JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Jia-Qian Wang,Xiao-Meng Liu,Zi-Shuo Zhu,Zhe Li,Cheng-Zhi Xie,Xin Qiao,Yu-Kuan Feng,Jing-Yuan Xu
Triple-negative breast cancer (TNBC) poses formidable challenges in the clinic owing to its particularly malignant and aggressive properties. Overexpression of eukaryotic elongation factor-2 kinase (eEF2K) is highly correlated with the poor prognosis of TNBC, representing a promising therapeutic target. Herein, Fluoxetine as eEF2K-inhibitor and chemosensitizer was conjugated with cisplatin/oxaliplatin to present two-in-one prodrugs 8–19. Multievaluation indicated that monosubstituted 8 and disubstituted 12 exhibited 407- and 174-fold higher cytotoxicity than cisplatin against MDA-MB-231 cells by elevating DNA damage-induced apoptosis and eEF2K-triggered autophagy. Moreover, 8 and 12 significantly overcame chemoresistance in A549cisR cells, evidenced by downregulating resistance-related key proteins P-gp, GST-π, ATM, and RAD51. Syngeneic and xenograft mouse models demonstrated that 8 and 12 could effectively inhibit tumor growth and metastasis, and reduce toxicity compared to cisplatin in vivo. Additionally, 8 and 12 stimulated immunomodulation including T-cell proliferation and Th1 cytokine production. All results hold the promise of 8 and 12 as multifunctional chemotherapeutic agents.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2020
·
IF 4.321
Yan Ma,Dong-Yang Zhang,Zhuo Peng,Shixia Guan,Junqiu Zhai
Combinational administration of photothermal therapy (PTT) and chemotherapy (CT) shows great potential in improving the efficiency of tumor treatment. Herein, we designed a novel nanocomposite Pt@Bi2Te3 composed of bismuth telluride (Bi2Te3) nanoparticles and platinum(IV) prodrugs (Pt) for PTT–CT combination therapy. The obtained Bi2Te3 was synthesized by a simple solvothermal method and modified by polyethylene glycol, which exhibited excellent photothermal (PT) efficiency and stability and could also serve as a bimodal bioimaging contrast agent in PT and photoacoustic (PA) imaging. In vitro experiment results showed that the nanocomposite Pt@Bi2Te3 could effectively increase the uptake of platinum in cancer cells, which could kill tumor cells through the combined effect of PTT and CT. Furthermore, combination therapy of cancer in vivo was achieved with obvious tumor-growth inhibition without inducing observed side effects. We revealed the great potential of Bi2Te3 nanocomposites in increasing therapeutic efficiency by PTT–CT therapy and PA–PT imaging.
研究领域:
肿瘤学
·
生物医学工程
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
Polymers
·
2022
·Vol. 14
·期 2
·287
·
IF 4.967
Shuying Li,Yanjuan Wu,Xiukun Xue,Siyuan Liu
The combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) based on a single nanosystem is highly desirable for cancer treatment. In this study, we developed a versatile Pt(IV) prodrug-based nanodrug, PVPt@Cy NPs, to realize synchronous chemotherapy, PDT and PTT and integrate cancer treatment with bioimaging. To construct PVPt@Cy NPs, the amphiphilic Pt(IV)-based polymeric prodrug PVPt was synthesized by a facile one-pot coupling reaction, and then it was used to encapsulate an optotheranostic agent (HOCyOH, Cy) via hydrophobic interaction-induced self-assembly. These NPs would disaggregate under acidic, reductive conditions and NIR irradiation, which are accompanied by photothermal conversion and reactive oxygen species (ROS) generation. Moreover, the PVPt@Cy NPs exhibited an enhanced in vitro anticancer efficiency with 808-nm light irradiation. Furthermore, the PVPt@Cy NPs showed strong NIR fluorescence and photothermal imaging in H22 tumor-bearing mice, allowing the detection of the tumor site and monitoring of the drug biodistribution. Therefore, PVPt@Cy NPs displayed an enormous potential in combined chemo-phototherapy.Keywords:combined chemo-phototherapy;Pt(IV) prodrug;nanoparticle;bioimaging
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 7
·1031-1041
·
IF 7.571
Shuying Li,Yanjuan Wu,Siyuan Liu,Ting Wu,Guozheng Liu,Tianduo Li,Zhaowei Chen
Imaging-guided chemo–phototherapy based on a single nanoplatform has a great significance to improve the efficiency of cancer therapy and diagnosis. However, high drug content, no burst release and real-time tracking of nanodrugs are the three main challenges for this kind of multifunctional nanotheranostics. In this work, we developed an innovative theranostic nanoplatform based on a Pt(IV) prodrug and a near-infrared (NIR) photosensitizer. A Pt(IV) prodrug and a cyanine dye (HOCyOH, Cy) were copolymerized and incorporated into the main chain of a polyprodrug (PCPP), which self-assembled into nanoparticles (NPs) with ∼27.61% Cy loading and ∼9.37% Pt loading, respectively. PCPP NPs enabled reduction-triggered backbone cleavage of polyprodrugs and bioactive Pt(II) release; Cy could be activated under 808 nm laser irradiation to produce local hyperthermia and reactive oxygen species (ROS) for phototherapy. Moreover, PCPP NPs with extremely high Cy and Pt heavy metal contents in the backbone of the polyprodrug could directly track the nanodrugs themselves via near-infrared fluorescence (NIRF) imaging, photothermal imaging, and computed tomography (CT) imaging in vitro and in vivo. As revealed by trimodal imaging, PCPP NPs were found to exhibit excellent tumor accumulation and antitumor efficiency after intravenous injection into H22-tumor-bearing mice. The dual-drug backboned polyprodrug nanoplatform exhibited great potential for bioimaging and combined chemo–phototherapy.
研究领域:
肿瘤学
·
生物医学工程
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Tang Ting,Gong Yufang,Gao Yuan,Pang Xinlong,Liu Shuangqing,Xia Yulan,Liu Dongsheng,Zhu Lin,Fan Qing,Sun Xiao
Introduction: The tumor microenvironment (TME) is mainly characterized by abnormally elevated intracellular redox levels and excessive oxidative stress. However, the balance of the TME is also very fragile and susceptible to be disturbed by external factors. Therefore, several researchers are now focusing on intervening in redox processes as a therapeutic strategy to treat tumors. Here, we have developed a liposomal drug delivery platform that can load a Pt(IV) prodrug (DSCP) and cinnamaldehyde (CA) into a pH-responsive liposome to enrich more drugs in the tumor region for better therapeutic efficacy through enhanced permeability and retention effect.Methods: Using the glutathione-depleting properties of DSCP together with the ROS-generating properties of cisplatin and CA, we synergistically altered ROS levels in the tumor microenvironment to damage tumor cells and achieve anti-tumor effects in vitro.Results: A liposome loaded with DSCP and CA was successfully established, and this liposome effectively increased the level of ROS in the tumor microenvironment and achieved effective killing of tumor cells in vitro.Conclusion: In this study, novel liposomal nanodrugs loaded with DSCP and CA provided a synergistic strategy between conventional chemotherapy and disruption of TME redox homeostasis, leading to a significant increase in antitumor effects in vitro.
研究领域:
药剂学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 11
·2115-2125
·
IF 4.543
Zhiyun Zhang,Yanjuan Wu,Gaizhen Kuang,Shi Liu,Dongfang Zhou,Xuesi Chen,Xiabin Jing,Yubin Huang
Drug-loaded nanocarriers, especially polymeric micelles, have attracted much attention in recent years, but their application is still limited due to their systemic toxicity and unsatisfactory tumor delivery efficiency through intravenous administration. In this study, we demonstrated an implantable prodrug micelle/small drug molecule co-loaded nanofiber strategy for enhanced local cancer treatment. A reduction-responsive Pt(IV) prodrug-backboned micelle, as a prodrug of bioactive Pt(II), and DCA were co-electrospun into poly(vinyl alcohol) (PVA) nanofibers. The prepared Pt(IV) prodrug-backboned micelle/DCA fibers exerted a synergistic effect on cancer cells. In contrast to systemic administration of chemotherapeutic agents, this implantable device exhibited enhanced anti-cancer efficacy with lower systemic toxicity against advanced cervical cancer in vivo. This work provides a facile, efficient and safe prospect of using a prodrug micelle and small molecular drug co-loaded electrospun device for localized and advanced cancer therapy.
研究领域:
肿瘤学
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纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 36
·7591-7597
·
IF 4.543
Zigui Wang,Peng Wu,Zhilong He,Hongyan He,Weifeng Rong,Jizhen Li,Dongfang Zhou,Yubin Huang
Chemotherapy is the most common therapeutic strategy for the treatment of unresectable hepatocellular carcinoma. However, the therapeutic efficacy is limited by the low delivery efficiency of chemotherapeutics and severe toxicity towards healthy tissues. To address these challenges, active-targeting mesoporous silica nanoparticles conjugating a platinum(IV) prodrug were developed as a therapy for liver cancer for the first time. Taking advantage of liver-targeting lactobionic acid (LA), the smart nano-carriers not only enhanced the circulation time, but also effectively concentrated at the liver tumor site. Moreover, the conjugated platinum(IV) could be reduced in the reductive tumor environment for the fast release of active platinum(II). The novel targeting and self-responsive drug-loading system offers new prospects for liver cancer chemotherapy.
研究领域:
药剂学
·
肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
BMC CANCER
·
2024
·Vol. 24
·期 1
·1-9
·
IF 3.4
Wang Zigui,Li Guilin,Zhao Qiaohui,Fu Guangyu,Yang Zengli,Zhang Guojun
Polymeric micelle systems for drug delivery, monitor and chemotherapy have gained significant attention, and reductive polymeric micelle systems have become particularly attractive due to their controlled release behavior without additional assistance. However, there are challenges in accurately controlling drug and probe release from the nanoparticles and determining the loading content of drug and probe. To address these issues, we have developed a reduction-responsive Pt(IV) prodrug-based polymeric delivery system that can be dynamically monitored using aggregation-induced emission luminogens (AIE) based bioprobes. These polymeric micelle can self-assemble into nanoparticles and release both bio-active Pt(II) drug and bio-probe upon reduction activation. TPE molecules released in the inner endo/lysosomal microenvironment aggregate and fluoresce upon irradiation, thus allowing real-time tracking of drug biodistribution without additional contrast agents. Advantages of this system include position-specific chemical bond cleavage, control of platinum content, and monitoring of drug reduction and biodistribution.
研究领域:
药物递送
·
生物医学工程
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Ruihan Li,Xuan Yin,Chuanke Chong,Yan Li,Qingqiang Yao,Yanling Mu,Chunyu Zhang
Polypeptides as drug delivery vehicles can achieve the targeted therapeutic effects of first-line platinum drugs in clinical practice, providing an important method to solve problems such as the high systemic toxicity of first-line platinum drugs. In this work, we employ a rational molecular conjugation strategy to design and synthesize two platinum(IV) prodrugs. The first, s-CisPt(IV)-TAT, is linked to a single nuclear-targeting polypeptide, while the second, d-CisPt(IV)-TAT, is conjugated with two of these polypeptides. Interestingly, despite the higher degree of functionalization, disubstituted d-CisPt(IV)-TAT exhibits lower reactivity and cytotoxicity than its monosubstituted counterpart. This counterintuitive result suggests that overloading with multiple ligands may reduce cellular uptake, thereby compromising therapeutic efficacy. Furthermore, both constructs are shown to induce apoptosis via DNA damage pathways, confirming their mechanism of action. These results underscore the importance of precisely tuning the ligand density in drug carriers. Our work provides valuable insights into the structure–activity relationships governing platinum prodrugs and highlights the need for a balance between functional density and biological performance in the design of next-generation polypeptide-conjugated chemotherapeutics.
研究领域:
肿瘤学
·
药物化学
·
分子药理学
·
纳米医学
·
转化医学
·
生物材料
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 8
·1185
·
IF 4.8
Ya Li,Siyang Liu,Meng Zhou,Zihan Zhao,Dongfan Song,Hongqian Guo,Rong Yang
Background: Bladder cancer is a common and heterogeneous malignancy of the urinary tract. Traditional chemotherapy using bivalent platinum drugs such as cisplatin(CDDP) is often limited by severe side effects and acquired resistance. To overcome these limitations, we explored a novel Pt(IV) prodrug, DNP, designed to release both cytotoxic cisplatin and the anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor naproxen(NPX).Methods: We evaluated the cytotoxic activity of DNP using both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid models of bladder cancer cells. Transcriptomic analysis via RNA-seq identified apoptosis- and inflammation-related signaling pathways modulated by DNP. RNA-seq-based transcriptomic profiling revealed that DNP regulates signaling pathways associated with apoptosis and inflammation. The anti-inflammatory effects were evaluated using a lipopolysaccharide (LPS)-induced macrophage model, while the in vivo antitumor efficacy was assessed in an orthotopic MB49 bladder cancer model.Results: Compared with CDDP, DNP significantly increased intracellular platinum accumulation and exhibited superior cytotoxicity. It effectively inhibited tumor proliferation, induced apoptosis, and attenuated inflammation both in vitro and in vivo.Conclusions: These findings suggest that DNP exerts dual antitumor effects through enhanced delivery of cytotoxic and anti-inflammatory agents, offering a promising strategy for bladder cancer therapy.
研究领域:
肿瘤学
·
药理学
·
分子医学
·
癌症治疗学
·
炎症生物学
✓ 已验证
DOI
PubMed
高影响因子
Polymer Chemistry
·
2019
·Vol. 10
·期 39
·5353-5363
·
IF 4.76
Jiaxu Li,Liuchun Zheng,Haihua Xiao,Chuncheng Li,Shaohua Wu,Yaonan Xiao,Jiajian Liu,Bo Zhang
Zwitterions of L-cysteine have been applied to modify polyester, and the obtained zwitterionic polyester is employed to load a platinum(IV) drug to prolong the circulation time of the drug in blood and improve the stability of drug loading due to the good biocompatibility and antifouling properties. When used as multifunctional drug delivery vehicles, the nanoparticles not only exhibit a pH- and reduction-responsive drug release character, but also possess high ovarian cancer treatment efficiency in vitro. As compared to cisplatin, the IC50 value of the platinum(IV) drug loaded nanoparticles decreased by 57.44%, demonstrating that the platinum(IV) drug loaded nanoparticles exhibit strong toxicity to A2780 cells. In particular, in this study, aliphatic amine highly selective dye 5(6)-carboxyfluorescein N-succinimidyl ester is first used to label the drug-loaded zwitterionic nanoparticles, aiming to trace the location of the nanoparticles in cancer cells. All these results demonstrate potential applications of this type of zwitterionic nanostructure in biomedical fields.
研究领域:
药学
·
生物医学工程
·
癌症研究
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xiao-Meng Liu,Zhen-Zhen Zhu,Xin-Rui He,Yun-Hong Zou,Qian Chen,Xiao-Ya Wang,Hui-Mei Liu,Xin Qiao,Xu Wang,Jing-Yuan Xu
Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of drug delivery, with the aim to promote bioavailability and minimize side effects. Herein, a multitargeting octahedral platinum(IV) prodrug with octadecyl aliphatic chain and histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions to improve the therapeutic effect of cisplatin was loaded on the upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment of DSPE-PEG2000 and arginine-glycine-aspartic (RGD) peptide endowed the nanovehicles with high biocompatibility and tumor specificity. The fabricated nanoparticles (UCNP/Pt(IV)-RGD) can be triggered by upconversion luminescence (UCL) irradiation and glutathione (GSH) reduction to controllably release Pt(II) species and PHB, inducing profound cytotoxicity. Both in vitro and in vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, high tumor-targeting specificity, and real-time UCL imaging capacity, presenting an intelligent platinum(IV) prodrug-loaded nanovehicle for UCL-guided dual-stimuli-responsive combination therapy.
研究领域:
癌症研究
·
纳米技术
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）