JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2025
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IF 4.9
Lei Chen,Jiabao Liu,Chunxiang Gui,Ke mei,Xiaoshuang Dai,Yang Song,Daobing Jiang,Lian Deng,Junda Liu,Neng Qiu
Malignant tumors are one of the most dangerous types of diseases seriously threatening global health, and how to better treat them is a difficult issue for the medical community. Podophyllotoxin and its derivatives were known to have good antitumor efficacy. But their poor water solubility, toxicity to normal tissues, susceptibility to drug resistance, and low absorption by cancer cells have limited their clinical application. A striking feature of cancer cells compared to normal cells is the existence of intracellular overproduction of reactive oxygen species (ROS), frequently used as stimuli for drug release from nanocarriers. In this study, we developed a ROS responsive twin prodrug PPT-S-PPT, in which two podophyllotoxins (PPTs) were coupled by 3,3′-thiodipropionic acid via a thioether bond. PPT-S-PPT can form spherical nanoparticles with a mean diameter of about 200 nm in water. These self-assembled nanoparticles maintained good storage stability for up to 3 weeks. In vitro release study showed that H 2 O 2 can accelerate the drug release of PPT-S-PPT NPs in PBS. Both HPLC assay and fluorescence study showed that the intracellular uptake of PPT-S-PPT NPs was significantly higher than free drug or free fluorescence probe. The PPT-S-PPT NPs were up-taken by Hela cells via multiple endocytic pathways, and lipid rafts may play a greater role in the endocytosis of PPT-S-PPT NPs. In addition, the PPT-S-PPT NPs showed higher inhibitory effect (almost 14-fold) than free PPT against Hela cells after 24h treatment. The potent cellular inhibition effect of NPs might be due to the increased cellular uptake as well as the enhanced intracellular drug release resulting from the ROS responsiveness. Moreover, PPT-S-PPT NPs revealed favorable cytocompatibility and good hemocompatiblity. This carrier-free ROS-sensitive twin drug nanoassebly provides possibilities for the development of ROS-responsive prodrugs or dimer nanoparticles for efficient cancer therapy.
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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产品关联
DOI
高影响因子
LANGMUIR
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2023
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IF 3.9
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG–NH–N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.
研究领域:
药学
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肿瘤学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Weiwei Jiang,Yuwei Cheng,Lei Hou,Ying Huang,Sizhen Wang,Yunchang Zhang,Tao Jiang,Feng Yang,Zhiqiang Ma
The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.
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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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2023
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IF 5.9
Liuwei Zhang,Haonan Zheng,Hongyan Cui,Xiaolan Yin,Cheng Zhang,Yue Wang,Yan Zhao,Jiaqi Lin,Zheng Wang,Jingyun Wang,Qixian Chen
One of the challenges in antitumor therapy is the precise delivery of the therapeutic agent to cancerous cells. The delivery of chemotherapy agents can benefit from nanoformulation of prodrugs, which integrates the benefits of nanotechnology and prodrugs, including enhanced drug loading, increased drug bioavailability, and targeted accumulation within cancerous cells. In this work, we designed a redox-responsive polymeric dual-prodrug nanocarrier, PL-ss-(C&J), for codelivery of a potent chemotherapeutic camptothecin (CPT) and an immune checkpoint inhibitor JQ1. Further investigations confirmed that the developed nanomedicine was able to respond to the highly reductive environment within tumor cells. Additionally, due to their quick reactions to the intracellular reducing microenvironment, cytotoxic CPT and JQ1 were simultaneously activated and released, exhibiting significant cytotoxicity. This dual-prodrug activation approach also demonstrated high efficiency in inhibiting tumor growth with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. These results indicated that this type of redox-sensitive dual-prodrug codelivery system based on polymeric prodrug nanomicelles would be a promising technology in chemotherapy and immunotherapy.
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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癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2021
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IF 4.539
Xia Chen,David H. Bremner,Yuhan Ye,Jiadong Lou,Shiwei Niu,Li-Min Zhu
The premature leakage of chemotherapeutics during delivery impedes drugs from entering tumor cells, which produces considerable side effects in normal organs. Herein, we describe a hydrophobic-hydrophilic balanced self-assembled prodrug nanoparticle ( [email protected] ), formed via a facile synthesis based on chitosan oligosaccharide to reduce the non-targeting risk of premature leakage of chemotherapeutics during their delivery. The [email protected] have a suitable size (~186 nm) with a doxorubicin (DOX) loading of 9.88% and an oleanolic acid (OA) loading efficiency of 27.34%. The release of DOX or OA is pH-dependent and responds particularly well to the acidic tumor microenvironment. In vitro antitumor activity studies revealed that [email protected] had enhanced performance in promoting tumor apoptosis and displayed significant anticancer effects compared to mono-delivery. In vitro cell studies showed that HA-functionalized nanoparticles could enhance the cellular uptake in tumor cells. Therefore, [email protected] is a promising vehicle for CD44-targeted co-delivery of cancer chemotherapy, which deserves further evaluation.
研究领域:
药剂学
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纳米技术
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肿瘤学
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
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2019
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IF 6.638
Zigui Wang,Gaizhen Kuang,Zhiqiang Yu,Aimin Li,Dongfang Zhou,Yubin Huang
The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, release, and adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Here, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography (DMCT) imaging without the introduction of any additional diagnostic imaging agent. DPP NP enables visible light-triggered prodrug polymer backbone cleavage and bioactive Pt(II) release in cancer cell/tumor site; the light-cleaved polymer fragments are further hydrolyzed to produce demethyl cantharidin (DMC). Notably, the drug loading ratio of Pt(IV) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo . Because of the high content of the heavy metal Pt in the polymer chain, the spatial/temporal dynamic biodistribution as well as metabolism of DPP NP in vivo can be monitored by Pt DMCT imaging to guide the light irradiation parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP was able to achieve an improved light-activatable antitumor efficacy, with 75% tumors fully cured and low toxicity. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine . Statement of Significance The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, delivery, and release, as well as adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Herein, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any additional diagnostic imaging agents. Notably, the drug loading ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo . The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine.
研究领域:
纳米技术
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药学
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生物医学工程
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2019
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IF 6.054
Ran Zhang,Xue-Qing Song,Rui-Ping Liu,Zhong-Ying Ma,Jing-Yuan Xu
As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of “dual-prodrug” by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10–17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower cytotoxicity toward the human normal lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62- and 825-fold amount of oxaliplatin and 8 at 9 h, respectively, significantly induced DNA damage and cell apoptosis, and inhibited migration and invasion in HCT-116 cells. Compound 14 arrested the cell cycle at S and G2 phases and up-regulated thymidylate synthase and p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to kill cancer cells. In vivo, compound 14 showed high antitumor effect and no observable toxicity in NOD/SCID mice bearing HCT-116 tumors.
研究领域:
肿瘤学
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药理学
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化疗
✓ 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）