy. In this study, a novel organic-inorganic hybrid drug delivery system (LDH/HA/5-FU) was conceived and prepared by the intercalation of 5-FU into the interlayer of copper-aluminum layered double hydroxide (CuAl-LDH) via ion exchange strategy and the adsorption of hyaluronic acid (HA) on the surface of CuAl-LDH. Taking advantage of the pH-degradable property of CuAl-LDH and the CD44-targeting property of HA, the formed LDH/HA/5-FU nanosheets could specifically target tumor cells overexpressing CD44 receptor, rapidly release Cu(II) and 5-FU in tumor cells, inducing tumor cell apoptosis and cuproptosis, and long-term intracellular GSH depletion and toxic hydroxyl radicals (·OH) generation could be achieved through the cyclic catalytic reaction of Cu(Ⅰ)/Cu(Ⅱ). Meanwhile, peritumoral injection of LDH/HA/5-FU nanosheets might function as an adjuvant to increase the levels of antitumor tumor-associated macrophages (TAMs) and T cells. In vivo experiments further verified that the intelligently designed LDH/HA/5-FU nanosheets successfully promoted the immune systems, with an excellent inhibition efficacy towards tumors by combining Cu-based CDT and chemotherapy, showing promising potential for solid tumor treatments.

Carrier-free 5-Fu nanoparticle-mediated domestication therapy for scar treatment: A preclinical and first-in-human study

Peng He,Sha Yi,Jianzhong Zhang,Chengchao Chu,Xuqi Peng,Changhong Li,Xinfei Sun,Yang Zhang,Hongwei Cheng,Xia Xiong,Gang Liu

Pathological scars, including hypertrophic scars (HTSs) and keloids, are abnormal wound healing responses, and current treatments are often unsatisfactory. Intralesional multi-injection of 5-fluorouracil (5-Fu), a commonly used approach, has raised great concerns due to its short retention time and adverse effects for anti-scar treatments. To address this, we developed a novel formulation of 5-Fu for scar management, carrier-free pure 5-Fu nanoparticles (nano 5-Fu), prepared by a super-stable pure-nanomedicine formulation technology. In vitro tests on keloid fibroblasts and human umbilical vein endothelial cells (HUVECs) showed that nano 5-Fu possessed superior ability to inactivate these cells compared to free 5-Fu. In vivo retention tests on rabbit HTSs and rat normal skin demonstrated that nano 5-Fu could coexist in soft tissues for a longer time, resulting in a more effective dosage in scar lesions. In vivo results on rabbit scars indicated that nano 5-Fu can lead to a significant reduction in scar elevation index (SEI), collagen fiber deposition and microvessels for skin remodeling. Importantly, the results of the first-in-human trial demonstrated that nano 5-Fu could decrease scar height and vascularity with excellent and stable efficacy as well as less topical side effects. Peripheral blood analyses demonstrated the high systemic safety of nano 5-Fu intralesional injection in HTSs. The carrier-free 5-Fu nanoparticle-mediated “domestication” therapy, featuring low dosage, outstanding efficacy and safety, represents a promising strategy for pathological scar treatment.

An injectable photo-crosslinking silk hydrogel system with biphasic release of BTXA and 5-Fu promotes scarless wound healing

Ming Xu,Xihang Wang,Ziyi Zhou,Linna Wang,Jia Zhou,Xinyue Hu,Yuanfei Wang,Tong Wu

Hypertrophic scarring is characterized by excessive dermal fibrosis and irregular collagen metabolism, mediated by fibroblasts derived from keloids. This condition typically arises from improper wound healing after deep burns, trauma, or surgical procedures. Although intralesional injections of botulinum toxin type A and 5-fluorouracil are common clinical treatments, their effectiveness is often limited by temporary drug retention, insufficient penetration depth, and complications from repeated injections. To overcome these challenges, we developed an injectable composite hydrogel system, F@P-B-SilMA, to promote scarless wound healing. Systematic characterization revealed that this system undergoes rapid UV-initiated in situ polymerization and exhibits a three-dimensional porous microstructure. It also demonstrates excellent tissue adhesion and mechanical compliance, along with favorable rheological properties, and tunable degradation kinetics that align with the various phases of wound healing. These attributes collectively meet the essential criteria for advanced wound dressings. Comprehensive in vitro and in vivo evaluations confirmed the system's biocompatibility and its dual ability to accelerate wound closure while suppressing fibrotic proliferation. The injectable F@P-B-SilMA composite hydrogel system represents a promising therapeutic approach for clinical scar management, showcasing significant potential as a next-generation wound dressing for scarless tissue regeneration.

Enzyme and PH responsive 5-flurouracil (5-FU) loaded hydrogels based on olsalazine derivatives for colon-specific drug delivery

Zhengang Ma,Rui Ma,Xue Wang,Jinlai Gao,Yufeng Zheng,Zhijie Sun

Colon-specific drug delivery systems are efficient for increasing the availability of drugs at colon region and are desirable for the treatment of local diseases such as ulcerative colitis and colonic cancer. We synthesized an acryloyl chloride modified olsalazine (olsalazine-AC) as an azo crosslinker which was copolymerized with hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA), and developed two types of azo hydrogels which contained single network hydrogel and interpenetrating network hydrogel as an enzyme responsive and pH responsive controlled release carrier for colon-specific drug delivery. The structure of the azo crosslinker was characterized by FT-IR and 1 H NMR spectra and the azo hydrogels were analyzed by using ultraviolet spectrophotometer and scanning electron microscopy. The in vitro release of the 5-flurouracil (5-FU) loaded azo hydrogels was carried out in PBS (pH 7.4), PBS (pH 2.0) and rat colonic fluid (RCF). The drug release profile revealed that 5-FU loaded in azo hydrogels released faster in rat colonic fluid. The results showed that these azo hydrogels could be potential drug carrier for colon-targeted delivery.

Neddylation Inhibition Sensitizes Gastric Cancer to 5-FU by Targeting the Post-Translational Stability of the Metabolic Enzyme DPD

Qianqian Zhang,Jingyi Hu,Yangbo Liu,Dongzhao Xie,Linyue Bai,Zhuang Hu,Yanjun Tang,Siqi Feng

The therapeutic efficacy of 5-fluorouracil (5-FU), a cornerstone of gastric cancer chemotherapy, is predominantly limited by its catabolic inactivation in tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme responsible for 5-FU inactivation, and its tumor-specific overexpression constitutes a primary mechanism of 5-FU resistance. Here, we report a novel strategy to increase the sensitivity of 5-FU by targeting the post-translational regulation of DPD. We demonstrate that the NEDD8-activating enzyme (NAE) inhibitor MLN4924 significantly enhancesthe antitumor activity of 5-FU in both cellular and animal models of gastric cancer without augmenting systemic toxicity. Mechanistically, MLN4924 treatment inhibits the neddylation of DPD, which is dependent on the NAE1/UBC12 axis. This inhibition triggers the ubiquitination and subsequent proteasomal degradation of DPD, thereby reducing intracellular 5-FU catabolism and augmenting its cytotoxic effects. Our findings identify neddylation as a previously unrecognized regulatory mechanism governing DPD protein stability and activity. This work identifies the neddylation-DPD axis as a novel therapeutic target and provides a strong rationale for combining NAE inhibition with 5-FU-based chemotherapy in gastric cancer.

Synthesis of liver-targeting dual-ligand modified GCGA/5-FU nanoparticles and their characteristics in vitro and in vivo

Mingrong Cheng,Xiaoyan Gao,Yong Wang,Houxiang Chen,Bing He,Yingchun Li,Jiang Han,Zhiping Zhang

Spalt-Like Transcription Factor 4 Mediates Fatty Acid Oxidation to Foster 5-Fluorouracil Resistance in Gastric Cancer Cells

Yong Zhu,Chuanmin Yi,Jin Zhao,Lei Wang,Tao Huang,Bo Xiang,Lvhai Zhang,Xiangfang He,Linke Wu

Platinum-based and pyrimidine drugs are first-line treatments for gastric cancer (GC), but their efficacy is often affected by drug resistance. High spalt-like transcription factor 4 (SALL4) expression is associated with poor prognosis, but its role in 5-fluorouracil (5-FU) resistance is not yet clear. In this study, we investigated the effect of SALL4 on 5-FU resistance in GC cells by bioinformatics analysis, real-time quantitative reverse transcription polymerase chain reaction, cell counting kit-8, colony formation assay, and western blot. The results showed that SALL4 was highly expressed in GC and significantly correlated with the fatty acid oxidation (FAO) pathway. Knockdown of SALL4 resulted in a notable attenuation of cellular proliferative capacity and heightened susceptibility to 5-FU resistance in GC cells, while overexpression of SALL4 enhanced 5-FU resistance. Rescue assays confirmed that SALL4 fostered 5-FU resistance in GC cells by enhancing FAO. Our research confirmed that SALL4 promoted the resistance of GC cells to 5-FU by enhancing the FAO pathway. This suggests that drug development targeting SALL4 may help overcome chemotherapy resistance in GC.

Ultrasensitive and Specific Detection of Anticancer Drug 5-Fluorouracil in Blood Samples by a Surface-Enhanced Raman Scattering (SERS)-Based Lateral Flow Immunochromatographic Assay

Hanwen Liu,Ying Liu,Ting Zhou,Penghui Zhou,Jianguo Li,Anping Deng

5-Fluorouracil (5-FU) is an effective anticancer drug widely used in the world. To improve therapy efficiency and reduce side effects, it is very important to frequently detect the concentration of 5-FU in blood samples of patients. In this work, a new type of lateral flow immunochromatographic assay (LFIA) based on surface-enhanced Raman scattering (SERS) for ultrasensitive and specific detection of 5-FU in blood samples was developed. Au@Ag/Au nanoparticles (NPs) employing Au particles as the core and Ag/Au alloy as the shell were synthesized, characterized and used as the substrate in SERS-LFIA due to their high SERS enhancement and biocompatibility. The immunoprobe was made in the form of AuMBA@Ag/Au-Ab in which mercaptobenzoic acid (MBA, a common Raman active reporter) was embedded in the core–shell layer and the monoclonal antibody (mAb) against 5-FU was immobilized on the surface. The performance of SERS-LFIA was similar to that in colloidal gold based-LFIA, and the entire assay time was within 20 min. According to the color intensity on the testing (T) lines of LFIA strips visualized by eyes, the contents of 5-FU in the samples could be qualitatively or semi-quantitatively identified. Furthermore, by measuring the characteristic Raman intensities of MBA on T lines, quantitative detection of 5-FU in the samples were achieved. The IC50and limit of detection (LOD) of the LFIA for 5-FU were found to be 20.9 pg mL−1and 4.4 pg mL−1, respectively. There was no cross-reactivity (CR) of the LFIA with nine relative compounds, and the CR with cytosine, tegafur and carmofur were less than 4.5%. The recoveries of 5-FU from spiked blood samples were in the range of 78.6~86.4% with the relative standard deviation (RSD) of 2.69~4.42%. Five blood samples containing 5-FU collected from the Cancer Hospital were measured by SERS-LFIA, and the results were confirmed by LC-MS/MS. It was proven that the proposed method was able to simply and rapidly detect 5-FU in blood samples with high sensitivity, specificity, accuracy and precision.Keywords:surface-enhanced Raman scattering (SERS);lateral flow immunochromatographic assay (LFIA);5-fluorouracil (5-FU);anticancer drug;blood samples

Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy

Yani Xu,Lan Yang,Min Li,Haozhou Shu,Na Jia,Yunzhen Gao,Rongying Shi,Xiaojia Yang,Zhirong Zhang,Ling Zhang

Osteosarcoma is usually resistant to immunotherapy and, thus primarily relies on surgical resection and high-dosage chemotherapy. Unfortunately, less invasive or toxic therapies such as photothermal therapy (PTT) and chemodynamic therapy (CDT) generally failed to show satisfactory outcomes. Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma. Herein, a simple nanocomposite that synergistically combines CDT, PTT, and chemotherapy for osteosarcoma treatment was fabricated. In this composite, small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil (5-FU) with high loading capacity. The nanospheres were then adsorbed onto larger 2D Ti 3 C 2 MXene monolayers and finally shielded by bovine serum albumin (BSA) to form 5-FU@NiFe-LDH/Ti 3 C 2 /BSA nanoplatforms (5NiTiB). Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy, NiFe-LDH driven chemodynamic effects, and MXene-based photothermal killing collectively exhibited a synergistic “all-in-one” anti-tumor effect. 5NiTiB improved tumor suppression rate from <5 % by 5-FU alone to ∼80.1 %. This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose, thereby minimizing side effects. Moreover, the composite is simple to produce, enabling the fine-tuning of dosages to suit different requirements. Thus, the platform is versatile and efficient, with potential for further development.