JOURNAL OF CONTROLLED RELEASE
·
2012
·
IF 6.499
Hongfang Zhang,Jinqiang Wang,Weiwei Mao,Jian Huang,Xianguo Wu,Youqing Shen,Meihua Sui
The clinical utility of CPT-11 is restricted by factors such as the low conversion rate to SN38 , high interpatient variability and dose-limiting toxicity. SN38 is significantly more potent than CPT-11, but parental administration of SN38 is impossible due to its poor solubility and low stability. This study aimed to develop a novel SN38 prodrug (OEG-SN38) that may overcome the various drawbacks of CPT-11 and SN38 and be useful for clinics. We attached a very low molecular weight oligo (ethylene glycol) (OEG) chain selected as the hydrophilic part to hydrophobic SN38 via ester bond at the C20 position to form the amphiphilic OEG-SN38. In aqueous solution OEG-SN38 formed micelles with diameter of 28.74 ± 2.51 nm, and showed greatly improved drug loading, solubility and stability, with drug loading as high as 36% (wt.%). Moreover, these micelles were stable in PBS with only 4.71% SN38 released from the prodrug even after 35 h incubation, but released SN38 promptly by esterase hydrolysis. Most importantly, OEG-SN38 exhibited potent antitumor activity against a panel of human tumor cell lines, as well as favorable antitumor activity and high safety in human xenograft models. These encouraging data merit further preclinical and clinical investigation on this novel SN38 delivery system.
研究领域:
药学
·
肿瘤学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Jiayu Zhao,Sheng Ma,Yudi Xu,Xinghui Si,Haochen Yao,Zichao Huang,Yu Zhang,Haiyang Yu,Zhaohui Tang,Wantong Song,Xuesi Chen
STING (stimulator of interferon genes) signaling pathway has attracted considerable attention in cancer immunotherapy due to its capacity to boost vigorous antitumor immunity. However, the shortage of effective STING agonists limits the promotion of STING pathway in cancer treatment. Herein, we present an approach for in situ activation of STING pathway with nanoparticles delivered DNA-targeting chemo agents, based on the understanding that cytosol DNA is a pre-requisite for STING pathway activation. Through in vitro screening among several DNA-targeting chemo agents, we identified 7-ethyl-10-hydroxycamptothecin (SN38) as the most potent drug for stimulating interferon (IFN)-β secretion and proved that this process is mediated by the passage of DNA-containing exosomes from treated tumor cells to bone marrow-derived dendritic cells (BMDCs) and subsequent activation of the STING pathway. Furthermore, we designed a polymeric-SN38 conjugate that could self-assemble into nanoparticles (SN38-NPs) for in vivo application. The SN38-NPs formulation reduced toxicity of free SN38, effectively stimulated the activation of STING pathway in E0771 tumors, and resulted in a tumor suppression rate (TSR%) of 82.6%. Our results revealed a new mechanism of SN38 in cancer treatment and should inspire using more DNA-targeting agents, especially in nanoformulation, for activating STING pathway and cancer chemoimmunotherapy.
研究领域:
癌症免疫治疗
·
药学
·
纳米技术
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Yaqiao Li,Lingxiao Li,Yanzhong Hao,Jingxuan Zhang,Cuiyun Liu,Erwei Zhao,XianBao Shi,Xiaohui Pu,Jin Sun,Zhonggui He,Bingjun Sun
Dimeric prodrug self-assembly nanoparticles (DPS NPs) present promising avenues for chemotherapeutic delivery, yet optimizing the linker design for effective SN38 delivery remains challenging. We developed various SN38 dimeric prodrugs with differing linker lengths to explore how linker length impacts DPS NP performance. Our study reveals that linker length critically affects the nanoparticles assembly stability and activation efficiency. Specifically, too short linkers compromise assembly stability and lead to premature drug activation in the bloodstream, raising safety concerns. Conversely, too long linkers hinder both assembly stability and activation efficiency within tumor cells, diminishing anti-tumor effectiveness. The optimal linker (C12) achieved the best balance, ensuring robust assembly stability and high activation efficiency, thereby enhancing anti-tumor efficacy while maintaining a favorable safety profile. This work underscores the significance of linker length in designing effective DPS NPs for cancer treatment.
研究领域:
药物化学
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Materials Research Express
·
2022
·Vol. 9
·期 11
·115011
·
IF 2.025
Yu Zeng,Huihui Chen,Fan Yang,Huiyong Li,Pengxiang Yang
Malignant gliomas are the most prevalent and deadly primary brain tumors. The life expectancy of people with gliomas only slightly increases through surgical procedures, radiation, and chemotherapy. Magnetic nanocarriers must be developed to enable drug delivery using a magnetic field. A utilized to fabricate holmium ferrite nanoparticles is described herein. β-Cyclodextrin-polyethylene glycol (PEG) conjugate is used as a coat for the holmium ferrite nanoparticles. X-ray diffraction, energy dispersive x-ray spectroscopy, and x-ray photoelectron spectroscopy are all used to study the nanoparticles. This size range of nanoparticles is optimal for efficient drug delivery. The in vitro cytotoxicity of the fabricated nanoparticles was examined using U87MG and LN229 glioma cancer cells. The acridine orange/ethidium bromide and nuclear staining methods examined the morphological changes in the U87MG and LN229 glioma cells. The mode of cell death mechanism was investigated by Annexin V-FITC/PI flow cytometry methods. The possibility for successful SN38 delivery for the treatment of glioma cancer exists with the SN38@HF-β-CD-PEG.
研究领域:
肿瘤学
·
纳米医学
·
药物递送
✓ 已验证
产品关联
DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2018
·Vol. 43
·期 1
·481-491
·
IF 3.201
Fan Chen,Yuanyuan Cai,Lei Huang,Yuanwei Chen,Xianglin Luo
Polymer prodrug micelles, combining the advantages of prodrugs and polymer micelles, can greatly improve the solubility, permeability and stability of drugs. In this work, amphiphilic block copolymers poly(α-azide caprolactone-co-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine), P(ACL-co-CL)-b-PMPC, were synthesized, and an antineoplastic drug 7-ethyl-10-hydroxy camptothecin (SN38) was grafted to the amphiphilic copolymers to obtain a prodrug and their micelles. The preparation of P(ACL-co-CL)-b-PMPC was proceeded by ring-opening polymerization of ε-caprolactone/α-bromide caprolactone, converting the bromide to an azide, and atom transfer radical polymerization (ATRP). The camptothecin derivative SN38-alkyne was bonded to the polymer to obtain P(CL/CL-g-SN38)-b-PMPC by a “click reaction”. The obtained polymer–drug complex can easily self-assemble to form prodrug micelles with the shell composed of PMPC and the core composed of PCL and SN38. The micelles presented characteristics including improved drug loading efficiency and stabilization of the drug. In vivo, the retention time of the prodrug micelles in blood could be tripled, and the clearance was delayed compared with the SN38 solution. The in vivo anti-tumor experiments demonstrated that the prodrug micelles had a better treatment effect and low toxicity to 4T1-bearing BALB/C mice.
研究领域:
药学
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
高影响因子
Nano Research
·
2022
·Vol. 15
·期 10
·9092-9104
·
IF 10.269
Wang Helin,Lu Qi,Miao Yifan,Song Jiaxuan,Zhang Mingyang,Wang Zixuan,Zhang Haotian,He Zhonggui,Tian Chutong,Sun Jin
The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells. However, the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions. Supplementing with an additional reductant is a promising strategy to further boost drug release. Herein, inspired by the specific absorption mechanism of triglyceride fat, structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin (SN38) were designed to improve intestinal permeability and bypass the first-pass effect. SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract. Surprisingly, we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38, indicating an effective oral delivery. In addition, the reduction-responsive disulfide bond was used as a linker, and ascorbic acid (ASC) was coadministrated to further promote the efficient release of SN38 from the prodrug. ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety. In summary, the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.
研究领域:
药剂学
·
肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Yimou Gong,Muchao Chen,Yanjun Tan,Jingjing Shen,Qiutong Jin,Wutong Deng,Jian Sun,Chao Wang,Zhuang Liu,Qian Chen
Chemotherapeutic agents have been widely used for cancer treatment in clinics. Aside from their direct cytotoxicity to cancer cells, some of them could activate the immune system of the host, contributing to the enhanced antitumor activity. Here, the reactive oxygen species (ROS)-responsive hydrogel, covalently cross-linked by phenylboronic acid-modified 7-ethyl-10-hydroxycamptothecin (SN38-SA–BA) with poly(vinyl alcohol) (PVA), is fabricated for topical delivery of anti-programmed cell death protein ligand 1 antibodies (aPDL1). In the presence of endogenous ROS, SN38-SA–BA will be oxidized and hydrolyzed, leading to the degradation of hydrogel and the release of initial free SN38 and encapsulated aPDL1. It is demonstrated that SN38 could elicit specific immune responses by triggering immunogenic cell death (ICD) of cancer cells, a distinct cell death pathway featured with the release of immunostimulatory damage-associated molecular patterns (DAMPs). Meanwhile, the released aPDL1 could bind to programmed cell death protein ligand 1 (PDL1) expressed on cancer cells to augment antitumor T cell responses. Thus, the ROS-responsive prodrug hydrogel loaded with aPDL1 could induce effective innate and adaptive antitumor immune responses after local injection, significantly inhibiting or even eliminating those tumors.
研究领域:
肿瘤学
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 41
·21234-21247
·
IF 6.895
Jinjin Chen,Lulu Zhou,Chunhui Wang,Yunhao Sun,Yonglin Lu,Ruihao Li,Xiaochun Hu,Mengyao Chen,Lv Chen,Keke Chai,Tianming Yao,Shuo Shi,Chunyan Dong
A combination of chemotherapy and phototherapy has been proposed as a promising treatment for esophageal cancer (EC). Irinotecan as a first-line treatment option is widely prescribed for metastatic EC, however, its clinical application is extremely restricted by the low conversion rate to SN38, severe myelosuppression and diarrhea. As a more potent active metabolite of irinotecan, SN38 is a better substitution for irinotecan, but the poor water solubility and the difficulty of encapsulation hindered its medical application. Herein, a multifunctional SN38-conjugated nanosystem (FA-PDA@PZM/SN38@BSA-MnO2, denoted as FA-PPSM) is designed for overcoming the above-mentioned drawbacks and achieving collaborative chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT). The tumor acidic microenvironment induces decomposition of BSA-MnO2 nanoparticles into O2 and Mn2+, thus enhancing oxygen-dependent PDT efficacy; meanwhile, Mn2+ can be employed as a magnetic resonance imaging (MRI) contrast agent. Under 650 and 808 nm laser irradiation, the FA-PPSM nanocomposites exhibit superior antitumor efficacy in Eca-109-tumor bearing mice. Notably, there is low gastrointestinal toxicity and myelosuppression in the FA-PPSM treated mice compared with those treated with irinotecan (alone). Taken together, this work highlights the great potential of the FA-PPSM nanocomposites for MRI-guided chemotherapy in combination with endoscopic light therapy for esophageal cancer.
研究领域:
肿瘤学
·
药学
·
生物医学工程
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaowen Hou,Chunlin Ren,Xiaodong Zeng,Yukun Hu,Yicheng Zhao,Yuxin Cheng,Qiusi Luo,Taotao Ding,Xue Qiao,Yuqin Liao,Guo-Bo Li,Bengui Ye,Xuechuan Hong,Yuling Xiao
DNA-targeting chemotherapies can activate the stimulator of interferon genes (STING) pathway but elicit limited immune responses. We engineered 3P-SN38 , a long-circulating nanoplatform enabling sustained, tumor-targeted SN38 delivery and NIR-II imaging. To further potentiate immune activation and minimize STING agonist toxicity, SR717 was co-encapsulated, forming 3P-SN38@SR717 . 3P-SN38@SR717 induced immunogenic cell death and dendritic cell maturation in vitro , with combination therapy showing superior effects. In vivo , 3P-SN38@SR717 effectively activated the cGAS-STING pathway, enhancing anti-tumor immunity. Significant increases in the populations of CD8 + T cells, mature dendritic cells, and M1-type macrophages were observed, along with elevated levels of cytokines, including IL-6 and TNF-α. This integrated nanoplatform offers a promising approach for chemoimmunotherapy, enabling durable tumor control with reduced dosing and improved safety.
研究领域:
纳米医学
·
免疫治疗
·
肿瘤学
·
药学
·
生物医学成像
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2022
·
IF 5.589
Chengzhi Gao,Lanfang Zhang,Minhao Xu,Yi Luo,Ben Wang,Meiyan Kuang,Xingyou Liu,Meng Sun,Yue Guo,Lesheng Teng,Chenhui Wang,Yan Zhang,Jing Xie
A co-delivery system of SN38 (7-ethyl-10-hydroxyl camptothecin) prodrug and CUR (curcumin) was designed for the treatment of lung cancer by pulmonary delivery. SN38 was linked to cell-penetrating peptide (CPP) TAT via a polyethylene glycol (PEG) linker to form the SN38 prodrug (TAT-PEG-SN38). Liposomes co-loaded with amphiphilic TAT-PEG-SN38 and curcumin (Lip-TAT-PEG-SN38/CUR) were successfully prepared by a microfluidic method for the treatment of lung cancer via pulmonary delivery. Lip-TAT-PEG-SN38/CUR showed nanometer-sized sphericity and a particle size of 171.21 nm. Besides, Lip-TAT-PEG-SN38/CUR exhibited enhanced antiproliferative effect, increased cell apoptosis induction and improved cell cycle arrest compared to the single agents in vitro. The combination induced significant tumor inhibition in a BALB/c mouse lung cancer model. These results indicated that our SN38 prodrug and curcumin co-delivery system was a promising candidate for lung cancer treatment.
研究领域:
药学
·
癌症研究
·
药物递送系统
·
分子生物学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Wei He,Yawei Du,Tao Wang,Ji Wang,Lei Cheng,Xinsong Li
7-Ethyl-10-hydroxycamptothecin (SN38), a potent camptothecin derivative specifically targeting DNA topoisomerase I cleavage complexes, has shown great potential in the treatment of solid tumors . Because of its poor solubility and chemical and metabolic stability, the clinical application of SN38 is highly limited. To address these problems, a novel redox-responsive SN38 conjugate based liposomal formulation is developed in this report. First, SN38 was conjugated with lysophospholipid by using a cleavable disulfide bond linker. After that, the conjugate (SN38-SS-PC) was assembled into liposomes by thin film method. Dynamic light scattering (DLS) characterization indicated that SN38-SS-PC liposomes possessed a narrow size distribution (172.8 ± 10.5 nm) and negative charged zeta potential (-8.9 ± 0.3 mV). The results of storage and physiological stabilities showed that SN38-SS-PC liposomes was stable under different conditions. More importantly, a reduction responsive release of parent drug SN38 was observed in the medium containing glutathione (GSH). In addition, SN38-SS-PC liposomes had a much more rapid cellular uptake behavior against cancer cells. The enhanced anti-cancer efficacy of SN38-SS-PC liposomes was further demonstrated by in vitro cytotoxicity assay against MCF-7 and A549 cells. Under in vivo evaluation in 4 T1 xenograft tumor model, SN38-SS-PC liposomes were observed to have lower systemic toxicity and higher tumor inhibition rate of 53.3% compared with the commercialized SN38 prodrug Irinotecan (Ir). In summary, SN38-SS-PC liposomes could be a promising redox responsive delivery system of SN38 for cancer therapy.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
生物药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Jie Huang,Xiao Tang,Ziqiong Yang,Jianqiu Chen,Kun Wang,Chengnan Shi,Zihan Liu,Ming Wu,Qian Du
Irinotecan (CPT-11) is used as a first or second-line chemotherapy drug for the treatment and management of colorectal cancers. In vitro studies have shown that 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, displays promising anticancer efficacy. However, its poor aqueous solubility and hydrolytic degradation result in its lower oral bioavailability and impracticable clinical application. To overcome these limitations, a novel amphiphilic chitosan derivative, deoxycholic acid decorated N’-nonyl-trimethyl chitosan, was synthesized. Nano-micelles loaded with SN38 were subsequently prepared to enhance the bioavailability and anti-tumor efficacy of the drug through oral administration. The nano-micelles demonstrated improved dilution stability, enhanced greater mucosal adherence, significant P-gp efflux inhibition, and increased drug transport in the intestine by paracellular and transcellular pathways. Consequently, both the in vivo pharmacokinetic profile and therapeutic efficacy of SN38 against cancer were substantially improved via the micellar system . Thus, the developed polymeric micelles can potentially enhance the SN38 oral absorption for cancer therapy, offering prospective avenues for further exploration.
研究领域:
药剂学
·
肿瘤学
·
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）