International Journal of Nanomedicine
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2023
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IF 8
Conglian Yang,Tingting Wu,Yuting Qin,Yan Qi,Yu Sun,Miao Kong,Xue Jiang,Xianya Qin,Yaqi Shen,Zhiping Zhang
Background Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns.Methods An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor.Results Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG2000, leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model.Conclusion This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.
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Theranostics
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2020
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IF 8.579
Liu Xu,Yutong Wang,Chenqi Zhu,Shujing Ren,Yurou Shao,Li Wu,Weidong Li,Xiaobin Jia,Rongfeng Hu,Rui Chen,Zhipeng Chen
Rationale: Both spatial accuracy and temporal persistence are crucial in drug delivery, especially for anti-tumor intravenous nanomedicines, which have limited persistence due to their small particle sizes and easy removal from tumors. The present study takes advantage of morphological transformation strategy to regulate intravenous nanomedicines to display different sizes in different areas, achieving high efficient enrichment and long retention in lesions. Methods: We designed and synthesized functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) consisting of self-assembled doxorubicin-peptide conjugates (DPCs) and an acidic-responsive shielding layer named the functional polylysine graft (FPG), which can regulate the assembly morphology of the DPCs from spherical DPC nanoparticles (DPC-NPs) to DPC-nanofibers (DPC-NFs) by preventing the assembly force from π-π stacking and hydrogen bond between the DPC-NPs. The morphology transformation and particle changes of FDPC-NPs in different environments were determined with DLS, TEM and SEM. We used FRET to explore the enhanced retention effect of FDPC-NPs in tumor site in vivo . HPLC-MS/MS analytical method was established to analyze the biodistribution of FDPC-NPs in H22 hepatoma xenograft mouse model. Finally, the antitumor effect and safety of FDPC-NPs was evaluated. Results: The FDPC-NPs were stable in blood circulation and responsively self-assembled into DPC-NFs when the FDPC-NPs underwent the acid-sensitive separation of the shielding layer in a mildly acidic microenvironment. The FDPC-NPs maintained a uniform spherical size of 80 nm and exhibited good morphological stability in neutral aqueous solution (pH 7.4) but aggregated into a long necklace-like chain structure or a crosslinked fiber structure over time in a weakly acidic solution (pH 6.5). These acidity-triggered transformable FDPC-NPs prolonged the accumulation in tumor tissue for more than 5 days after a single injection and improved the relative uptake rate of doxorubicin in tumors 31-fold. As a result, FDPC-NPs exhibited a preferable anti-tumor efficacy and a reduced side effect in vivo compared with free DOX solution and DOX liposomes. Conclusions: Morphology-transformable FDPC-NPs represent a promising therapeutic approach for prolonging the residence time of drugs at the target site to reduce side effect and enhance therapeutic efficacy. Our studies provide a new and simple idea for the design of long-term delivery systems for intravenous chemotherapeutic drugs.
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LANGMUIR
·
2018
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IF 3.789
Weifeng Lin,Guanglong Ma,Zhefan Yuan,Haofeng Qian,Liangbo Xu,Elie Sidransky,Shengfu Chen
Much attention has been drawn to targeted nanodrug delivery systems due to their high therapeutic efficacy in cancer treatment. In this work, doxorubicin (DOX) was incorporated into a zwitterionic arginyl–glycyl–aspartic acid (RGD)-conjugated polypeptide by an emulsion solvent evaporation technique with high drug loading content (45%) and high drug loading efficiency (95%). This zwitterionic nanoformulation showed excellent colloidal stability at high dilution and in serum. The pH-induced disintegration and enzyme-induced degradation of the nanoformulation were confirmed by dynamic light scattering and gel permeation chromatography. Efficient internalization of DOX in the cells and high antitumor activity in vitro was observed. Compared with the free drug, this nanoformulation showed higher accumulation in tumor and lower systemic toxicity in vivo. The DOX-loaded zwitterionic RGD-conjugated polypeptide vesicles show potential application for targeted drug delivery in the clinic.
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Communications Biology
·
2026
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IF 5.8
Gu Qingqing,Chen Qianwen,Deng Ye,Deng Li,Huang Jianya,Wang Jingyi,Ji Yuan,Wang Ruxing,Wang Qingjie,Sun Ling
Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application is limited by cardiotoxicity. Mitochondrial dysfunction and apoptosis are key mechanisms underlying DOX-induced cardiomyopathy (DIC), while the role of telomerase reverse transcriptase (TERT) and its specific regulatory mechanisms remain unclear. An in vitro DOX-induced H9C2 cardiomyocyte injury model was established. TERT was overexpressed via adenoviral transfection or inhibited using BIBR1532. An in vivo mouse model of DOX-induced acute myocardial injury was constructed, with TERT expression regulated via intramyocardial adenoviral injection. Cardiac function was evaluated by echocardiography, and myocardial pathology was observed via staining. Additionally, exosome-encapsulated growth differentiation factor 15 (EXO-GDF15) was extracted and identified. Its regulatory mechanism on TERT was explored using DNA pull-down and luciferase reporter gene assays. Metabolomics was used to analyze the effect of TERT on mitochondrial metabolites in cardiomyocytes. TERT overexpression reduced DOX-induced apoptosis, increased mitochondrial membrane potential, and promoted autophagy in cardiomyocyte. In mice, TERT overexpression improved cardiac function and alleviated myocardial fibrosis, inflammation, and cardiomyocyte hypertrophy. Conversely, TERT inhibition exacerbated these injuries. EXO-GDF15 could be endocytosed by cardiomyocytes and alleviated DOX-induced myocardial injury by downregulating SUB1 to promote TERT transcription. Luciferase reporter assays showed that SUB1 binds to the BS4 site of the TERT promoter. Metabolomics showed that TERT increased the mitochondrial metabolite thiamine pyrophosphate (TPP) in cardiomyocytes, which alleviated myocardial injury by participating in the tricarboxylic acid cycle. EXO-GDF15 alleviates doxorubicin-induced cardiotoxicity via the SUB1/TERT/TPP signaling axis, thereby providing advanced insights for future DIC treatment.
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Yiwen Li,Fulin Ye,Lei Qu,Jialin Duan,Liangliang Kong,Guangfeng Liu,Chunming Yang,Na Li,Xiaohui Wei
The clinical success of PEGylated liposomal doxorubicin (DOX) is fundamentally attributed to its unique internal nanocrystalline structure. However, a notable discrepancy exists between the rapid drug uptake predicted by loading kinetics and the extended incubation times employed in actual manufacturing. By integrating in situ time-resolved synchrotron small-angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM), and in vitro release kinetics analysis, this study systematically elucidates the multi-step structural evolution and formation mechanism of DOX-sulfate nanocrystals during remote loading via the ammonium sulfate gradient method, along with its correlation with the final functional performance of the formulation. Our results demonstrate that the rapid drug uptake and achievement of target encapsulation efficiency (EE%) do not necessarily indicate the formation of a mature, stable nanocrystalline structure. Instead, during a critical post-loading maturation stage, the intraliposomal nanocrystals undergo gradual lattice optimization into a thermodynamically stable structure. Liposomes containing “sub-mature” aggregates exhibit pronounced burst leakage, whereas those with fully matured nanocrystals ensure near-zero-order release kinetics and superior stability. These observations provide useful insights that may inform future process optimization and offer a potential basis for structural quality control of liposomal nanodrugs. Download: Download high-res image (170KB) Download: Download full-size image
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BIOMACROMOLECULES
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2026
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IF 5.4
Yunan Yuan,Jiaxuan Yang,Yijun Wu,Fujiang Li,Yan Rong,Huayu Tian,Chaoliang He
Chemo-immunotherapy has been an emerging synergistic strategy for melanoma treatment. However, major challenges still remain, including side effects of chemotherapeutic agents and insufficient efficacy of immunotherapy. In the present work, we designed a thermosensitive polypeptide hydrogel-based drug delivery system to achieve the codelivery of doxorubicin (DOX) and a Toll-like receptor (TLR)-9 agonist, CpG. The hydrogel system was engineered by incorporating cancer cell membrane enveloped hollow mesoporous silica loaded with DOX and the mPEG-ss-PEI/CpG nanocomplex, resulting in an enhanced therapeutic effect. Drug-loaded hydrogel system exhibited sustained drug release, enhanced immune cell activation, and induction of immunogenic cell death (ICD) of tumor cells. In vivo antitumor studies revealed that the drug-loaded hydrogel effectively inhibited tumor growth, and promoted expansion of CD8+ T cells and maturation of dendritic cells (DCs), facilitating favorable modulation of the tumor microenvironment. Hence, the developed drug-loaded hydrogel system has considerable potential as a platform for combinatorial chemo-immunotherapy in melanoma treatment.
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Pharmaceutics
·
2026
·Vol. 18
·期 7
·796
·
IF 6.9
Yijie Li,Chuan Chen,Yuxin Feng,Jiahe Zou,Yuqiao Qi,Weidong Huang,Yuekang Xu,Jinyao Li
Background/Objectives: In situ vaccines that directly release endogenous tumor antigens in situ to elicit anti-tumor immune responses without exogenous antigen preparation have emerged as a promising cancer immunotherapy strategy, due to their enhanced safety by local immunization that minimizes systematically adverse reactions. However, the anti-tumor efficacy of most in situ vaccines is affected by their limited access to tumors in distant sites and the toxicity of the adjuvants contained.Methods: To overcome these shortcomings, the present study explored the feasibility of utilizing extracellular vesicles from the probiotic bacteriaLactococcus lactisas both immune activators and drug carriers, which were formulated into nanoparticles to target distant tumors.Results: Using confocal microscopy and flow cytometry, we confirmed that theLactococcus lactis-derived extracellular vesicles possess adjuvant activity that promoted the maturation of dendritic cells without affecting their viability or apoptosis rate. Moreover, theLactococcus lactis-derived extracellular vesicles, both alone and when carrying the drug doxorubicin, could target and accumulate in solid tumor tissues via the enhanced permeability and retention effect. Interestingly, compared to healthy cells, theLactococcus lactis-derived extracellular vesicles tended to be taken up more by tumor cells and readily released their encapsulated doxorubicin in the acidic tumor environment, which resulted in their enhanced reactive oxygen species production and immunogenic cell death. Ultimately, systemic administration ofLactococcus lactis-derived extracellular vesicle-encapsulated doxorubicin greatly increased the anti-tumor efficacy by boosting the number of infiltrating dendritic cells and CD8+T cells in the tumor tissues and doxorubicin-mediated immunogenic cell death.Conclusions: Collectively, this study demonstrated that the probioticLactococcus lactis-derived extracellular vesicles are both safer adjuvants and effective drug carriers with immunostimulatory activity and tumor-targeting capability, shedding an interesting light on this vaccine design platform for future cancer immunotherapy.
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Cancer Nanotechnology
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2026
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IF 5.8
Liu Chang,He Yanlin,Tang Huimin,Chen Jiayan,Li Jiale,Liu Rubing,Liu Xueli,Chen Hongrang,Ren Chunxia
As a common malignant tumor, achieving better treatment outcomes for liver cancer remains our constant pursuit. To enhance tumor cell killing efficiency, this study designed a nanozyme—gambogic acid-iron-doxorubicin (GAFe@Dox)—that simultaneously improved the tumor microenvironment (TME) and sensitized cells to chemotherapy. Its antitumor efficacy was systematically evaluated using 3D hydrogel cell scaffolds model simulating the human TME. First, transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) confirmed the successful synthesis of GAFe@Dox and verified its peroxidase activity. Cellular experiments demonstrated that GAFe@Dox generated substantial reactive oxygen species (ROS) via the Fenton reaction, synergistically killing tumor cells through multiple pathways with other components. Its killing mechanism was preliminarily validated at the cellular level. Transcriptomic analysis revealed GAFe@Dox effectively regulated signaling pathways including p53, MAPK and so on, further substantiating its mechanism of action. Additionally, we successfully constructed and cultured 3D hydrogel cell scaffolds model, simulating the in vivo 3D environment for cell growth and proliferation, achieving preliminary success. Subsequent validation confirmed that GAFe@Dox effectively penetrated and inhibited cell proliferation while inducing tumor cell apoptosis. This study demonstrated GAFe@Dox’s potent cytotoxic effects through synergistic multi-mechanistic tumor cell killing and established a physiologically relevant drug efficacy evaluation model, offering novel insights for nanozymes therapy research in liver cancer.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2023
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IF 5.8
Jingmou Yu,Liangliang Wang,Yun Ling,Xin Xiao,Juntao Gong,Hongguang Jin,Jing Xu,Pu Chen,Xin Xie,Lei Zhang
Triple-negative breast cancer is an offensive tumor that is highly challenging to cure. In this study, we developed novel polymeric nanoparticles that target dual receptors and respond to reducing conditions for chemotherapeutic drug release in the treatment of triple-negative breast cancer. Then we synthesized and characterized a targeted peptide-grafted chondroitin sulfate A-ss-deoxycholic acid (TCSSD) copolymer and prepare doxorubicin (DOX)-loaded TCSSD (TCSSD-D) micelles high-loading content. The bioresponsive drug release of TCSSD-D nanoparticles was demonstrated in a glutathione-containing phosphate buffer solution . We found that TCSSD-D effectively targeted CD44 and P-selectin receptors both in vitro and in vivo . TCSSD-D micelles were higher cytotoxicity and cellular uptake than unmodified DOX-containing micelles in MDA-MB-231 cells. Furthermore, TCSSD-D micelles showed the strongest suppression of tumor growth among three DOX-based formulations in triple-negative MDA-MB-231-bearing nude mice . These results suggest that amphiphilic TCSSD nanoparticles can serve as a targeted and intelligent delivery vehicle for triple-negative breast cancer therapy.
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RSC Advances
·
2022
·Vol. 12
·期 55
·35666-35675
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IF 4.036
Junhao Hu,Qiong Yi,Ziyi Xiao,Feng Tian,Tingting Shu,Xiaolan Liu,Yingxi Wang,Ling Li,Jiangang Zhou
Doxorubicin (DOX) has been an emerging environmental pollutant due to its significant genotoxicity to mankind. Advanced oxidation processes are a potential strategy to remove DOX in water solution. To develop a highly efficient catalytic agent to remove DOX, bimetal MOFs were synthesized, with Cu2+ and Co2+ as the central ions and adenine as the organic ligand. This study investigated the degradation of DOX by Co/Cu-MOFs combined with peroxymonosulfate (PMS). It was found that the degradation of DOX by Co/Cu-MOFs can reach 80% in only 10 seconds. This can be explained by the charge transfer from Co(III) to Co(II) being accelerated by Cu2+, resulting in the rapid generation of free radicals, which was proved by the EIS Nyquist diagram. Co/Cu-MOFs can be reused by simply washing with water without inactivation. Therefore, Co/Cu-MOFs can be used as an efficient catalytic agent to degrade DOX in environmental water.
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INVESTIGATIONAL NEW DRUGS
·
2023
·Vol. 41
·期 5
·664-676
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IF 3.4
Pan Mingzhu,Liu Yali,Sang Tian,Xie Jiajun,Lin Huishu,Wei Jianpeng,Shao Shuai,Zheng Yanying,Zhang Juan
Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug’s lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2–MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.
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RSC Advances
·
2023
·Vol. 13
·期 28
·19065-19078
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IF 3.9
Xia Ou,Zhong Zhang,Li Lin,Yan Du,Yu Tang,Yaotai Wang,Jianzhong Zou
Objective: To make up for the insufficient ultrasound ablation of tumors, the energy output or synergist is increased but faces the big challenge of normal tissue damage. In this study, we report a tumor-homing bacterium, Bifidobacterium bifidum (B. bifidum), adsorbing liposomes that encapsulate perfluorohexane (PFH) and doxorubicin (DOX) to enhance the pulsed-focused ultrasound (PFUS) for tumor therapy, so as to improve the efficacy, safety and controllability of ultrasound treatment. Methods: The PFH and DOX co-loaded cationic liposomal nanoparticles (CL-PFH-DOX-NPs) were prepared for ultrasound (US) imaging, cell-killing, and B. bifidum adsorption for the reactive oxygen species (ROS) testing. The aggregation of B. bifidum and CL-PFH-DOX-NPs is called tumor-homing aggregation (B. bifidum@CL-PFH-DOX-NPs) in this study, and the synergistic effects of B. bifidum@CL-PFH-DOX-NPs were analyzed in vivo. Results: Comprehensive studies validated that CL-PFH-DOX-NPs can enhance US imaging and cell-killing and B. bifidum can promote ROS, and B. bifidum@CL-PFH-DOX-NPs achieve PFUS synergism in vivo. Importantly, active homing of B. bifidum facilitated the delivery and retention of CL-PFH-DOX-NPs in tumors, reducing dispersion in normal tissues, achieving the targeting ability of B. bifidum@CL-PFH-DOX-NPs. The best sonication time was chosen according to the distribution of CL-PFH-DOX-NPs in vivo to achieve efficient therapy. Especially, B. bifidum@CL-PFH-DOX-NPs amplified cavitation and the immune-boosting effects. Conclusion: Multifunctional B. bifidum@CL-PFH-DOX-NPs were successfully constructed with well targeting, which not only realized US imaging monitoring, strong cavitation and complementary killing during PFUS, but also achieved immunity enhancement after PFUS. The combination of PFUS, B. bifidum and CL-PFH-DOX-NPs provides a new idea for the potential application of ultrasound therapy in solid tumors.
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