1391914-41-2Relevant articles and documents
Degradation kinetics of model hyperbranched chains with uniform subchains and controlled locations of cleavable disulfide linkages
Li, Lianwei,Wang, Xu,Yang, Jinxian,Ye, Xiaodong,Wu, Chi
, p. 650 - 658 (2014)
We developed a strategy to make model hyperbranched structure with uniform subchains and controlled locations of cleavable linkages. First, a novel seesaw-type tetrafunctional initiator with one alkyne, one disulfide linkage, and two bromine groups (≡-S-S-(Br)2) was prepared. Using such an initiator, an AB2-type macromonomer (azide～～alkyne～ ～azide) with one disulfide linkage at its center was prepared via successive atom transfer radical polymerization (ATRP) and azidation substitution reaction, where ～～ represents polystyrene chains. Further interchain "clicking" coupling between the azide and alkyne groups on the macromonomers led to model hyperbranched polystyrenes with uniform subchains and controllablly located cleavable disulfide linkages. The 1H nuclear magnetic resonance spectra, Fourier transform infrared spectroscopy, and size exclusion chromatography with a multiangle laser light scattering detector confirmed the designed degradable hyperbranched structure. Armed with this novel sample, we studied its dithiothreitol (DTT)-induced degradation in various organic solvents by a combination of static and dynamic LLS. We found that the cleavage of disulfide bonds contains a fast and a slow process. The fast one reflects the degradation of disulfide bonds on the chain periphery; while the slow one involves those inside. Both the fast and slow degradation reaction rate constants (Kfast and Kslow) are a linear function of the initial DTT concentration ([DTT]0), but the relative contribution of the two processes is mainly governed by the hyperbranched chain structure, nearly independent of [DTT]0.
Efficient Click Synthesis of a Protonized and Reduction-Sensitive Amphiphilic Small-Molecule Prodrug Containing Camptothecin and Gemcitabine for a Drug Self-Delivery System
Dong, Shuxiang,He, Jinlin,Li, Dian,Li, Lei,Ni, Peihong,Sun, Yue,Zhang, Mingzu
, (2019)
Drug self-delivery systems consisting of small-molecule active drugs with nanoscale features for intracellular delivery without the need for additional polymeric carriers have drawn much attention recently. In this work, we proposed a highly efficient strategy to fabricate protonized and reduction-responsive self-assembled drug nanoparticles from an amphiphilic small-molecule camptothecin-ss-1,2,3-triazole-gemcitabine conjugate (abbreviated as CPT-ss-triazole-GEM) for combination chemotherapy, which was prepared via a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. To obtain this drug-triazole-drug conjugate, we first prepared a CPT derivate containing a propargyl group linked with a disulfide group and a GEM derivate attached to an azide group. Subsequently, the two kinds of modified drugs were connected together through a CuAAC reaction between the alkynyl and azide groups to yield the CPT-ss-triazole-GEM prodrug. The characterizations of chemical structures of these intermediates and the final product were performed by 1H NMR, Fourier transform infrared, and liquid chromatography/mass spectrometry measurements. This amphiphilic small-molecule drug-triazole-drug conjugate displayed a high drug loading content, that is, 36.0percent of CPT and 27.2percent of GEM. This kind of amphiphilic small-molecule prodrugs could form spherical nanoparticles in an aqueous solution in the absence of any other polymeric carriers, in which the hydrophobic CPT formed the core of the nanoparticles, whereas the hydrophilic GEM and protonated 1,2,3-triazole group yielded the shell. In the tumor microenvironment, the prodrug nanoparticles could release both pristine drugs simultaneously. Under the conditions of pH 7.4, and pH 7.4 and 2 μM glutathione (GSH), the prodrug nanoparticles could maintain stability and only 7percent of CPT was leaked. However, in a high-GSH environment (pH 7.4 and 10 mM GSH) with the same incubation time, the disulfide linkage would be dissociated and lead to about 34percent of CPT release. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test demonstrated that these prodrug nanoparticles showed a higher cytotoxicity toward HepG2 cells than free CPT and free GEM on both 48 and 72 h of incubation. Both in vitro cellular uptake and flow cytometry results implied that these prodrug nanoparticles could be internalized by HepG2 cells with efficient drug release inside cells. The pharmacokinetics and tissue distribution of the prodrug showed a moderate half-life in vivo, and the prodrug peak concentration in most of the collected tissues appeared at 0.25 h after administration. In addition, the CPT-ss-triazole-GEM prodrug could not cross the blood-brain barrier. Even more important is the fact that there is no accumulation in tissues and a rapid elimination of this small-molecule prodrug could be achieved. In brief, this protonized and reduction-sensitive prodrug simultaneously binds both antitumor drugs and has good self-delivery behavior through the donor-acceptor interaction of the H-bonding ligand, that is, the 1,2,3-triazole group. It provides a new method for combined drug therapy.
GSH-Responsive supramolecular nanoparticles constructed by β-d-galactose-modified pillar[5]arene and camptothecin prodrug for targeted anticancer drug delivery
Liu, Xin,Shao, Wei,Zheng, Yanjing,Yao, Chenhao,Peng, Luming,Zhang, Dongmei,Hu, Xiao-Yu,Wang, Leyong
, p. 8596 - 8599 (2017)
Supramolecular construction of a targeted and stimuli-responsive drug delivery system is still a challenging task. Herein, GSH-responsive supramolecular prodrug nanoparticles were constructed by the host-guest complexation between a β-d-galactose-functionalized water-soluble pillar[5]arene (GalP5) and a disulfide bond containing camptothecin prodrug (G). The obtained prodrug nanoparticles were stable under physiological conditions, whereas efficient drug release was triggered in a simulated tumor environment with high GSH concentration. In vitro studies revealed that these prodrug nanoparticles preferentially entered asialoglycoprotein receptor-overexpressing HepG2 cells due to the active targeting effect of galactose units. This active targeting effect resulted in the maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells.
Development of Asialoglycoprotein-Mediated Hepatocyte-Targeting Antitumor Prodrugs Triggered by Glutathione
Li, Yajie,Li, Zhenjie,Liang, Jian,Liu, Feiyang,Luo, Tingrong,Pu, Chunxiao,Wang, Jianyi,Wang, Mian,Yi, Qingyuan
supporting information, p. 14793 - 14808 (2021/10/20)
One antitumor β-elemene derivative W-105 and three novel hepatocyte-targeting prodrugs (W-1-5, W-2-9, and W-3-8) were designed and synthesized. W-105 (IC50 6.107 μM) could cause cell apoptosis through upregulating the activity of caspase-3. The hepatocyte-targeting capacities of the aimed compounds followed the W-105 (parent compound) W-1-5 (monodentate-galactose) W-2-9 (bidentate-galactose) W-3-8 (tridentate-galactose) order, which is attributed to the excellent affinity of the galactose ligand to ASGPR and the galactose-cluster recognition effect. Furthermore, prodrugs W-3-8 exhibited good antitumor activity and low toxic side effects. The liquid chromatography-mass spectrometry (LC-MS) assays revealed that prodrugs (W-1-5, W-2-9, and W-3-8) could release the antitumor pharmacophore in the presence of GSH (mimic the condition of the tumor cell) and maintain the low-toxic structures in the absence of GSH (mimic the condition of the normal cell). The release mechanisms of prodrugs were also proposed. Overall, these prodrugs developed in this study had potential in the treatment of liver cancer.
Bifunctional supramolecular prodrug vesicles constructed from a camptothecin derivative with a water-soluble pillar[5]arene for cancer diagnosis and therapy
Sun, Guangping,He, Zhimei,Hao, Min,Xu, Zuqiang,Hu, Xiao-Yu,Zhu, Jun-Jie,Wang, Leyong
supporting information, p. 10892 - 10895 (2019/09/16)
Bifunctional supramolecular prodrug vesicles have been successfully constructed based on the complexation between a glutathione (GSH)-responsive prodrug guest molecule (DNS-CPT) and a water-soluble pillar[5]arene (WP5) for cancer diagnosis and therapy. Un
