Polymer Chemistry
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2012
·Vol. 4
·期 4
·933-941
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IF 5.321
Fuyin Zheng,Shige Wang,Mingwu Shen,Meifang Zhu,Xiangyang Shi
Electrospun composite nanofibrous scaffolds have attracted much interest for use as drug delivery vehicles in recent years. Herein, we attempted to first encapsulate the anticancer drug doxorubicin (DOX) using inorganic rod-like nano-hydroxyapatite (n-HA) as a carrier. Then, the DOX-loaded n-HA particles were mixed with poly(lactic-co-glycolic acid) (PLGA) solution to fabricate electrospun hybrid nanofibers. The formation of drug–n-HA complexes and the drug-loaded composite nanofibers were characterized using different techniques. In vitro DOX release behavior was examined using UV-vis spectroscopy under both neutral and acidic conditions. The anticancer activity of the drug-loaded composite nanofibers was evaluated via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay and phase contrast microscopic morphology observation of a model KB cancer cell line (a human epithelial carcinoma cell line). We show that DOX can be successfully loaded onto the surface of the n-HA and the formed composite fibers have a uniform and continuous fibrous morphology. Importantly, the loaded DOX shows a sustained release profile, and the released DOX from the nanofibers displays non-compromised antitumor activity towards the growth inhibition of KB cells. With the significantly reduced burst release profile and the improved mechanical durability of the composite nanofiber system compared with n-HA-free PLGA nanofibers, the designed organic–inorganic hybrid nanofibers could be used as a versatile drug delivery system for encapsulation and sustained release of different drugs with prolonged therapeutic efficacy for different biomedical applications.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2021
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IF 6.953
Yanmei Shi,Ronghua Tan,Chan Yu,Ying Wan
Image-guided chemo-photothermal therapy based on near-infrared (NIR) theranostic agents has found promising applications in treating tumors. In this multimodal treatment, it is of critical importance to image real-time distribution of photothermal agents in vivo and to monitor therapeutic outcomes for implementing personalized treatment. In this study, an optimally synthesized dextran-polylactide (DEX-PLA) copolymer was assembled with doxorubicin (DOX) and DiR, a kind of NIR dye, to construct desirable micelles ((DiR + DOX)/DEX-PLA) for performing image-guided chemo-photothermal therapy. These (DiR + DOX)/DEX-PLA micelles had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. Based on the H22-tumor-bearing mouse model, (DiR + DOX)/DEX-PLA micelles were found to accumulate inside tumors sustainably and to emit strong fluorescence signals for more than three days. The (DiR + DOX)@DEX-PLA micelles together with NIR laser irradiation were able to highly inhibit tumor growth or even eradicate tumors with one injection and two dose-designated 5-minute laser irradiations at the tumor site during 14 days of treatment. Furthermore, they showed almost no impairment to the body of the treated mice. These (DiR + DOX)@DEX-PLA micelles have confirmative translational potential in clinical tumor therapy on account of their persistent image-guided capacity, high antitumor efficacy and good in vivo safety.
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REDOX REPORT
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2025
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IF 7.4
Fang Cheng,Minzhu Zhao,Qi Wang,Hongli Xiong,Kai Yu,Chong Chen,Ying Zhu,Yemiao Chen,Jianbo Li
Objectives Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD+ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD+ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.Methods Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD+ in DIC were investigated using a range of methods.Results Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD+ depletion. Exogenous NAD+ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD+ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD+ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.Conclusion This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD+ depletion in DIC. Targeting this axis through NAD+ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.
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ACS Applied Polymer Materials
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2025
·
IF 4.7
Chunyan Li,Linyin Xu,Yili Yin,Fengjiao Wei,Yanwei Hou,Yingyu Su,Jingya Zhao,Chenxu Lv,Tong Ren,Saifei Lv,Xue Yang,Lu Yue
Postoperative recurrence and impaired wound healing remain two critical challenges in colorectal cancer treatment. Local chemotherapy, as a promising strategy to address these issues, has attracted considerable attention. This study aimed to develop a sodium alginate (SA)-based injectable hydrogel encapsulating doxorubicin (DOX), with the dual goals of preventing postoperative colorectal cancer recurrence and promoting wound healing. The medicated hydrogel, termed DOX@OSAgel, enabled the sustained release of DOX, which effectively inhibited the proliferation of CT-26 cells and significantly suppressed tumor recurrence. Multiple lines of evidence strongly support this conclusion, including a marked reduction in tumor volumes, and a higher rate of tumor recurrence inhibition, and a substantial increase in apoptosis within CT-26 cells. Furthermore, Hematoxylin & Eosin (H&E) and Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining assays further confirmed that DOX@OSAgel effectively suppressed postoperative recurrence of CT-26 tumors. Moreover, treatment with cargo-free OSAgel resulted in smaller wound sizes, accelerated wound closure, reduced inflammatory responses, and increased microangiogenesis, which indicated that the hydrogel accelerated wound healing. Collectively, DOX@OSAgel presents a promising local chemotherapeutic platform with the dual potential to inhibit postoperative recurrence and promote wound healing in colorectal cancer treatment.
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ACS Applied Materials & Interfaces
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2024
·
IF 8.3
Yi-Fei Xue,Xiaojie Song,Xiao-Qing Ling,Qi-Yan Lv,Yu Xia,Hui-Fang Cui
Nanoassemblies based on drug conjugates with high drug loading efficiency and stability have been regarded as promising candidates for the next generation of drug formulations. However, they are mostly amphiphilic. Here, a dual-hydrophobic drug conjugate-based nanoassembly has been created for enhanced synergistic antiproliferation against colorectal cancer cells. Camptothecin (CPT) and doxorubicin (DOX) were chosen as the hydrophobic drugs and covalently linked with a disulfide bond (-ss-). The synthesized CPT-ss-DOX can self-assemble into nanocubes (NCs) in an aqueous solution with the assistance of a small amount of polyethylene glycol (PEG), named PEGylated CPT-ss-DOX NCs. The PEGylated CPT-ss-DOX NCs were approximately 111.8 nm, possessing a crystal structure and a very low critical aggregation concentration (8.36 μg·mL–1). The self-assembly mechanism was studied using molecular docking and molecular dynamic simulation methods. The NCs demonstrated excellent storage stability and improved water solubility of CPT and DOX. These NCs could be taken up by cancer cells and gradually release the drugs. In addition, they had higher toxicity to cancer cells than a mixture of CPT and DOX, while they displayed reduced toxicity to normal cells. Due to assembly and PEG modification, the NCs improved drug retention time and enhanced accumulation at the tumor site. More importantly, they significantly inhibited colorectal tumor growth (58.37%) in vivo, superior to the CPT+DOX mix (42.63%). Moreover, the NCs reduced the cardiac toxicity of free drugs. Therefore, the prepared PEGylated CPT-ss-DOX NCs hold great potential for clinical transformation and provide a novel method for the self-delivery of hydrophobic molecules in cancer therapy.
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Science China-Life Sciences
·
2026
·
IF 9.6
Ye Hanyi,Jin Wei,Feng Yifan,Wu Ze,Sun Shuhui,Cui Mengyao,Lv Shun,Jin Bing,Liu Chang,Wang Siming,Li Ying,Dong Zhengqi
Breast cancer remains a therapeutic challenge due to its high malignancy and the lack of safe and effective treatments. Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated remarkable efficacy against various malignancies by enhancing antitumor immunity when used in combination with chemotherapy. However, conventional antibody-based therapies are associated with adverse effects. Plant-derived microRNAs capable of regulating gene expression represent a highly promising alternative strategy, with substantial potential in disease treatment. In this study, we identified that miR152, a plant-derived microRNA from Taxus×media Rehder, has antitumor activity. Our results demonstrated that miR152 exerts antitumor immune activity by silencing CTLA-4 expression in regulatory T cells. Furthermore, we observed that miR152 maintains a favorable safety profile in normal cells at therapeutic doses, while eliciting direct cytotoxic effects on specific cancer cell lines at higher concentrations. In a mouse tumor model, the combination of anti-CTLA-4 miRNA with doxorubicin significantly improved the efficacy of both monotherapies. Mechanistically, miR152 augmented the antitumor immune response by reducing the proportion of Treg cells within the T-cell compartment and increasing the proportion of CD8 + cytotoxic T cells at tumor sites, enhancing the secretion of Th1- and M1-associated cytokines and suppressing interleukin-10 production. This study reveals for the first time that plant-derived miR152 may serve as a cancer immunotherapy agent in combination with a chemotherapeutic drug to inhibit cancer growth in mammals.
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Biology Direct
·
2026
·Vol. 21
·期 1
·113
·
IF 5.5
Wang Wei,Hu Yuanyuan,Xu Yan,Ding Ning,Wei Jiping,Li Cairong,Chen Yong
Background Doxorubicin (DOX) is a widely used broad-spectrum chemotherapy drug, but its severe organ toxic and side effects limit its clinical application. Tetrahydropalmatine (THP) protects against DOX-induced renal injury, yet its underlying mechanism remains unclear. This study aimed to verify THP’s protective effect and explore if it acts via the SIRT3-mediated Nrf2/HO-1 signaling pathway. Methods This study adopted an integrated in vivo and in vitro research system to explore the relevant mechanisms. In vivo, a DOX-induced mouse renal injury model was established with THP intervention; renal function was evaluated by detecting serum creatinine (Scr) and blood urea nitrogen (BUN), while renal injury severity was assessed via urine microalbumin (mALB) and urine albumin/creatinine ratio (UACR). Renal histopathological changes including glomerular injury and tubulointerstitial fibrosis were observed, and subcellular structures such as podocyte integrity and mitochondrial morphology were analyzed by transmission electron microscopy (TEM); additionally, the expression of pathway-related proteins was detected. In vitro, a DOX-induced cell injury model was constructed using mouse podocytes (MPC-5), and Western blot and immunofluorescence techniques were employed to determine the expression of key molecules in the Sirt3-Nrf2/HO-1 pathway, combined with in vivo and in vitro experiments to clarify the underlying mechanism. Results THP significantly attenuated DOX-induced renal injury, improved renal function (reduced Scr/BUN), mitigated histopathological/mitochondrial abnormalities, and preserved podocyte integrity. Molecularly, THP upregulates podocyte markers Nephrin/Podocin, enhances antioxidant capacity (increased GSH, SOD, and CAT, decreased MDA), inhibits inflammation (downregulated IL-6, IL-1β, and TNF-α), and suppresses apoptosis (downregulated Bax/caspase-3, upregulated Bcl-2). Notably, both in vivo and in vitro data link THP’s protection to SIRT3-mediated Nrf2/HO-1 pathway activation. Conclusion THP protects against DOX-induced renal injury in mice. Mechanistically, this may involve activating the SIRT3-mediated Nrf2/HO-1 pathway, improving podocyte function, and inhibiting oxidative stress, inflammation, and apoptosis.
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NEW JOURNAL OF CHEMISTRY
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2026
·
IF 2.6
Liezhi Cao,Qiang Gao,Xiaoming Zuo,Yong Kong,Haiying Chen
Iron-based metal organic framework (Fe-MOF) is first synthesized by using tetra(4-carboxyphenyl)-porphyrin (TCPP) as the organic building blocks, which is then co-encapsulated with doxorubicin (DOX) in the oxidized sodium alginate (OSA)/carboxymethyl chitosan (CMCS) hydrogels cross-linked through the Schiff base reaction. The imine bonds (–HC=N–) between OSA and CMCS can be hydrolyzed in the acidic tumor microenvironment (TME), resulting in the release of DOX and Fe-MOF. The Fe-MOF can be further decomposed by the acidic TME to release TCPP and Fe3+. Oxygen molecules are catalyzed to singlet oxygen (1O2) by the photosensitizer TCPP upon exposure to near infrared (NIR) light, and the generated 1O2 can bring about photodynamic therapy (PDT). Additionally, the released Fe3+ can be reduced to Fe2+ by glutathione (GSH), which can react with H2O2 in the TME through the Fenton reaction to generate hydroxyl radicals (·OH) for chemodynamic therapy (CDT). Due to the synergistic therapy of PDT, CDT and chemotherapy, the Fe-MOF/DOX/OSA/CMCS hydrogels exhibit significant cytotoxicity against murine breast cancer cell line 4T1.
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2025
·
IF 3.1
Chenchen Jiang,Siqi Chen,Min Huang,Xiaojiao Yi,Haiying Ding,Junfeng Zhu,Luo Fang
Doxorubicin (DOX) is an effective chemotherapeutic agent, but its use is limited by dose-dependent cardiotoxicity. Palmatine (PAL) has shown potential in preventing doxorubicin-induced cardiotoxicity (DIC); however, the underlying mechanism remains unclear. Since DOX accumulation in cardiomyocytes is a key factor in the development of cardiotoxicity, this study aims to explore the pharmacokinetic mechanisms through which PAL alleviates DIC. First, the effect of PAL on DIC was assessed based on H9c2 cardiomyocytes model using sulforhodamine B (SRB), lactate dehydrogenase (LDH), flow cytometry and Western blot assays, which demonstrated that PAL significantly attenuated DOX-induced cardiac toxicity and apoptosis. Second, a sensitive and efficient LC–MS/MS method was established to quantify DOX in H9c2 cells, with a lower limit of quantification of 10 nM and a total run time of 4 min per sample. Cellular pharmacokinetic study revealed that PAL significantly reduced DOX concentration in H9c2 cells. Finally, molecular docking analysis revealed that PAL exhibited low binding energies and formed hydrogen with uptake transporter proteins involved in DOX transport in cardiomyocytes, including organic cardi transporter (OCT) 1, OCT3, organic cation/carnitine transporter (OCTN) 1, OCTN2, and plasma membrane monoamine transporter (PMAT). This suggests a stable interaction between PAL and these transporters. In conclusion, PAL alleviates DIC, most likely by reducing myocardial DOX accumulation through the inhibition of uptake transporters. This study provides novel pharmacokinetic insights into the mechanism by which PAL mitigates DIC and underscores its potential as a complementary therapeutic agent in combination with DOX in clinical applications.
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JOURNAL OF BIOMATERIALS APPLICATIONS
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2018
·
IF 2.082
Hongying Su,Wen Zhang,Yayun Wu,Xiaodong Han,Gang Liu,Qingming Jia,Shaoyun Shan
Stimuli-responsive hydrogels have been widely researched as carrier systems, due to their excellent biocompatibility and responsiveness to external physiologic environment factors. In this study, dextran-based nanogel with covalently conjugated doxorubicin (DOX) was developed via Schiff base formation using the inverse microemulsion technique. Since the Schiff base linkages are acid-sensitive, drug release profile of the DOX-loaded nanogel would be pH-dependent. In vitro drug release studies confirmed that DOX was released much faster under acidic condition (pH 2.0, 5.0) than that at pH 7.4. Approximately 66, 28, and 9% of drug was released in 72 h at pH 2.0, 5.0, and 7.4, respectively. Cell uptake by the human breast cancer cell (MCF-7) demonstrated that the DOX-loaded dextran nanogel could be internalized through endocytosis and distributed in endocytic compartments inside tumor cells. These results indicated that the Schiff base-containing nanogel can serve as a pH-sensitive drug delivery system. And the presence of multiple aldehyde groups on the nanogel are available for further conjugations of targeting ligands or imaging probes.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
·
IF 6
Yanxia Wang,Yue Dou,Huan Chen,Jianhong Qi,Pei Zhou,Yu Ding,Wei Zhou
A novel CHP-based carrier targets HCC via cholesterol-mediated uptake. • CHP enables ER-specific drug delivery through cholesterol-mediated transport. • ER-targeted delivery of doxorubicin via CHP enhances immunogenic cell death and reduces cardiotoxicity. Severe endoplasmic reticulum stress (ERS) activates ER autophagy and related apoptotic pathways, promoting cell death, a characteristic that has been applied in cancer treatment. Targeted delivery of immunogenic cell death (ICD) inducers, such as doxorubicin (DOX), to the ER can significantly enhance ERS and induce ICD in cells, thereby activating the body’s anti-tumor immune response and effectively killing cancer cells. Based on the cholesterol metabolism and intracellular transport characteristics of Hepatocellular carcinoma (HCC) cells, this study designed a nanoparticle delivery system using cholesterol phosphate conjugates (CHP) as carriers for the delivery of DOX (DOX@HCCP). The results show that DOX@HCCP exhibits an endocytosis pathway similar to that of cholesterol, characterized by a high dependence on energy. The endocytosis pathways primarily involve caveolin-mediated endocytosis, macropinocytosis, and clathrin-mediated endocytosis, followed by lysosomal escape to the ER via the cholesterol-mediated intracellular transport pathway. The targeted delivery of DOX to the ER induces strong ERS, effectively triggers cell apoptosis, and promotes ICD, significantly activating the body’s anti-tumor immune response, thereby enhancing the anti-tumor effects. Download: Download high-res image (158KB) Download: Download full-size image
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Autophagy
·
2026
·
IF 18.6
Yiping Shi,Long Chen,Yuxiao Feng,Jingtao Liu,Wendi Wu,Yawei Jin,Huan Tong,Yijie Huang,Yiming Li,Zhaokuan Li,Guo Zhou,Ben He,Yu Wang,Qin Shao
Doxorubicin is a widely used chemotherapeutic agent, but its clinical application is hindered by severe cardiotoxicity. Among immune cells, Cx3cr1+ macrophages have emerged as key regulators of cardiovascular disease, with their development and maturation tightly controlled by CSF1R (colony stimulating factor 1 receptor). Using multi-omics sequencing, we observed a marked expansion of Cx3cr1+ macrophages in doxorubicin-induced cardiomyopathy, yet their precise functional role in this pathological process has remained elusive. This study employed various genetically modified mouse models, including cell depletion models, lineage tracing models, and conditional gene knockout models targeting Cx3cr1+ macrophages, alongside transcriptomic sequencing, proteomic profiling, and multi-level in vivo and in vitro experiments to elucidate the role and mechanisms of Cx3cr1+ macrophages and their receptor CSF1R in doxorubicin-induced cardiac injury. We found that Cx3cr1+ macrophages are significantly enriched in hearts affected by doxorubicin-induced cardiomyopathy, and their depletion notably improves cardiac function. Further investigation revealed that in these macrophages, CSF1R competitively binds to the E3 ubiquitin ligase NEDD4, thereby inhibiting the ubiquitination and degradation of PARP1. This process promotes inflammasome activation and pyroptosis, driving massive IL1B secretion. IL1B directly suppresses cardiomyocyte mitophagy, disrupts energy metabolic homeostasis, and ultimately leads to cardiac dysfunction. Notably, the use of the CSF1R inhibitor PLX3397 or an IL1B-neutralizing antibody effectively halted these pathological processes and significantly improved cardiac function. In summary, this study unveils a novel mechanism through which Cx3cr1+ macrophages regulate cardiomyocyte function via the CSF1R-PARP1-IL1B-mitophagy signaling axis, providing a new theoretical foundation and intervention strategy for doxorubicin-induced cardiomyopathy targeted therapy.Abbreviations: BMDM: bone marrow-derived macrophages; CKMB: creatine kinase MB isoenzyme; CSF1R: colony stimulating factor 1 receptor; csf1r-cKO: csf1r conditional knockout; DIC: doxorubicin-induced cardiomyopathy; DOX: doxorubicin; HE: hematoxylin and eosin; HW:TL: heart weight:tibial length; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtuble-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; TNNT2/cTnT: troponin T2, cardiac; WGA: wheat germ agglutinin.
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