ABSTRACT
Paclitaxel is a natural compound with efficient broad-spectrum antitumor activity .However ,the clinical ap-plication has been limited owing to the undesirable drawbacks ,such as the poor water-solubility ,cardiovascular toxicity and neurotoxicity .The design of paclitaxel prodrugs is an effective measure which can improve the drug's druggability ,alleviate its toxicity adverse effect and enhance its antitumor effect .With the in-depth research of prodrugs ,tumor-targeting paclitaxel pro-drugs which using the excessive receptors ,specific enzymes ,transporters ,reactive oxide species ,glutathione in tumor tissues as well as acidosis and hypoxia in tumors as specific targets ,have made great progress .The relevant literature about paclitaxel prodrugs were reviewed in this paper ,which targeted to the specific pathological and physiological features of tumor microenvi-ronment in recent years.
ABSTRACT
Objective To design and synthesize a novel paclitaxel loaded nanoparticle with reactive oxygen species (ROS) response, and characterize its structure, and investigate its stability, in vitro drug responsive release, cellular uptake and in vitro antitumor activity. Methods The PEG-2S-PTX monomer was synthesized by coupling the hydrophilic polyethylene glycol (PEG) with hydrophobic paclitaxel (PTX) via a thioether chain (2S), and the prodrug nanoparticles (PEG-2S-PTX NPs) were prepared by self-assembly. Meanwhile, using succinic anhydride (SA) as the linking group to synthesize the PEG-SA-PTX monomer and prepare the other prodrug nanoparticles (PEG-SA-PTX NPs) as control. The structures of PEG-2S-PTX and PEG-SA-PTX monomer were confirmed by 1H-NMR. The diameter and stability of the nanoparticles were detected by dynamic light scattering (DLS). The PTX release kinetics under oxidizing condition was detected by high performance liquid chromatography (HPLC) method. And the cellular uptake efficiency of nanoparticles by MCF-7 cells was observed by fluorescence microscope. The in vitro antitumor effects of nanoparticles were compared by MTT assay. Results PEG-2S-PTX and PEG-SA-PTX could both be self-assemble into nanoparticles with the diameter of (92.15±12.42) nm and (113.20±12.16) nm. PEG-2S-PTX NPs could rapidly release PTX under oxidative condition while PEG-SA-PTX NPs only showed weak responsiveness. PEG-2S-PTX NPs could be more rapidly taken up by MCF-7 cells compared with PEG-SA-PTX NPs. They both showed concentration dependent anti-tumor effects, but the cytotoxicity of PEG-2S-PTX NPs was stronger than that of PEG-SA-PTX NPs in the concentrations of 0.05, 0.1, 5, 10, 50 and 100 mg/L (P<0.05). Conclusion As paclitaxel prodrug nanoparticles with ROS responsive ability, PEG-2S-PTX NPs can rapidly release PTX in response to ROS in tumor cells, and exhibit great anti-tumor activity in vitro.
ABSTRACT
Aim Paclitaxel(PTX)has shown an effect against human cancer. However, serious drawbacks hamper PTX clinical use.Overcoming paclitaxel limi-tations is one of the best approaches to enhance water solubility.Methods In this study,water-soluble pa-clitaxel prodrug was prepared,folic acid-polyethylene glycol-glutamic-paclitaxel (FA-PEG-Glu-PTX ) com-posed of folic acid (FA,target),amino acids (Glu, linker),and polyethylene glycol(PEG)in order to im-prove the solubilization and stability. The chemical structure and physicochemical property of prodrug were measured by LC-MS,solubility,drug release rate to e-valuate the antitumor activity and cytotoxicity of FA-PEG-Glu-PTX.MTT assays were conducted on MDA-MB-231,MCF-7,A549 and HELF cell lines.FA-PEG-Glu-PTX prodrugs were labeled with 5 amino flu-orescence visible fluorescent dye (5 AF ) for fluores-cence microscopy.Results The successful conjugation of FA-PEG-Glu-PTX was confirmed by LC-MS,and had better water solubility,release rate curve.In vitro studies indicated that foliate receptor(FR-α)mediated uptake of PTX-conjugated multi-small molecules carri-ers induced highly targeting ability,and antitumor ac-tivity,as well as reduced side toxicity effects of PTX. Conclusion FA-PEG-Glu-PTX has a good antitumor activity.