Asian Journal of Pharmaceutical Sciences
·
2026
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IF 12.6
Min Liu,Xin Hu,Siyi Liu,Jingya Xiu,Dan Li,Jiulong Zhang,Xiuli Zhao
Nanomedicines have been constructed to enhance the efficacy and safety of traditional anti-cancer drugs. However, the clinical translation of these nanomedicines was hindered by the complexity of carrier materials and functional integration. In this study, a carrier-free nanomedicine composed of doxorubicin (DOX), Cu 2+ and siRNA of GPX4 was constructed for combination therapy of tumors. DOX, Cu 2+ , and siRNA were assembled through multiple forces and decorated with hyaluronic acid (HA) to prepare tumor targeted carrier-free nanomedicines (HDCS). The HA coating on the surface of HDCS ensured specific tumor targeting, and the released drugs triggered by acidity could eliminate tumor cells. The nanomedicine showed significant anti-cancer efficiency and quite reduced side effects in the breast cancer model when compared with DOX solution. HDCS treatment led to significant accelerated production of ROS, reduced GPX4 expression, and sustained decrease in GSH at tumor sites, ultimately forming a powerful chemodynamic effect enhancing circuit. The HDCS provides an effective strategy for tumor combination therapy with good clinical translation and application potential.
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iScience
·
2026
·Vol. 29
·期 4
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IF 4.5
Chuanchuan He,Shuaizhi Kong,Jie Zhang,Lihua Chen,Guoqing Zhang,Limin Jin,Xiaojuan Zhang,Baoyue Ding
Efficient completion of the CAPIR (circulation, accumulation, penetration, internalization, and release) cascade is essential for nanosystems to achieve satisfactory therapeutic efficacy and prognosis. Herein, we fabricated a manganese dioxide (MnO 2 )-coated cationic liposomal nanocarrier (MnO 2 @CLDOX) for enhanced doxorubicin (DOX) delivery via a multistage strategy. The anionic MnO 2 shell conferred negative zeta potential, enabling prolonged blood circulation and reduced systemic toxicity. In the tumor microenvironment, MnO 2 selectively decomposed under acidic pH and high hydrogen peroxide, exposing cationic CLDOX and generating O 2 . Cationic CLDOX facilitated cellular uptake via electrostatic interactions with tumor cell membranes. Meanwhile, O 2 alleviated tumor hypoxia, downregulated hypoxia-inducible factor-1 α , decreased collagen deposition, and improved extracellular matrix permeability, thus boosting drug penetration. Collectively, MnO 2 @CLDOX enhanced DOX delivery efficiency through synergistic mechanisms, achieving superior therapeutic efficacy against breast cancer.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
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IF 8
Xie-Huang Sheng,Lin-Song Teng,Xin-Hui Wang,Li-Qi Jiang,Xue-Cheng Sun,Jin-Long Mao,Lei Zhang
Cardiovascular diseases arise from intertwined cell-death and stress-response pathways, underscoring the need for therapeutics that extend beyond single-target mechanisms. Seeking drug-repurposing opportunities within existing cardiovascular agents, we screened clinically explored compounds for unrecognized cytoprotective activity and identified the hERG/Kv11.1 activator NS-1643—originally developed as an antiarrhythmic candidate—as a potent ferroptosis inhibitor. NS-1643 broadly suppressed GPX4 inhibitor–induced ferroptotic death across diverse cell types, whereas other hERG modulators were inactive, and neither pharmacologic blockade nor genetic silencing of hERG altered its efficacy, demonstrating that its protective mechanism is independent of ion-channel modulation. Mechanistic profiling showed that NS-1643 does not restore canonical ferroptosis-defense systems, but instead operates as a direct lipid-peroxyl radical trapper, supported by radical-scavenging assays and density functional theory revealing an energetically favorable hydrogen-atom transfer mediated by its ortho-amino–phenolic motif. In a murine model of doxorubicin (DOX) cardiotoxicity, NS-1643 markedly improved survival, preserved systolic performance, and reduced myocardial injury, fibrosis, and 4-HNE accumulation, whereas the comparator hERG agonist NS-3623 conferred no benefit. These findings reposition NS-1643 as a dual-mechanism, ferroptosis-targeting cardioprotective agent and illustrate how drug repurposing can reveal multi-target therapeutic potential within existing cardiovascular chemical space, offering a promising strategy to mitigate anthracycline-induced cardiac injury.
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2026
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IF 5
Yulong Yan,Jing Shi,Zhenqiao Zheng,Xiaojing Shi,Xubo Zhao
Conventional nanocarriers often face challenges of insufficient tumor specificity and poor cellular internalization. To overcome these limitations, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. Doxorubicin (DOX) was covalently conjugated to oxidized HA via a pH-sensitive imine bond, while a charge-reversal polymer (PLL-DMMA) was grafted onto the HA backbone. This design enables CD44-mediated active targeting toward cancer cells. Crucially, the nanoplatform exhibits a smart charge-reversal characteristic: maintaining a negative surface charge (−32.8 mV) at physiological condition (pH 7.4) for extended circulation, while switching to positive (+16.5 mV) in the acidic tumor microenvironment (pH 6.5) to enhance cellular uptake. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. The release profile showed high stability at pH 7.4 (<5% release in 5 days) and rapid drug release at endo/lysosomal pH (61.6% at pH 5.0). Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC 50 values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery. In this study, we developed an all-in-one prodrug nanoplatform based on hyaluronic acid (HA) that synergistically integrates active targeting, pH-responsive charge reversal, and controlled drug release. In vitro studies demonstrated significantly improved internalization in CD44-overexpressing MKN-45 cells compared to SNU-216 cells with low CD44 expression. Cytotoxicity assays confirmed enhanced efficacy of the charge-reversed formulation, with lower IC50 values in both cell lines. This multifunctional prodrug nanoplatform represents a promising strategy for precision cancer chemotherapy through synergistic enhancement of tumor targeting and intracellular drug delivery. Download: Download high-res image (132KB) Download: Download full-size image
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BMEMat
·
2026
·
IF 17.2
Xingzhou Peng,Wei Chen,Shuyu Li,Xiaomin Ma,Yanfeng Dai,Yan Wang,Changqiang Xie,Yazhe Xiao,Hesong Han,Yumiao Zhang,Junjie Wang
Cancer therapeutic efficacy is significantly influenced by tumor immunosuppressive environment possibly induced by chemotherapy-mediated tumor-intrinsic programmed death-ligand 1 (PD-L1) upregulation or tumor-associated macrophages (TAMs) promoting additional PD-L1 expression on tumor cells through distinct paracrine signaling pathways. To overcome this dual resistance mechanism, we developed a hyaluronic acid-functionalized nanoplatform for co-delivering DOX and nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP), termed HA-DS@PLGA. This system facilitates dual targeting of CD44-overexpressing tumor cells and TAMs via HA-mediated recognition while the PLGA core ensures sustained release of both agents. SNAP-derived NO effectively attenuates DOX-induced PD-L1 expression through NO-mediated signaling disruption while synergistically potentiating DOX's immunogenic cell death effects. In TAMs, the system synergistically eliminates M2 macrophages and reprograms residual macrophages toward the tumoricidal M1 phenotype via PI3K-AKT signaling. In 4T1-tumor-bearing mouse models, HA-DS@PLGA achieved 95.8%, 94.5%, and 88.4% tumor inhibition versus PBS, HA-S@PLGA (SNAP alone), and HA-D@PLGA (DOX alone), respectively. Meanwhile, HA-DS@PLGA elicited systemic immunity, as evidenced by enhanced dendritic cell maturation, increased cytotoxic T lymphocyte infiltration, elevated IFN-γ production, and downregulation of PD-L1. By simultaneously targeting tumor-intrinsic and microenvironment-mediated immunosuppression, HA-DS@PLGA overcomes multifaceted resistance mechanisms and amplifies antitumor immunity, offering a promising paradigm for combinatorial cancer nanomedicine.
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International Journal of Pharmaceutics-X
·
2025
·
IF 6.4
Junxia Gao,Wenhui Zhang,Qiang Wang,Jingdan Cao,Ying Zhu,Guifang Liu,Youbiao Jia,Fengbo Yu
To mitigate the adverse effects of doxorubicin (DOX) during the treatment of liver cancer, this study aimed to develop a novel DOX-encapsulated active-targeted nanodelivery system. The auxiliary materials hydroxyapatite (HAP), polysuccinimide (PSI), galactose-modified polyethylene glycol (Gal-PEG), PSI covalently linked with three different mole ratios of polyethylene glycol (PEG-PSIs), and galactose covalently linked with PEG-PSIs (Gal-PSIs) were synthesized and structurally characterized. The Box-Behnken and Three-Level Factorial Design response surface methodologies were employed to optimize the formulations and synthesis protocols for DOX@HAP/PSI (DOX@DC, where DC denotes the drug carrier), DOX@PEG-DCs, and DOX@Gal-DCs. The in vitro drug release and in vivo tissue distribution of each formulation were examined. Furthermore, in vitro studies were conducted to examine the effects of these formulations on the proliferation, apoptosis, and migration of Huh-7 liver cancer cells. The formulations and synthesis protocols for different DOX-based preparations were optimized. All nanoparticles gradually released DOX at pH levels >5, with the release rate increasing with the pH value. Among the tested formulations, DOX@Gal-DC20 (mole ratio of Gal-PEG to PSI = 1:20) showed the best hepatic targeting in mice in vivo. Furthermore, in vitro pharmacodynamic experiments indicated that Gal-DC20 had low cytotoxicity, could be taken up by cancer cells, and could significantly inhibit the proliferation of Huh-7 cells. Hemolysis experiments confirmed that none of the prepared formulations induced hemolysis. The novel nanodelivery system established in the study (DOX@Gal-DC) is simple to prepare and shows significant hepatic targeting.
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CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Yating Lian,Junyi Zhou,Wei Li,Zhijie Yuan,Minghui Zhong,Tian Wei,Huishan Liang,Shicong Yang,Li Ding,Li-Ming Zhang,Fen Wang
Chemoresistance is the main cause of recurrence and metastasis in osteosarcoma patients; therefore, efficient therapeutic measures need to be developed to reverse chemoresistance. In this study, we designed and synthesized selenium-hybrid degradable hollow mesoporous silica nanoparticles (SeNPs) to simultaneously encapsulate doxorubicin (DOX) and carbon monoxide (CO)-releasing molecule-3 (CORM-3), and modified their surfaces with polyethylene glycol (PEG) via disulfide bonds (SeNP-PEG@DOX-CO). Subsequently, after incubation with SeNP-PEG@DOX-CO, DOX was effectively delivered into 143B cells, and CO was released in the mitochondria under the stimulation of high concentrations of glutathione (GSH) and reactive oxygen species (ROS). All in vitro anticancer functional experiments and animal experiments confirmed that DOX had CO-enhanced antitumor efficacy and that CO cooperated with chemotherapeutic drugs to resist tumors. Meanwhile, we provided for the first time a combined proteomic and metabolomic landscape of CO reversing chemotherapy resistance in osteosarcoma. This study revealed a revolutionizing osteosarcoma therapy to treat resistance for chemotherapy.
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Nano Today
·
2026
·
IF 10.7
Hongkai Fang,Jingxuan Zhang,Jialin Xing,Yuebin Dai,Yanzhong Hao,Wenjing Wang,Zhiyu Kuang,Mingyang Han,Zhonggui He,Bingjun Sun,Jin Sun
Albumin-based nanoparticle (ANP) drug delivery systems have achieved significant clinical success. However, the low affinity between Doxorubicin (DOX) and human serum albumin (HSA) hinders the formation of stable nanoparticles. In our studies, we initially conjugated DOX to disulfide bond-containing fatty alcohols via carboxamide bond to systematically evaluate the impact of carbon chain length (C4, C8, C12, C20) on the binding affinity between DOX and HSA. Notably, when the carbon chain length of fatty alcohols reached eight (C8), DOX exhibited strong binding affinity to HSA. However, these prodrugs exhibited weak cytotoxicity, indicating insufficient DOX release due to the stable carboxamide bond. To address this issue, we further replaced the stable carboxamide bond with relative active carbamate bond (DOX-OCO-C 8 ). Under high glutathione (GSH) conditions in tumor cells, DOX-OCO-C 8 ANPs exhibited accelerated hydrolytic activity and efficient release of DOX. The ANPs significantly improved the pharmacokinetic profile and antitumor efficacy of DOX while reducing systemic toxicity. Our findings suggested optimizing alkyl chain lengths and linker chemistry offers a promising strategy for developing effective and safe DOX prodrug ANPs.
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Experimental and Therapeutic Medicine
·
2026
·Vol. 32
·期 2
·1-16
·
IF 2.2
Hongchen Jin,Huasong Bai,Tong Liu,Hengyan Wang,Yunliang Li,Zhanzhong Wang
Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
·
IF 5.2
Xia Cao,Zhangxintian Ding,Yize Lv,Xuedi Weng,Hongran Huang,Jinghan Li,Ximing Xu,Qilong Wang
The clinical treatment of melanoma is severely limited by the rapid development of intrinsic and acquired resistance to conventional chemotherapeutic drugs, such as doxorubicin (DOX), as well as their severe, dose-limiting systemic toxicities. To address this issue, we developed a novel nanoplatform for near-infrared (NIR)- activatable nanoplatform leveraging microfluidics as a precision fabrication tool to overcome the limitations of conventional nanocarrier synthesis, including poor batch-to-batch reproducibility, heterogeneous size distribution, and suboptimal drug co-loading. A photocrosslinkable copolymer, Pluronic F127 diacrylate (F127DA), was synthesized and processed using a custom-designed dual-zone microfluidic chip that integrates sequential flow-focusing and turbulent mixing. This approach enabled the one-step, highly controlled co-encapsulation of DOX and indocyanine green (ICG) into monodisperse F127DA nanoparticles (43.9 ± 0.6 nm, polydispersity index: 0.18) with superior encapsulation efficiency (DOX: 60.4%) and drug loading (12.8%). Upon NIR irradiation, the resulting DOX/ICG@F127DA nanoparticles mediated synergistic chemo-photothermal-photodynamic therapy, as evidenced by potent cytotoxicity (melanoma cell viability reduced to 35%), a significant 3.1-fold increase in reactive oxygen species (ROS) generation, and effective inhibition of cell migration (wound closure rate of 17.2% compared to 21.7% with free DOX). Mechanistically, the NIR-triggered ROS burst induced mitochondrial-mediated apoptosis by dysregulating the Bax/Bcl-2 ratio (increased by 2.7-fold), culminating in an apoptosis rate of up to 68.3%. Collectively, this work establishes microfluidics as a robust and scalable platform for engineering complex nanomedicines and delineates the “NIR light–ROS–Bax/Bcl-2” axis as a critical molecular pathway for overcoming chemoresistance in melanoma. Download: Download high-res image (231KB) Download: Download full-size image
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COLLOID AND POLYMER SCIENCE
·
2023
·Vol. 301
·期 8
·879-891
·
IF 2.4
Li Danyang,Xu Wenshuang,Liu Hui
Stimuli-responsive hydrogel could respond rapidly to environmental changes, whereas the limitation of gel scale usually led to a single route of drug delivery and restricted application. Herein, a pH and temperature dual responsive nanogel CS/P(MAA-co-NIPAM) was successfully prepared by radical polymerization. The change of both turbidity and hydration diameter at different conditions indicated that the nanogel possessed obvious pH and temperature sensitive properties. Specifically, the hydration diameters of the nanogel were 234 nm at T = 20 °C and 145 nm at T = 45 °C. The schematic flowable characteristic by injection experiment indicated that CS/P(MAA-co-NIPAM) might have the potential application possibility of injectable drug delivery. In addition, with doxorubicin as the model drug, the drug loading efficiency of the nanogel was 84.00% and the maximum release efficiency reached 66.30% at pH = 2.0 & T = 20 °C. The nanogel was able to realize drug delivery process in physiological environment according to in-vitro controlled releasing experiments.
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Cancers
·
2023
·Vol. 15
·期 6
·1724
·
IF 5.2
Khalil Ur Rahman,Shuo Yang,Nasir Azam,Zhen Yuan,Jiawen Yu,Chunhui Zhao,Bin Feng
Simple SummaryBreast cancer is a disease that begins in the cells of the breast. Although it is most common in women, it can also occur in men, though this is rare. Early detection and treatment are crucial to improving outcomes and survival rates. Risk factors include age, family history, certain gene mutations, prior history of breast cancer, exposure to estrogen, and lifestyle habits like alcohol consumption and inactivity. Symptoms include changes in the skin on the breast, such as dimpling, lumps or thickening, changes in size or shape, and discharge from the nipple. Diagnosis is often made through a clinical breast exam, mammogram, biopsy, and possibly additional imaging tests. Treatment options include surgery, chemotherapy, radiation therapy, hormone therapy, and targeted therapy. The choice of treatment method depends on the stage and characteristics of cancer.AbstractBreast cancer is considered the solid tumor most sensitive to chemotherapy. However, it can become resistant to various chemotherapeutic drugs, including doxorubicin, which triggers cell death by intercalation between DNA bases, free radical formation, and topoisomerase II inhibition. When drug resistance develops, several miRNAs are dysregulated, suggesting that miRNAs may play a significant role in resistance formation. In the current study, we investigated how doxorubicin sensitivity of breast cancer cells is affected by miR-153-3p and its target gene. The MTT method was used to determine the chemo-sensitizing effect of miR-153-3p on doxorubicin in MCF-7 and MDA-MB-231 cell lines. Results of Western blot and dual luciferase confirmed that miR-153-3p targets KIF20A and decreases its expression. Transwell and flow cytometry experiments showed that miR-153-3p and doxorubicin together had higher effects on MCF-7 and MDA-MB-231 cell proliferation, migration, and invasion, as well as increasing apoptosis and arresting cells in the G1 phase. Proteins related to apoptosis and the cell cycle exhibited the same tendency. Intracellular vesicle formation was inhibited and RAB26 was also downregulated by treatment with miR-153-3p alone or in combination with doxorubicin. Doxorubicin’s ability to suppress tumors may be enhanced by miR-153-3p, according to in vivo studies. According to our findings, miR-153-3p has a direct effect on KIF20A and may regulate the formation of intracellular vesicles, which in turn makes breast cancer cells more susceptible to doxorubicin.Keywords:miR-153-3p;chemosensitivity;breast cancer;doxorubicin;KIF20A
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