Asian Journal of Pharmaceutical Sciences
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2017
·
IF 0
Yang Ou,Zhao-hui Tang,Lu Sun,Hai-yang Yu,Jia Li,Mei-hui Zhao,Hui Xu
Combretastatin A4 (CA4) possesses varying ability to cause vascular disruption in tumors, while the short half-life, low water solubility and deactivation of many CA4 analogs during storage limited its antitumor efficacy and drug stability. A novel macromolecular conjugate of CA4 (CA4-PL) was synthesized by covalent bonding of CA4 onto poly( L -glutamic acid)-graft-polyethylene glycol (PLG-g-PEG) via Yamaguchi reaction. The obtained CA4-PL was characterized by 1 H NMR, GPC, and UV methods, and the properties of the nanoparticles composed of CA4-PL, including critical aggregation concentration, size and size distribution, and morphology, were investigated. CA4-PL can self-assemble to form micelle-like nanoparticles of 80~120 nm in diameter, which may have potential to improve the blood circulation period as well as the targetability of CA4, and find applications to treat various tumors when combined with traditional chemotherapy or radio therapy.
研究领域:
药剂学
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肿瘤学
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生物材料学
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DOI
PubMed
MACROMOLECULAR BIOSCIENCE
·
2021
·Vol. 21
·期 8
·2100077
·
IF 4.979
Yu Zhang,Xinming Liu,Xueping Wang,Pan He,Chunsheng Xiao,Haiyang Yu,Xuesi Chen
Chemotherapy using vascular targeting agents is an emerging new approach for cancer therapy. Combretastatin A4 (CA4) is a leading vascular-disrupting agent that targets the tumor blood vasculature for clinical tumor elimination. However, the extremely poor water solubility of CA4 hinders its biomedical applications. In this study, nanoparticles composed of novel PEGylated alternating copolymer-CA4 conjugates are designed to improve the therapeutic efficiency of CA4. First, an alternating copolymer with an alkene-pendant is synthesized by mPEG-OH-initiated ring-opening copolymerization. Then, side carboxyl groups are introduced by a thio-ene “click” chemical reaction, followed with CA4 conjugation through the Yamaguchi-reaction, resulting in the target copolymer, mPEG- b -P(PA- alt -GCA4). Interestingly, the polymer-drug conjugates can self-assemble into nanoparticles with an average diameter of 55.6 nm. The in vitro drug release and cytotoxicity of the obtained CA4-NPs toward 4T1 cells are investigated. Finally, the antitumor efficiency is evaluated in a 4T1-tumor bearing murine model. The in vivo test results demonstrate that CA4-NPs inhibited tumor growth much more efficiently at doses of 30 and 60 mg kg −1 , compared with the control group.
研究领域:
药学
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肿瘤学
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生物材料学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 4
·期 4
·760-767
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IF 4.726
Liping wu,Liyan Qiu
Combretastatin A4 phosphate (CA4P), the water-soluble phosphate pro-drug of combretastatin A4 (CA4), acts as a novel vascular disrupting agent (VDA). It strongly inhibits tubulin polymerization and selectively exerts action against tumor blood vessels. However, its quite short half-life (∼30 min) results in a short action time and consequently limits its application. Therefore, it is beneficial to develop a sustained-release preparation of CA4P for relatively long action duration. On the other hand, conventional PLGA microspheres display poor encapsulation capability for water-soluble small molecules due to rapid diffusion outside. Hence, we developed CA4P-loaded microspheres (CA4P-MS) composed of methoxy poly(ethylene glycol)-b-polylactide (PELA) reverse micelles and PLGA with a nano-in-micro sea-island structure. The CA4P encapsulation efficiency of CA4P-MS reached 92.88%. More interestingly, sustained drug release was achieved, which contributed to the prolonged inhibition effect on S180 tumor during a 30-day period with one-time subcutaneous administration. In conclusion, our study established a biodegradable polymer based platform to construct microspheres for water-soluble small molecular compounds with sustained release and a long-lasting action.
研究领域:
药剂学
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肿瘤学
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生物材料
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DOI
PubMed
高影响因子
Materials
·
2024
·Vol. 17
·期 11
·2570
·
IF 3.1
Yu Kong,Rong Zhang,Boyang Li,Wei Zhao,Ji Wang,Xiao-Wen Sun,Huihui Lv,Rui Liu,Juan Tang,Biao Wu
Phosphates play a crucial role in drug design, but their negative charge and high polarity make the transmembrane transport of phosphate species challenging. This leads to poor bioavailability of phosphate drugs. Combretastatin-A4 phosphate (CA4P) is such an anticancer monoester phosphate compound, but its absorption and clinical applicability are greatly limited. Therefore, developing carrier systems to effectively deliver phosphate drugs like CA4P is essential. Anion receptors have been found to facilitate the transmembrane transport of anions through hydrogen bonding. In this study, we developed a tripodal hexaurea anion receptor (L1) capable of binding anionic CA4P through hydrogen bonding, with a binding constant larger than 104M−1in a DMSO/water mixed solvent.L1demonstrated superior binding ability compared to other common anions, and exhibited negligible cell cytotoxicity, making it a promising candidate for future use as a carrier for drug delivery.
研究领域:
药学
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药物递送系统
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药物化学
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 2.713
Yurun Shen,Liping Wu,Liyan Qiu
Combretastatin A4 phosphate (CA4P) is a novel vascular disrupting agent for cancer therapy. However, frequent dosing and negative patient compliance have been encountered over CA4P by injection administration due to its quite short-term action and acute side effects . Therefore, it is significant to develop an oral formulation of CA4P. We established a novel method to prepare CA4P-loaded nanoparticles (CA4P-NPs) for oral administration by combining methoxy poly(ethylene glycol)-b-polylactide (PELA) and poly( d , l -lactic-co-glycolic acid) (PLGA) polymers. Transport study in vitro was evaluated on Madin-Darby canine kidney cell models, and antitumor effect evaluation in vivo was performed on S180 subcutaneous xenotransplanted tumor models in mice. The highest entrapment efficiency of CA4P-NPs was achieved when the weight ratio of PELA to PLGA was optimized to 1:1. The apparent permeability coefficient of CA4P-NPs was found to be 2.08-fold higher than that of free CA4P in transport study. CA4P-NPs reached an absolute bioavailability of 77.6% with the tumor inhibition ratio of 41.2% that was significantly superior to free CA4P. These results suggest a promising application of this composite nanoparticle for the oral delivery of water-soluble drugs.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Huihui Li,Kang Liu,Zexin Yang,Quanwei Sun,Wencui Shang,Yunlong Li,Mingjing Wang,Ye Yang,Hanmeng Liu,Dengke Yin,Wei Shen
Although vascular disrupting agents (VDAs) can induce shutdown of blood flow and necrosis in the tumor core, eradicating tumor rim cells remains a significant challenge. Recently, researchers have developed various combination treatment strategies to improve the efficacy of VDAs. However, the aggravated hypoxic tumor microenvironment following vascular disruption limits the effectiveness of conventional therapeutic approaches. Here, we developed an ε-polylysine-derived oncolytic polymer (named OPAA) with membrane lytic activity. Its cytotoxic effect on tumor cells is largely unaffected by hypoxic conditions, as evidenced by the ratio of its IC50 value for 4 T1 cells under normoxic conditions to that under hypoxic conditions, which is 0.98. Subsequently, a pH-responsive combretastatin A4 phosphate disodium salt (CA4P)-loaded nanoparticle (OPAA@CA4P NPs) has been designed to efficiently deliver OPAA and CA4P to solid tumors. OPAA@CA4P NPs exhibited a prolonged serum half-life (t 1/2 = 3.15 h) compared to CA4P (t 1/2 = 0.31 h) and an enhanced tumor accumulation. In addition, CA4P can be responsively released within the tumor microenvironment, leading to necrosis in the tumor center. Concurrently, OPAA released from the nanoparticles eradicated the surviving cancer cells at the tumor periphery, thereby improving the overall therapeutic effect. Notably, compared to the CA4P + doxorubicin group (tumor suppression rates, TSR = 36.17 %), the OPAA@CA4P NPs group demonstrated superior therapeutic outcomes (TSR = 60.30 %). Overall, the introduction of oncolytic polymers provides new insights into the potential future applications of VDAs.
研究领域:
药理学
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肿瘤学
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生物材料科学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Yu-Jing Wang,Shuai-Bing Ying,Lin Liu,Qiu-Dan Zhang,Yong Pan,Yu-Qi Hong,Hao-Yang Hu,Yi Liu,Jia-Ni Wei,Zhi-Juan Zhang,Yun-Qing Qiu,Yan Lou
Combretastatin A4 (CA4) is a potent microtubule inhibitor, but its phenolic hydroxyl group is prone to oxidation into toxic quinone products, leading to poor metabolic stability and dose-limiting toxicity that restricts its clinical application. To overcome this limitation, we propose a novel dimer prodrug strategy that covalently links two CA4 molecules via an enzyme-cleavable linker, achieving temporary masking of the phenolic hydroxyl group. The resulting CA4-dimer1 and CA4-dimer2 exhibited potent in vitro antiproliferative activity. Of the two dimers evaluated, CA4-dimer1 demonstrated superior in vitro potency. Crucially, CA4-dimer1 achieved significant tumor suppression rates in patient-derived xenograft (PDX) liver cancer models without notable toxicity. CA4-dimer2 releases active CA4 through gradual hydrolysis but showed slightly lower in vivo release efficiency compared to CA4-dimer1. Flow cytometry and Western blot analysis revealed that this prodrug exerts antitumor activity through the same mechanism as the parent compound CA4. Collectively, the reported CA4-dimer prodrug strategy offers a highly promising approach for treating liver cancer and enhancing the therapeutic index of phenolic drugs, while also providing a potential strategy for structural optimization of drugs containing phenolic hydroxyl groups
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
·
IF 10.8
Mengfei Zheng,Hang Xu,Yue Huang,Jiali Sun,Honglei Zhang,Zheng Lv,Zhilin Liu,Zhaohui Tang,Xuesi Chen
6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. However, there are currently no reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. To improve the selective toxicity of DON to tumor cells while reducing systemic toxicity, a hypoxia-activated prodrug, termed HDON, was designed. HDON achieved remarkable tumor suppression of 76.4 ± 5.2% without leading to weight loss in an H22 murine liver cancer model with high hypoxia . Moreover, to augment the therapeutic efficacy of HDON, combretastatin A4 nanoparticles were used to aggravate tumor hypoxia of MC38 murine colon cancer and 4T1 murine breast cancer, activate HDON to DON, and stimulate a robust anti-tumor immune response while selectively killing in tumor cells in vivo , achieving significantly elevated tumor suppression rates of 98.3 ± 3.4% and 98.1 ± 3.1%, with cure rates of 80.0% and 20.0%, respectively.
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Zhao Bonan,Dong Zhipeng,Liu Weixing,Lou Fangning,Wang Qiyan,Hong Hao,Wang Yue
Background According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. Results In this study, the use of poly( l -Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. Conclusions We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment. Graphic abstract
研究领域:
肿瘤学
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药学
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免疫疗法
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2019
·
IF 4.471
Hong Jiang,Zhi-Peng Li,Gui-Xiang Tian,Rui-Yan Pan,Chong-Mei Xu,Bo Zhang,Jing-liang Wu
Background Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drug-delivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. Methods Glycyrrhetinic acid (GA)–modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. Results Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence–imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. Conclusion GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.
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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药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Yuchen Wang,Yang Liu,Long Wang,Zhong Chen,Qingsong Ye,Kaiyuan Chen,Chenxuan Zhao,Mingkang Yang,Wen Xia,Min Zhang,Jun Qiao,Guangxin Zhou,Jinhui Wu
The immunosuppressive tumor microenvironment formed by many solid tumors, particularly colon cancer, suppresses innate immune molecule expression and consequently limits T cell infiltration. Microtubule inhibitors were originally developed to eliminate tumors by inducing mitotic arrest. However, recent studies have shown that these inhibitors can also disrupt the microtubule dynamics and enhance the efficacy of immunotherapies. These findings highlight the target microtubule as a promising strategy for immune modulation. In this study, we investigated the use of Combretastatin A4 (CA4), a hydrophobic microtubule inhibitor that targets tumor vascular endothelial cells. To improve its solubility and delivery efficiency, CA4 was encapsulated in human serum albumin to form CA4@Alb. This formulation effectively inhibited microtubules in tumor endothelial cells, resulting in the promoted infiltration of erythrocytes into the tumor microenvironment. These erythrocytes were subsequently phagocytosed by intratumoral macrophages, leading to their pro-inflammatory activation. Notably, erythrophagocytic macrophages upregulated innate immune molecules, including chemokine CXCL10 and costimulatory molecule CD86, and enhanced T cell infiltration and activation. As a result, CA4@Alb significantly improved the responsiveness to T cell-based immunotherapies. Overall, our findings indicate that CA4@Alb effectively reprograms the immunosuppressive microenvironment of colon cancer and holds promising translational potential for enhancing immunotherapy efficacy.
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Youqiang Fang,Zheng Liu,Haixia Wang,Xing Luo,Yanteng Xu,Hon Fai Chan,Shixian Lv,Yu Tao,Mingqiang Li
Tumor recurrence is a critical conundrum in the postoperative therapy, on account of severe bleeding with disseminated tumor cells, residual tumor cells, and the rich nutrient and oxygen supply transported to tumors by the abundant blood vessels. Biodegradable drug-loaded implants, inserted in the resection cavity right away upon the surgery, possess bleeding prevention and efficient chemotherapeutic capabilities, considered to be a promising strategy to efficiently inhibit the recurrence of the solid tumor. Here, we developed a sandwich-like composite consisting of the combretastatin A4 (CA4)-loaded 3D-printed scaffold and doxorubicin (DOX)-loaded electrospun fiber (Scaffold-CA4@Fiber-DOX), presenting hemostatic, chemotherapeutic, and antibacterial potencies. The lyophilized 3D-printed scaffold with a porous structure rapidly absorbed and clotted the blood cells and disseminated tumor cells to prevent bleeding and tumor metastasis. Subsequently, the preferentially released CA4 from the scaffold disrupted the microtubules of the vascular endothelial cell, resulting in vascular deformation and consequent insufficient nutrient supply to the solid tumor. The sustained release of DOX from the sandwiched electrospun fiber dramatically inhibited the peripheral tumor cell proliferation. This all-in-one multifunctional implant system, combining efficient vascular disruption and chemotherapy, provides a promising strategy for postoperative tumor therapy.
研究领域:
药学
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生物医学工程
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肿瘤学
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材料科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）