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
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
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
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
危险品化学品经营许可证（带存储）