International Journal of Nanomedicine
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2023
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IF 8
Wenzhe Yang,Xue Pan,Peng Zhang,Xue Yang,Huashi Guan,Huan Dou,Qian Lu
Rationale Reversing the hypoxic and immunosuppressive tumor microenvironment (TME) is crucial for treating malignant melanoma. Seeking a robust platform for the effective reversion of hypoxic and immunosuppressive TME may be an excellent solution to revolutionizing the current landscape of malignant melanoma treatment. Here, we demonstrated a transdermal and intravenous dual-administration paradigm. A tailor-made Ato/cabo@PEG-TK-PLGA NPs were administrated transdermally to melanoma with the help of a gel spray containing a skin-penetrating material borneol. Nanoparticles encased Ato and cabo were released and thereby reversed the hypoxic and immunosuppressive tumor microenvironment (TME).Methods Ato/cabo@PEG-TK-PLGA NPs were synthesized through a self-assembly emulsion process, and the transdermal ability was assessed using Franz diffusion cell assembly. The inhibition effect on cell respiration was measured by OCR, ATP, and pO2 detection and in vivo photoacoustic (PA) imaging. The reversing of the immunosuppressive was detected through flow cytometry analysis of MDSCs and T cells. At last, the in vivo anti-tumor efficacy and histopathology, immunohistochemical analysis and safety detection were performed using tumor-bearing mice.Results The transdermally administrated Ato/cabo@PEG-TK-PLGA NPs successfully spread to the skin surface of melanoma and then entered deep inside the tumor with the help of a gel spray and a skin puncturing material borneol. Atovaquone (Ato, a mitochondrial-respiration inhibitor) and cabozantinib (cabo, a MDSCs eliminator) were concurrently released in response to the intratumorally overexpressed H2O2. The released Ato and cabo respectively reversed the hypoxic and immunosuppressive TME. The reversed hypoxic TME offered sufficient O2 for the intravenously administrated indocyanine green (ICG, an FDA-approved photosensitizer) to produce adequate amount of ROS. In contrast, the reversed immunosuppressive TME conferred amplified systemic immune responses.Conclusion Taken together, we developed a transdermal and intravenous dual-administration paradigm, which effectively reversed the hypoxic and immunosuppressive tumor microenvironment in the treatment of the malignant melanoma. We believe our study will open a new path for the effective elimination of the primary tumors and the real-time control of tumor metastasis.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2022
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IF 6.51
Wenhao Gao,Jialiang Zhang,Weifeng Wang,Zhihong Liu,Mulan Chen,Xiaomu Hu,Lingjun Zeng,Changqing Zheng,Hongtao Song,Qian Zhang
Photodynamic therapy (PDT) shows very high potential for the clinical treatment of triple-negative breast cancer. However, the efficacy of PDT is significantly weakened by tumor hypoxia , the relatively high intracellular glutathione levels and the active proliferation of cancer cells. To address these issues, we developed a novel drug self-delivery nanorod (defined as AINRs) through the hydrophobic interaction among the mitochondrial complex III inhibitor (atovaquone, ATO), the photosensitizer (indocyanine green, ICG) and the dispersion stabilizer (distearoyl phosphoethanolamine-polyethylene glycol 2000, DSPE-PEG 2000). The AINRs showed a rod-like morphology with a mean diameter of 120.6 ± 5.4 nm , a zeta potential of −26.35 ± 1.63 mV and a significantly high drug loading rate of 93.48%. The results of in vitro cell experiments involving triple-negative breast cancer cell lines (4T1 cells and MDA-MB-231 cells) indicated that the AINRs could effectively block the oxidative phosphorylation of cancer cells through the inhibition of mitochondrial complex III, which results in the reduction of endogenous oxygen consumption and the decrease of the intracellular ATP level. The reduction of ATP content further inhibited the glutathione synthesis and arrested the cell cycle at the S-phase, which results in enhanced in vitro PDT efficacy of ICG. The results of in vivo antitumor activity in 4T1-bearing mice showed that the tumor growth inhibition rate of the AINRs with near-infrared laser irradiation (NIR) was greater than 90%, whereas the tumor growth inhibition rates of the AINRs without NIR, ICG with NIR and doxorubicin (3 mg/kg) were only 31.68%, 61.15% and 24.59%, respectively. In addition, the results of safety studies, including body weights, biochemical indicators and H&E staining images of the main organs demonstrated the security of the AINRs. In summary, this study showed that the oxidative phosphorylation inhibition of triple-negative breast cancer was a safe and effective method to enhance its PDT efficacy.
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ACS Nano
·
2023
·
IF 17.1
Yifan Zhao,Min Zhang,Bai Lv,Guanghe Xue,Huimei Jiang,Gang Chen,Yi Ma,Yong Sun,Jie Cao
Therapeutic tumor vaccines, which use tumor antigens to stimulate a cancer patient’s immune system to eventually kill the tumor tissues, have emerged as one of the most attractive strategies in anticancer research. Especially, exploring in situ vaccines has become a potential field in cancer immunotherapy. However, due to the hypoxic tumor microenvironment, the generation of tumor antigens is always mild and not sufficient. Hence, in this study, we designed a closed-loop mitochondrial oxygen-economizer (TPCA) to induce enhanced phototherapy-driven in situ vaccines. The O2-economizer was developed by the integration of the photosensitizer CyI and the mitochondrial inhibitor atovaquone into the PAMAM dendrimer. In vitro and in vivo studies showed that TPCA could enter the mitochondria through (3-propylcarboxyl) triphenylphosphine bromide (TPP) and effectively restrict the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced iodinated cyanine dye mediated photodynamic therapy, which could further induce in situ vaccines for ablating the primary tumor directly and inhibiting the tumor metastasis and recurrence. Furthermore, the antitumor mechanism revealed that O2-economizer-based oxygen-boosted PDT elicited immunogenic cancer cell death with enhanced exposure and release of DAMPs and altered the immunosuppressive tumor microenvironment with increased recruitment of T cells in tumors, thereby inducing in situ vaccines and provoking the systematic antitumor responses against CT26 tumors. This study will provide innovative approaches for local, abscopal, and metastatic tumor treatment.
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BMC CANCER
·
2023
·Vol. 23
·期 1
·1-13
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IF 3.8
Liu Bin,Zheng Xin,Li Jiajun,Yao Peng,Guo Peng,Liu Wei,Zhao Gaoping
Background Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer. Methods To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification. Results This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone. Conclusion In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
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BIOMATERIALS
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2020
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IF 10.317
Dan Wang,Bin Xue,Tymish Y. Ohulchanskyy,Yubin Liu,Artem Yakovliev,Roman Ziniuk,Mengze Xu,Jun Song,Junle Qu,Zhen Yuan
Hypoxia is one of the hallmarks of solid tumor, which heavily restricts the clinical cancer therapy treatments, especially for the oxygen (O 2 ) -dependent photodynamic therapy (PDT). Herein, an intelligent multi-layer nanostructure was developed for decreasing the O 2 -consumption and elevating the O 2 -supply simultaneously. The cell respiration inhibitor –atovaquone (ATO) molecules were reserved in the middle mesoporous silicon layer, and thus were intelligently released at the tumor site after the degradation of gatekeeper of MnO 2 layer, which effectively inhibit tumor respiration metabolism to elevate oxygen content. Meanwhile, the degradation of MnO 2 layer can generate O 2 , further boosting oxygen content. Moreover, the inner upconversion nanostructures as the near infrared (NIR) light-transducers enable to activate photosensitizers for deep-tissue PDT. Systematic experiments demonstrate that this suppressing O 2 -consumption and O 2 -generation strategy improved oxygen supply to boost the singlet oxygen generation to eradicate cancer cells under NIR light excitation. Better still, superior trimodality imaging capabilities (computed tomography (CT), NIR-II window fluorescence , and tumor microenvironment-responsive T1-weighted magnetic resonance (MR) imaging) of the nanoplatform were evaluated. Our findings offer a promising aproach to conquer the serious hypoxia problem in cancer therapy by turning down the O 2 metabolism aveneue and simultaneously generating O 2 .
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ADVANCED FUNCTIONAL MATERIALS
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2019
·Vol. 29
·期 13
·1807294
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IF 15.621
Donglin Xia,Peipei Xu,Xingyu Luo,Jianfeng Zhu,Haiying Gu,Da Huo,Yong Hu
Hypoxia, as characterized by the low local oxygen, confers on cancer cells resistance to oxygen-consuming photodynamic therapy (PDT). The limited success reached by current approaches harnessing reoxygenation to enhance PDT outcome promotes the reconsideration of the design of the therapeutic approach. In this study, a multistage delivery system capable of reversing hypoxia is demonstrated. Unlike previous strategies that only expect to affect the peripheral tumor tissue, the size-shrinkable system allows those deeply located hypoxia regions to be treated. Specifically, therapeutics, including atovaquone and indocyanine green derivatives that are respectively responsible for oxidative phosphorylation blockage and PDT, are encapsulated in a gelatin nanoparticle, whose structure would rupture to promote deep penetration when facing matrix metallopeptidase 2 enzyme overexpression in tumor tissue. The antihypoxic performance of the platform has been evaluated using a variety of analyses including flow-cytometry assay, immunofluorescence, and micro-positron-emission tomography imaging. Tumor regression in animal models confirms the feasibility and effectiveness of conquering the PDT-resistance through abrogating the oxygen consumption. It is hopeful that such a strategy could shed light on the development of next-generation PDT-adjuvant treatment.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2025
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IF 5.2
Enqin Zheng,Wenhao Gao,Qingyu Lu,Xiaoliang Deng,Shiting Xu,Zhihong Liu,Lingjun Zeng,Linlin Liu,Qian Zhang,Hongtao Song
Photothermal therapy has been observed to upregulate the heat shock protein 70 (HSP 70) expression in tumor cells, consequently diminishing the anti-tumor efficacy of the treatment. The expression of HSP 70 is intricately linked to the adenosine triphosphate (ATP) levels within tumors, suggesting that modulating energy metabolism could potentially enhance the effectiveness of photothermal therapy. To address these challenges, ATO-QUE-Fe 2+ -PVP K30 nanoparticles (AQFP NPs) were synthesized through the coordinated self-assembly of the oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO) and the glycolysis inhibitor quercetin (QUE) with ferrous ions (Fe 2+ ) for synergetic energy depletion and low-temperature photothermal therapy (LTPTT). The synthesized AQFP NPs exhibited a small particle size and demonstrated high encapsulation efficiency of ATO and QUE. AQFP NPs could effectively downregulate the expression of HSP 70 by inhibiting the activity of mitochondrial complex Ⅲ and hexokinase Ⅱ (HK Ⅱ) to inhibiting suppress mitochondrial OXPHOS and glycolytic pathways in 4T1 cells, respectively. This inhibition resulted in a reduction of ATP levels within tumor cells, subsequently leading to decreased expression of HSP 70 and enhancing the therapeutic efficacy of LTPTT. Furthermore, AQFP NPs can remarkably inhibit the growth of tumors when subjected to laser irradiation. Furthermore, the analysis of blood biochemical indices and hematoxylin and eosin (H&E) staining of major organs suggested that AQFP NPs exhibit a preferable in vivo safety profile. In conclusion, the anti-tumor efficacy of LTPTT could be substantially enhanced by concurrently inhibiting OXPHOS and glycolysis, thereby offering an innovative therapeutic for the clinical treatment of tumors.
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Xiaoliang Deng,Xianquan Feng,Xiaohui Tang,Zhihui Zheng,Da Zheng,Enqin Zheng,Lingjun Zeng,Shiying Xu,Boxin Chen,Qian Zhang,Zhihong Liu,Hongtao Song
The clinical efficacy of immunotherapy in triple-negative breast cancer (TNBC) faces dual barriers: poor immunogenicity and a suppressive tumor microenvironment. While low-temperature photothermal therapy (LTPTT) has emerged as a potential immunostimulatory strategy, its efficacy is counteracted by heat shock protein (HSP) induction and COX-2/PGE2-mediated immunosuppression. To address these challenges, we developed a multifunctional immunophotothermal nanoplatform (IAC NPs) through rational engineering of human serum albumin for combinatorial delivery of indocyanine green as a photothermal converter, atovaquone for HSP70-mediated thermoresistance blockade, and celecoxib for COX-2/PGE2 pathway inhibition. The IAC NPs achieved tumor-targeted delivery and NIR-activated immunogenic phototherapy while coinhibiting HSP70 (via atovaquone’s mitochondrial complex III blockade) and the COX-2/PGE2 immunosuppressive axis (via celecoxib). The triple medications’ synergistic action improved the expression of effector memory T cells, boosted the maturation of dendritic cells, encouraged the infiltration of CD4+ and CD8+ T cells, and reduced regulatory T cells. In vivo, the IAC NPs mediated profound suppression of both primary tumors and metastatic dissemination while exhibiting optimal biocompatibility for clinical translation. Our work validates a nanoenabled self-delivery system that augments the efficacy of LTPTT immunotherapy against TNBC by orchestrating coordinated inhibition of HSPs and inflammatory responses.
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International Journal of Pharmaceutics-X
·
2025
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IF 6.4
Shiying Xu,Lina Wu,Boxin Chen,Xiaoliang Deng,Zhihui Zheng,Fei Wu,Lingjun Zeng,Changqing Zheng,Xiaomu Hu,Aiwen Huang,Xin Zhou,Xianquan Feng,Zhihong Liu
Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment due to its selective tumor ablation and excellent safety characteristics. However, its efficacy is limited by tumor hypoxia and excessive inflammation. In this study, we fabricated human serum albumin-based nanoparticles (CAI NPs) encapsulating celecoxib (CXB), atovaquone (ATO), and IR820 via sonication. The CAI NPs exhibited favorable physicochemical properties, including a uniform size distribution (<200 nm), high encapsulation efficiency and excellent colloidal stability. Initially, ATO acts as a mitochondrial complex III inhibitor, suppressing oxidative phosphorylation to ameliorate tumor hypoxia. This hypoxia alleviation potentiates PDT efficacy by enhancing tumor cell ROS generation. Furthermore, concomitant COX-2/PGE2 inhibition by CXB attenuates the excessive inflammatory cascade triggered during PDT, resulting in enhanced therapeutic outcomes through microenvironment modulation. Eventually, the dual-enhanced CAI NPs demonstrate potent antitumor activity in both in vivo and ex vivo models, while maintaining excellent biocompatibility under physiological conditions. In summary, the integrated three-drug regimen conclusively enhances photodynamic therapeutic outcomes through multimodal mechanisms, establishing a viable treatment approach for esophageal cancer.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Yilin Wang,Wenting Cheng,Yang Chen,Hailong Tian,Canhua Huang,Ka Li
Cancer stemness in colorectal cancer (CRC) drives immune evasion and fosters an immunosuppressive tumor microenvironment (TME), limiting the efficacy of immunotherapy. To counteract this stemness-driven immune evasion, we developed a hyaluronic acid (HA) surface-modified dual-targeting nanoplatform (HA/pCe6-Ato NPs) that induces both endoplasmic reticulum stress and mitochondrial dysfunction. HA functionalization facilitates tumor-specific targeting via CD44 receptor-mediated endocytosis. The nanoplatform incorporates an ER-targeting photosensitizer, pCe6, synthesized by conjugating Chlorin e6 with p-Toluenesulfonamide, and the mitochondrial respiratory chain inhibitor atovaquone (Ato), which self-assembles into nanoparticles. Upon activation, HA/pCe6-Ato NPs induce ER stress and mitochondrial dysfunction, disrupting cancer stemness and reprogramming the immunosuppressive TME. Preclinical evaluations showed that HA/pCe6-Ato NPs promote apoptosis and accelerate reactive oxygen species production in cancer stem-like cells (CSCs), while reducing immunosuppressive factor secretion and enhancing immune effector cell infiltration. These effects synergistically enhance the efficacy of immunotherapy, achieving superior tumor inhibition compared with conventional monotherapies. Collectively, HA/pCe6-Ato NPs highlight the potential of organelle-targeting strategies to dismantle cancer resilience mechanisms, providing a foundation for dual-targeting nanomedicines to overcome resistance and enhance immunotherapy in CRC.
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