| Drug-loaded polymeric nanoparticles have been recently attracted wide attention in the tumor therapy, however some key issues, including active targeting, stability in blood circulation, and responsive drug release et al, are still challenging. In view of the environmental characteristics, such as acid, rich in GSH and Hyal-1, of breast tumor cells, this work prepared a kind of pH/GSH/Hyal-1 multiple stimuli responsive nanoparticle derived from hyaluronic acid(HA) capable of targeting CD-44 receptor on the breast cancer cell membrane surface, for the loading and controlled release of a new anti-breast cancer drug, tetralin indazolone(SNX2112), in the breast tumor therapy. The physicochemical properties and in vitro pH/GSH/Hyal-1 multiple stimulus responsive release of SNX2112 from these nanoparticles under mimicking breast tumor environment, were studied. The application feasibility of these nanoparticles in breast cancer therapy was explored.Firstly, histidine and cysteamine were bonded to hyaluronan by coupled reaction in the presence of EDC and NHS, such that a functional hyaluronan derivative named as His-HA-Cys was obtained. Secondly, the carboxyl activated anti-cancer drug SNX2112 was bonded to His-HA-Cys by esterification reaction, such that an amphiphilic multi-functional hyaluronan derivative named as His-HA-Cys-g-SNX2112 was obtained. The composition of these hyaluronan derivatives were characterized by 1H NMR, and the substitution degree of His, Cys and SNX2112 on hyaluronan was calculated to be about 16%, 21% and 2% respectively.His-HA-Cys-g-SNX2112 nanoparticles were prepared by an ultrasonic oscillation method. The particle size of nanoparticles was measured to be about 266 nm by a dynamic light scattering method, and a Zeta potential of-13.5 mV was obtained. The critical micelle concentration(CMC) of nanoparticles was measured to be 1.58×10-2 mg/mL by a fluorescent spectrometry. Spherical nanoparticles were observed by TEM. At a pH value of lower than 6, the particle size of nanoparticles got increased, while these nanoparticles were stable in the diluted physiological saline, solution containing serum or in the presence of lauryl sodium sulfate destabilizer.Drug-loaded nanoparticles of His-HA-Cys-g-SNX2112 were prepared by a solvent evaporation method. The maximum drug loading capacity and encapsulation efficiency were 11% and 30% respectively. The drug in nanoparticles slowly released under the physiological conditions of pH 7.4, and a total cumulative release percentage of 13% was obtained within 48 hours; meanwhile a burst release of 7% within the initial 4 hours was observed maybe due to the fast delivery of drugs adsorbed on the nanoparticle surface. Acidity(pH 5.0), GSH or Hyal-1 can significantly speed up the drug delivery, indicative of the pH, GSH or Hyal-1 stimulus responsive drug release of HisHA-Cys-g-SNX2112 nanoparticles. Among the three factors, the effect of Hyal-1 was the most significant. Under the condition of pH/GSH/Hyal-1multi-stimuli, the drug release of nano-particle was further accelerated, releasing 50% within 9 hours. The first portion of rapidly released drugs may mainly come from the physically loaded drugs, while the chemically bonded drugs released after the degradation of nanoparticles. After a delivery period of 48 hours, nanoparticles were deformed with a fuzzy surface by TEM observation, indicating the partial degradation of nanoparticles took place. Thus, the drug delivery of His-HA-Cys-g-SNX2112 nano-particle newly prepared in this work is pH/ GSH/Hyal-1 multi-timuli responsive, which is a promising drug nanocarrier against breast cancer. |
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