Materials Today Advances
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2025
·
IF 8
Lingmei Li,Shuwan Li,Lin Gao,Sitong Chen,Dejin Zang,Qing Fan,Zhiyuan Lu,Teng Liu
Amphiphilic self-assembly bridges nanoscale engineering with biological functionality, forming compartmentalized nanocarriers that enable stimuli-responsive drug delivery. We engineered a glutathione (GSH)-responsive amphiphilic conjugate (POMs-SS-CPT) by covalently linking hydrophilic polyoxometalates (POMs) with hydrophobic drug camptothecin (CPT) through disulfide bonds, alongside a non-responsive carbon-bonded control (POMs-CC-CPT). Both compounds spontaneously self-assembled into vesicles in aqueous solution, enhancing cellular internalization. The GSH-responsive POMs-SS-CPT vesicles leveraged amphiphilic nanostructuring to achieve tumor-specific triggered co-release of POMs and CPT. This spatially controlled release minimized off-target toxicity while exerting potent synergistic antitumor activity. Both in vitro and in vivo studies demonstrated that POMs-SS-CPT vesicles exhibited superior antitumor efficacy and markedly inhibited tumor growth. This work establishes a novel GSH-responsive vesicular platform for efficient POM-based combination chemotherapy and elucidates critical design principles for redox-responsive delivery, providing a mechanistic framework for nanomedicine delivery systems.
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Recent Patents on Anti-Cancer Drug Discovery
·
2021
·Vol. 16
·期 2
·258-272
·
IF 4.169
Zhang Xiangli,Shen Qin,Wang Yi,Zhou Leilei,Weng Qi,Li Qingyong
Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues, modified deoxycholic acid at 20-position of CPT(camptothecin) with greater anticancer activity
and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase I and Phase II metabolism of E2 and G2 in rat liver microsomes were performed, respectively, and the mixed incubation of phase I and
phase II metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some
difference. The intrinsic clearance of G2 was 174.7 mL/min. mg protein, more than three times that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations
and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except for some differences in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in
the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).
研究领域:
药理学
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生物化学
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肿瘤学
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PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2019
·
IF 3.621
Mengzhen Wang,Junjie Yan,Cong Li,Xinyu Wang,Jianjun Xiong,Donghui Pan,Lizhen Wang,Yuping Xu,Xiaotian Li,Min Yang
Poly(amide-imide)s (PAIs) present limited use in bioapplications due to their poor aqueous solubility and difficulty in functional accessibility. Herein, we prepared PAI-based prodrugs by leveraging aliphatic PAIs as the polymer scaffolds and conjugating camptothecin (CPT) via thiol-disulfide exchange reaction. The degree of CPT attachment can be smoothly controlled by initial feed ratios of PEG and a pyridinedisulfide-modified CPT precursor. Due to the abundant secondary amine groups in PAI backbones, amphiphilic PAI-CPT prodrugs self-assembled into cationic nanoparticles and showed an efficient cellular internalization (<2 h). The presence of disulfide linkers between PAI scaffolds and CPT endowed PAI-CPT prodrugs a reductive-responsive drug release profile. Moreover, when PAI-CPT prodrug nanoparticles were further used as nanocarriers, doxorubicin (DOX) was additionally encapsulated and variable nanomorphologies (nanospheres, branched nanoparticles) were obtained, and an enhanced chemotherapy efficacy was achieved as well.
研究领域:
聚合物化学
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药学
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纳米医学
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癌症治疗
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高影响因子
MOLECULES
·
2022
·Vol. 27
·期 12
·3669
·
IF 4.927
Yi Wang,Xiangli Zhang,Wenya Zhuang,Yanlei Yu,Xuanrong Sun,Hong Wang,Fengzhi Li,Qingyong Li
Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). To reverse this resistance, two novel CPTs, FL77-28 (7-(3-Fluoro-4-methylphenyl)-10,11-methylenedioxy-20(S)-CPT) and FL77-29 (7-(4-Fluoro-3-methylphenyl)-10,11-methylenedioxy-20(S)-CPT), were synthesized by our group. In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118. The transport and uptake of FL118, FL77-28, and FL77-29 were investigated in Caco-2 cells for the preliminary prediction of intestinal absorption. The apparent permeability coefficient from apical to basolateral (Papp AP-BL) values of FL77-28 and FL77-29 were (2.32 ± 0.04) × 10−6cm/s and (2.48 ± 0.18) × 10−6cm/s, respectively, suggesting that the compounds had moderate absorption. Since the transport property of FL77-28 was passive diffusion and the efflux ratio (ER) was less than 2, two chemical inhibitors were added to further confirm the involvement of efflux proteins. The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins.Keywords:Camptothecin derivatives;cytotoxicity;bioavailability;Caco-2 cells model;drug resistance
研究领域:
药理学
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肿瘤学
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药物递送系统
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PubMed
高影响因子
Acta Biomaterialia
·
2021
·
IF 8.947
Qian Huang,Xun Liu,Haiyang Wang,Xiangrui Liu,Qianzhi Zhang,Ke Li,Yu Chen,Qian Zhu,Youqing Shen,Meihua Sui
Clinical development of 7-ethyl-10‑hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT-11), is hindered by its insolubility and poor stability. Another obstacle is that tumors could become resistant to SN38/CPT-11 through multiple mechanisms involving breast cancer resistance protein (BCRP). Herein one of the most potent and selective BCRP inhibitors, Ko143, is encapsulated into a recently constructed prodrug PEG-S-S-SN38 displaying a high and fixed drug loading, multiple intratumoral stimuli (oxidative stress, GSH and esterase)-responsive drug release and significant in vitro and in vivo superiorities over CPT-11. The obtained “combo” for simultaneous delivery of SN38 and Ko143, named as [email protected] , has a high SN38 loading efficacy (14.85 wt.%) and a good Ko143 encapsulation efficacy (3.79%). Through generating panels of human colorectal cancer models expressing altered levels of BCRP via lentiviral transfection and CRISPR-Cas9, characteristics of different drug formulations are carefully evaluated. Impressively, [email protected] nanoparticles effectively reverse chemoresistance to CPT-11 (resistance index dropping from ∼274.00–456.00 to ∼1.70–4.68) and PEG-S-S-SN38 (resistance index dropping from ∼5.83–14.00 to ∼1.70–4.68) in three BCRP-overexpressing cancer cell lines. More importantly, reversal of BCRP-mediated chemoresistance to CPT-11 ( P values lower than 0.001–0.0001) and PEG-S-S-SN38 ( P values lower than 0.01–0.001) by [email protected] nanoparticles are further confirmed with two panels of colorectal cancer xenograft models in vivo . As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, [email protected] provides a new approach for resolving the bottlenecks for clinical translation of SN38 and numerous “chemosensitizers” like Ko143, and exhibits promising applicability in precision cancer medicine. Statement of significance To resolve the bottlenecks in clinical application of anticancer agents SN38/CPT-11 and the most potent breast cancer resistant protein (BCRP) inhibitor Ko143, a “combo” nanotherapeutic simultaneously delivering SN38 and Ko143 was constructed and named as [email protected] By generating panels of colorectal cancer models, we demonstrate that [email protected] nanoparticles effectively and selectively reversed BCRP-mediated tumor resistance to SN38/CPT-11 in vitro and in vivo . As the first nano-formulation of Ko143 and the first systemic co-delivery vehicle of SN38/CPT-11 and a BCRP inhibitor, [email protected] provides a new strategy for clinical development of SN38 and numerous “chemosensitizers”, and exhibits promising applicability in precision cancer medicine. Panels of cancer cell lines established here provides a useful platform for BCRP- and cancer-related research and technology development.
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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分子生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Yi-Fei Xue,Xiaojie Song,Xiao-Qing Ling,Qi-Yan Lv,Yu Xia,Hui-Fang Cui
Nanoassemblies based on drug conjugates with high drug loading efficiency and stability have been regarded as promising candidates for the next generation of drug formulations. However, they are mostly amphiphilic. Here, a dual-hydrophobic drug conjugate-based nanoassembly has been created for enhanced synergistic antiproliferation against colorectal cancer cells. Camptothecin (CPT) and doxorubicin (DOX) were chosen as the hydrophobic drugs and covalently linked with a disulfide bond (-ss-). The synthesized CPT-ss-DOX can self-assemble into nanocubes (NCs) in an aqueous solution with the assistance of a small amount of polyethylene glycol (PEG), named PEGylated CPT-ss-DOX NCs. The PEGylated CPT-ss-DOX NCs were approximately 111.8 nm, possessing a crystal structure and a very low critical aggregation concentration (8.36 μg·mL–1). The self-assembly mechanism was studied using molecular docking and molecular dynamic simulation methods. The NCs demonstrated excellent storage stability and improved water solubility of CPT and DOX. These NCs could be taken up by cancer cells and gradually release the drugs. In addition, they had higher toxicity to cancer cells than a mixture of CPT and DOX, while they displayed reduced toxicity to normal cells. Due to assembly and PEG modification, the NCs improved drug retention time and enhanced accumulation at the tumor site. More importantly, they significantly inhibited colorectal tumor growth (58.37%) in vivo, superior to the CPT+DOX mix (42.63%). Moreover, the NCs reduced the cardiac toxicity of free drugs. Therefore, the prepared PEGylated CPT-ss-DOX NCs hold great potential for clinical transformation and provide a novel method for the self-delivery of hydrophobic molecules in cancer therapy.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·
IF 10.6
Wenjie Xu,Zhaokui Zeng,Yucheng Tang,Jingjing Tian,Xinyan Hao,Pengcheng Sun,Yanjin Peng,Tian Tian,Daxiong Xiang,Rongrong Wang,Chuanpin Chen,Junyong Wu
Chemotherapy is still one of the major approaches in triple-negative breast cancer (TNBC) treatment. The development of new formulations for classic chemotherapeutic drugs remains interests in studies. Camptothecin (CPT) is powerful antitumor agents in TNBC treatment though its clinic applications are limited by its low water solubility and systemic toxicity. To prepare a spatiotemporal controllable CPT nano-formulation, we construct a ROS-responsive self-assembly nanoparticle by combining hydrophobic CPT and hydrophilic 5-floxuridine (FUDR). A ROS-sensitive thioketal (TK) linker is used to prepare CPT-TK-FUDR (CTF). Next, we introduced IR780-based phototherapy to elicit massive ROS regeneration due to the endogenous ROS is not sufficient. IR780 is modified with hyaluronic acid (HA) to prepare HA-modified IR780 (HAIR) for its biocompatibility and tumor targeting ability improvement. CTF and HAIR self-assemble to form an attractive nano-bomb (HAIR/CTF NPs). HA accurately guides the NPs to tumor sites via HA-receptor recognition on tumor cells. After internalization, overexpressed intracellular HAase in tumor cells disassembles the NPs to free the contents. Due to the presence of IR780 molecules, the scheduled irradiation of 808 nm laser induces massive reactive oxygen species (ROS) generation, which further result in the cleavage of TK linker for free drugs release. Additionally, ROS-mediated photodynamic therapy (PDT) and near-infrared laser-mediated photothermal therapy (PTT) synergistically worked to eradicate tumor cells. Then immunogenic cell death (ICD) was evoked by CPT and phototherapy to amplify antitumor immunity, thereby achieving primary and abscopal tumor inhibition. In conclusion, the HAIR/CTF nano-bomb realized spatiotemporal controllable drug release, exciting tumor eradication and attractive anti-metastasis efficacy via combination chemo/photo/immunotherapy, offering a valuable reference for the re-development of classic drug in future clinical practice.
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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癌症治疗
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生物医学工程
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PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Yipiao Zhang,Tian Tian,Zhaokui Zeng,Chuanpin Chen,Rongrong Wang,Suhong Chen,Hongliang Zheng
The treatment of breast cancer (BC) remains a major challenge. Although chemotherapy is currently the most common treatment, it is limited by high side effects. Responsive drug delivery systems (DDS) enable the controlled release of drugs, which can decrease the side effects of chemotherapy and improve efficacy. However, achieving precise delivery and targeted release of drugs is a major challenge. Here, we present ultrasound-triggered reactive oxygen species (ROS)-responsive conjugated polymer nanoparticles for combination therapy of BC. The conjugated polymer nanoparticles are candidates for the development of potential acoustic sensitizers due to their structural properties with good stability and biocompatible acoustic activation properties. In this study, sono-sensitive polymer nanoparticles (SPN) were used for spatiotemporally controlled sonodynamic therapy (SDT) and ROS-responsive chemotherapy. It was demonstrated that the SPN possessed potent acoustic-dynamic properties and could be activated by ultrasound to generate high levels of ROS, which cleaved ROS-responsive junctions, thereby facilitating the release of camptothecin. Furthermore, the SPN exhibited good long circulation properties and biocompatibility in vivo. The SPN combined with ultrasound treatment showed significant therapeutic effects in both BC cell lines and hormonal mouse models, with tumor suppression rates as high as 76.98 ± 9.09%, and no cardiotoxicity or other side effects were observed. Therefore, the present study provides a feasible strategy for designing novel controlled-release drug systems to improve the therapeutic efficacy of BC.
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高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2021
·
IF 5.571
Qihong Zhang,Zongmiao Feng,Hui Wang,Chen Su,Zhaohui Lu,Jingbo Yu,Alexandr V. Dushkin,Weike Su
Natural compounds as carriers for hydrophobic drugs have been increasingly used in drug delivery systems . In this study, disodium glycyrrhizin (Na 2 GA), tannic acid (TA) and camptothecin (CPT) were firstly used to prepare the camptothecin solid dispersion (CPT SD). When dissolved in a solution medium, Na 2 GA self-assembled to form micelles and CPT was encapsulated in micelles, meanwhile, TA connected with Na 2 GA through hydrogen bonds to form a contract shell. The average diameter of the CPT-loaded micelles is 80 nm with the critical micellar concentration of 0.303 mg/mL, the zeta potential of −33 mV, the PDI of 0.25 and drug loading 6.22%. In vitro experiments confirmed that the drug-loaded micelles exhibited excellent stability and permeability in the intestinal environment. Furthermore, the formulation showed excellent anti-tumor activity in vitro and in vivo . These findings imply that this nano-micelles provide a more potential and efficacious oral drug formulation for chemotherapy.
研究领域:
药剂学
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肿瘤学
·
药物递送系统
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DOI
PubMed
高影响因子
Horticulture Research
·
2021
·
IF 6.793
Hao Xiaolong,Xie Chenhong,Ruan Qingyan,Zhang Xichen,Wu Chao,Han Bing,Qian Jun,Zhou Wei,Nützmann Hans-Wilhelm,Kai Guoyin
The limited bioavailability of plant-derived natural products with anticancer activity poses major challenges to the pharmaceutical industry. An example of this is camptothecin, a monoterpene indole alkaloid with potent anticancer activity that is extracted at very low concentrations from woody plants. Recently, camptothecin biosynthesis has been shown to become biotechnologically amenable in hairy-root systems of the natural producer Ophiorrhiza pumila. Here, time-course expression and metabolite analyses were performed to identify novel transcriptional regulators of camptothecin biosynthesis in O. pumila. It is shown here that camptothecin production increased over cultivation time and that the expression pattern of the WRKY transcription factor encoding gene OpWRKY2 is closely correlated with camptothecin accumulation. Overexpression of OpWRKY2 led to a more than three-fold increase in camptothecin levels. Accordingly, silencing of OpWRKY2 correlated with decreased camptothecin levels in the plant. Further detailed molecular characterization by electrophoretic mobility shift, yeast one-hybrid and dual-luciferase assays showed that OpWRKY2 directly binds and activates the central camptothecin pathway gene OpTDC. Taken together, the results of this study demonstrate that OpWRKY2 acts as a direct positive regulator of camptothecin biosynthesis. As such, a feasible strategy for the over-accumulation of camptothecin in a biotechnologically amenable system is presented.
研究领域:
植物生物技术
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分子生物学
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药理学
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PubMed
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 4
·期 1
·141-151
·
IF 4.726
Liang Qiu,Qing Liu,Chun-Yan Hong,Cai-Yuan Pan
In order to develop pH- and redox-responsive unimolecular micelles composed of camptothecin (CPT)-conjugated hyperbranched star copolymers via acid-labile β-thiopropionate linkage, a new monomer, methacryloyloxy-3-thiohexanoyl–CPT, is synthesized through conjugation of CPT with methacrylate via β-thiopropionate linkage, and then used in synthesis of the CPT-conjugated hyperbranched star copolymers by two steps of atom transfer radical polymerization (ATRP): self-condensation vinyl polymerization of the CPT-based monomer, 2-hydroxypropyl methacrylate and inimer, and subsequent ATRP of oligo(ethylene glycol) methacrylate using the obtained hyperbranched polymers as the macroinitiator. The obtained polymers dissolve in water to form unimolecular micelles, and their release of CPT in water at various pHs and their anticancer efficacy are studied. The CPT-loaded unimolecular micelles with diameters of 3.56–6.08 nm are quite stable under neutral environment, and are easily triggered by mild acidic pH, such as 6.0 and 5.0. They can be easily internalized by the tumor cells, releasing the CPT. The CPT-conjugated unimolecular micelles via acid-labile β-thiopropionate linkage have potential for application as tumor-targeted drug release systems.
研究领域:
药物化学
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高分子化学
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肿瘤治疗学
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DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2022
·
IF 6.449
Yanmei Ma,Minwen Jiang,Xinjian Liu,Xiaoyu Xu,Xinxin Jiang,Ligang Chen,Na Niu
This work has prepared a hyper-crosslinked molecularly imprinted resins (MIRs) with chloromethylated polystyrene resin as a carrier through post-crosslinked Friedel-Crafts and surface imprinting. The prepared MIRs were used for the selective separation and purification of camptothecin (CPT). The prepared MIRs are grafted with a large amount of active group phenol, which have good hydrophilicity and are favorable for application in aqueous environments. The results of Scatchard analysis and contact angle test have proved that MIRs have good adsorption capacity and excellent hydrophilicity. In addition, the results of density functional theory (DFT) analysis show that the possible interaction forces between the template molecule CPT and the functional monomer phenol are the hydrogen bonds and electrostatic attraction. Moreover, MIRs are successfully used as a solid phase extraction (SPE) adsorbent to separate and purify CPT from Camptotheca acuminata fruit. The eluent obtained by SPE is analyzed through HPLC. The detection limit for CPT is 0.23 μg mL −1 . The established method preforms high the recovery of CPT (91.2–103.4%) with relative standard deviation less than 4.5%. The reusability of MIRs adsorbent is also investigated, and the adsorption efficiency is still above 95% after being recycled five times. The study provides a feasible and efficient method for selective separate and purify CPT from complicated system.
研究领域:
化学工程
·
药学
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分析化学
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材料科学
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高影响因子
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