BIOMATERIALS
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2024
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IF 12.8
Shuchen Yu,Yitong Jiang,Qian Li,Mengmeng Li,Jiamin Su,Shicong Lai,Zhihua Gan,Zhenshan Ding,Qingsong Yu
The hypoxic nature of pancreatic cancer , one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy . Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia . The heterogeneity of hypoxia—primarily caused by limited oxygen penetration—has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.
研究领域:
肿瘤学
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药理学
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生物医学工程
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PubMed
高影响因子
JOURNAL OF POLYMER SCIENCE
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2023
·Vol. 61
·期 12
·1111-1119
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IF 3.4
Yajun Xu,Jianlin Lv,Chaoying Kong,Yanran Li,Kun Wang,Na Shen,Zhaohui Tang
Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-dioxide), a representative hypoxia-activated prodrugs (HAPs), has entered Phase II/III clinical trials. Despite a promising phase II clinical trial results, TPZ does not bring benefits to cancer therapy in most phase III clinical trials, which making the clinical trials failed. To improve its therapeutic effects, in this study, we synthesize a novel TPZ derivative, 3-(3-(5-hydroxypentyl)ureido)benzo[e][1,2,4]triazine 1,4-dioxide (TPZH), and covalently conjugated it to poly (L-glutamic acid) (PLG) to obtain TPZH nanoparticles (TPZH-NPs). The TPZH-NPs shows prolonged blood circulation, enhanced tumor accumulation, and increased maximum tolerated dose (MTD) than TPZH. In addition, TPZH-NPs exhibits significantly enhanced antitumor therapeutic efficiency than free TPZH against 4T1 breast tumors. Graphical
研究领域:
药学
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肿瘤学
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纳米技术
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DOI
高影响因子
Nanoscale
·
2022
·Vol. 15
·期 1
·237-247
·
IF 8.307
Panli Han,Lianxue Zhang,Yaqi Fu,Youyu Fu,Jianxiang Huang,Jinlin He,Peihong Ni,Taimoor Khan,Yang Jiao,Zaixing Yang,Ruhong Zhou
The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials. Thus, the development of effective clinical applications of TPZ requires advanced strategies to intensify hypoxia levels in tumors effectively and safely. In this study, we designed and fabricated a paclitaxel (PTX)-loaded dual-response delivery system with a low dose (e.g., 2 Gy) of X-ray and reactive oxygen species on the basis of diselenide block copolymers. Upon the external X-ray stimulus, the system accurately released encapsulated PTX at tumor sites and remarkably improved tumor hypoxia levels by causing severe damage to tumor blood vessels. Subsequently, these enhanced tumor hypoxia levels effectively activated the reduction of TPZ into benzotriazinyl free radicals, which significantly improved the antitumor efficacy of our system against 4T1 breast cancer cells with an initial tumor volume of 500 mm3. Moreover, the dual-stimulus coordinated and controlled release of PTX was found to largely avoid the off-target effects of PTX on normal cells while exhibiting very limited side effects in experimental mice. The current novel strategy for regulating tumor hypoxia levels offers an effective and safe way to activate TPZ for the treatment of large solid tumors.
研究领域:
药学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Xing Gao,Hongwei Cheng,Minglei Teng,Hongrui Zhang,Hu Chen,Songnan Qu,Gang Liu
Transcatheter arterial chemoembolization (TACE) is the principal treatment option for patients with unresectable hepatocellular carcinoma (HCC). However, the hypoxic microenvironment following TACE can promote angiogenesis and suppress tumor ferroptosis, resulting in an unfavorable prognosis. Tirapazamine (TPZ), a hypoxia-activated prodrug with specific cytotoxicity for hypoxic cells, making it a potential candidate for TACE. To develop an effective hypoxia-responsive drug delivery platform for TACE, we propose a novel lipiodol embolic formulation that integrates TPZ and sorafenib (SFB) by super-stable homogeneous intermixed formulation technology (SHIFT). This approach achieves the manufacture of embolic agents with stable drug dispersion characteristics, fulfilling the need for sustained drug release in TACE. The prolonged tumor penetration of TPZ exhibited embolization-responsive tumor killing, and its combination with SFB can suppress hypoxia-induced angiogenesis and trigger tumor ferroptosis, maintaining low oxygen levels, thereby boosting the therapeutic efficacy of TPZ. Conversely, TPZ can combat the resistance to SFB in hypoxic tumor cells. In summary, this study developed a novel embolization drug formulation based on embolic hypoxic microenvironment. The synergistic mechanism of TPZ and SFB enhances the therapeutic effects of hypoxia-activated prodrugs and mitigates the adverse effects of hypoxia.
研究领域:
肿瘤学
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药理学
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介入放射学
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药物递送系统
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高影响因子
JOURNAL OF MATERIALS SCIENCE
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2026
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IF 4.4
Li Yifan,Li Zhen,Zhang Yuyuan,Wang Menghe,Ye Shuwen,Wu Bailu,Lv Peijie,Pang Pengfei,Li Xin,Zhan Pengchao
Tirapazamine (TPZ) is a bioreductive agent with selective antitumor activity under hypoxic conditions; however, its systemic toxicity and delivery efficiency limit its clinical application. This study aimed to develop a TPZ delivery system based on nanobubbles (NBs), combining ultrasound-targeted microbubble destruction (UTMD) and transcatheter arterial chemoembolization (TACE) for treating hepatocellular carcinoma (HCC) to enhance therapeutic efficacy and reduce adverse effects. TPZ-NBs were fabricated using a high-shear dispersion method and characterized for their physicochemical properties, encapsulation efficiency, and drug release profiles. In vitro studies evaluated the effects of TPZ-NBs on hepatoma cell proliferation and migration under hypoxic conditions. Using a rabbit VX2 liver cancer model, we compared the control group, TACE group, TPZ-NBs + TACE group, and TPZ-NBs + UTMD + TACE group in terms of tumor necrosis, drug delivery efficiency, and safety profiles. TPZ-NBs demonstrated favorable encapsulation efficiency (35.81%) and sustained-release characteristics (58% cumulative release over 48 h). In vitro experiments showed that TPZ-NBs significantly inhibited hepatoma cell proliferation and migration under hypoxic conditions. In animal studies, the TPZ-NBs + UTMD + TACE group significantly enhanced intratumoral drug delivery efficiency, induced tumor cell apoptosis, reduced microvessel density (MVD), and decreased tumor recurrence. Compared to other groups, this combination therapy exhibited higher tumor necrosis rates and deeper drug penetration while maintaining favorable safety profiles. The combination of TPZ-NBs with UTMD and TACE represents an efficient and safe therapeutic strategy that overcomes the limitations of conventional TACE, offering new possibilities for hepatocellular carcinoma treatment.
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DOI
高影响因子
Surfaces and Interfaces
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2026
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IF 6
Guihao Hu,Yu Li,Yao Liu,Jie Yang,Tiantian Luo,Jie Zhong,Wensheng Yue,Zhike Li,Xianfu Li,Jiang Zhu
Tumor hypoxia limits radiotherapy and chemotherapy efficacy by promoting treatment resistance, while hypoxia-activated prodrugs (HAPs) like Tirapazamine (TPZ) face clinical failure due to insufficient tumor hypoxia. To address this challenge, we engineered HRP-catalyzed Mn(II) chelate-doped TPZ@CaCO₃/PDA-Mn@PEG nanoparticles (TCPPM NPs) that actively amplify hypoxia for potent TPZ activation. The hollow CaCO₃ core enables pH-responsive TPZ release (80% at pH 5.5), while the Mn-DopaCDTA-doped PDA shell provides enhanced T1-weighted MRI contrast ( r ₁ = 17.6 mM⁻¹s⁻¹, per Mn, 25 °C, 0.5 T), photoacoustic/ultrasound imaging, and synergistic PTT/PDT via ROS generation (4.0-fold increase, 1% O₂ conditions). In 4T1 tumor models, TCPPM NPs achieved 85% tumor reduction (vs. 45% for TPZ alone) and 45-day survival, overcoming HAP limitations through hypoxia amplification (PDA ROS O₂ consumption + 61.3 °C PTT) and calcium-mediated mitochondrial damage. This HAP-specific theranostic platform integrates precise imaging-guided therapy, presenting a breakthrough for hypoxia-targeted cancer treatment.
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高影响因子
ACS Applied Materials & Interfaces
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2026
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IF 7.8
Hangyang Ling,Rui Zhang,Jiaxin Niu,Gongxian Sun,Xu Sun,Yao Li,Yeting Hu,Hua Yang,Han Zhang,Xiangdong Kong
Tumor microenvironment-responsive nanomedicines offer significant advantages in enhancing treatment specificity and minimizing systemic toxicity. Nevertheless, the therapeutic efficacy of single-modality treatments is often limited by tumor heterogeneity, necessitating the development of multimodal nanoplatforms capable of leveraging multiple tumor microenvironment characteristics for efficient synergistic therapy. In this study, a multifunctional nanocomposite comprising cobalt zeolitic imidazolate framework-67-encapsulated Au nanodendrites coloaded with tirapazamine is developed for tumor-selective therapy. To address the inherent limitations of traditional preclinical models, human healthy and colorectal cancer organoids are utilized as advanced in vitro assessment platforms. Mechanistic studies revealed that multibranched Au nanodendrites disrupt cellular membrane integrity, whereas the acidic condition induces the degradation of the cobalt zeolitic imidazolate framework-67, facilitating targeted drug release. These combined actions synergistically amplify intracellular reactive oxygen species generation and disrupt mitochondrial membranes, leading to the selective elimination of tumor cells. This work presents a highly efficient, tumor microenvironment-responsive nanotherapeutic platform and demonstrates the critical value of organoid-based evaluation systems in advancing the clinical translation of targeted nanomedicines.
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PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2022
·
IF 9.965
Lu Yang,Zhao Wang,HaiJiang Gong,Shili Gai,RuiFang Shen
Chemodynamic therapy (CDT), an emerging oncology treatment, has received considerable attention owing to its high selectivity, less aggressiveness, and endogenous stimulation. However, the complex intra-tumor environment limits the therapeutic effect. In this study, Cu + was directly doped into the structure of the UiO-66 matrix using an in situ one-pot oil bath method. The as-formed UiO-66/Cu possessed a large surface area, making it feasible to modify folic acid (FA) and carry more chemotherapeutic agents like tirapazamine (TPZ), thus forming UiO-66/Cu-FA-TPZ nanoplatforms. For CDT, the nanoplatform catalyzed the cyclic generation of the highly oxidizing hydroxyl radical (·OH) from H 2 O 2 . Particularly, low-frequency ultrasound enhanced the curative effect. Notably, in a tumor, a severe hypoxic environment and ultrasound can activate more TPZ for safe and efficient chemotherapy, achieving synergistic and hypoxia-activated tumor treatment with a low risk of side effects. Moreover, the nanoplatform exhibits computed tomography imaging functions for combined diagnosis and treatment. Our designed nanoplatform overcomes the dilemma of insufficient efficacy from conventional therapy attributed to a hypoxic environment, expecting to guide the design of future treatment regimens for hypoxic tumors.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Jianlin Lv,Yajun Xu,Ya Liu,Kazuo Sakurai,Haiyang Yu,Zhaohui Tang
ABSTRACT It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)- b -poly( D,L -lactide) (mPEG- b -PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG- b -PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9% tumor suppression rate and a 20% cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.
研究领域:
肿瘤学
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药学
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纳米技术
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DOI
PubMed
高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
·
2023
·
IF 5.4
Yuehong Gong,Tianjiao Zhou,Wusimanjiang Aimaiti,Yuxia Lin,Yuan Xu,Jianhua Yang,Zhangjian Huang,Hao Wen,Hulin Jiang,Jianhua Wang
Background Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with PDT will greatly limit its effects. As a hypoxic-activated pre-chemotherapeutic drug, tirapazamine (TPZ) can be only activated and produce cytotoxicity under hypoxia environment. Albendazole sulfoxide (ABZSO) is the first choice for the treatment of Egs. This study aimed to explore the effects of ABZSO nanoparticles (ABZSO NPs), TPZ combined with PDT on the activity of Egs in vitro and in vivo . Methods The Egs were divided into control, ABZSO NPs, ABZSO NPs + PDT, and ABZSO NPs + TPZ + PDT groups, and the viability of Egs was determined using methylene blue staining. Then, the ROS , LDH and ATP levels were measured using their corresponding assay kit, and H2AX and TopoI protein expression was detected by western blot . The morphology of Egs with different treatments was observed using hematoxylin eosin (HE) staining and scanning electron microscopy (SEM). After that, the in vivo efficacy of ABZSO NPs, TPZ and PDT on Egs was determined in a Egs infected mouse model. Results In vitro experiments showed that the combined treatment of TPZ, ABZSO NPs and PDT significantly inhibited Egs viability; and significantly increased ROS levels and LDH contents, while decreased ATP contents in Egs; as well as up-regulated H2AX and down-regulated TopoI protein expression . HE staining and SEM results showed that breaking-then-curing treatment seriously damaged the Egs wall. Additionally, in vivo experiments found that the combination of ABZSO NPs, PDT and TPZ had more serious calcification and damage of the wall structure of cysts. Conclusions ABZSO NPs combined with TPZ and PDT has a better inhibitory effect on the growth of Egs in vitro and in vivo based on the strategy of “breaking-then-curing”.
研究领域:
寄生虫学
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药理学
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治疗学
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PubMed
高影响因子
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