Experimental Study On The Sequential Dual-targeting Treatment Of Breast Cancer With Nanodrug Combined With Vascular-disrupting Agent

Background:Elevated interstitial fluid pressure in the tumor seriously hinders transvascular convection and interstitial transport of nanodrug.Nanodrug can generally only reach cancer cells at the edges of tumors,leaving most tumor cells in the central regions untreated.Combretastatin-A4-phosphate?CA4P?can disrupt the existing vasculature of the tumor,causing vascular shutdown and leading to massive necrosis in the tumor core.Co-administration of the two drugs may provide a synergetic antitumor effect.Objective:In this experiment,we explored the effect of co-administration of CA4P on the antitumor activity of nanoparticle albumin-bound paclitaxel?nab-paclitaxel?in Walker 256 tumor-bearing rats.Methods:We labeled iodine-131 on nab-paclitaxel and then evaluated the intratumoral uptake of ¹³¹I-nab-paclitaxel in the ¹³¹I-nab-paclitaxel group and the¹³¹I-nab-paclitaxel+CA4P group in Walker 256 tumor-bearing rats,respectively.Gamma counting and phosphor screen autoradiography were used to determine the uptake of ¹³¹I-nab-paclitaxel in the tumor.Liquid chromatography coupled with tandem mass spectrometry was performed to detect the intratumoral concentration of paclitaxel in the ¹³¹I-nab-paclitaxel group and the ¹³¹I-nab-paclitaxel+CA4P group,respectively.Magnetic resonance imaging was used to evaluate the effect of tumor treatment in the phosphate buffered saline group,the CA4P group,the nab-paclitaxel group,and the nab-paclitaxel+CA4P group.Microvessels were stained by CD31antibody to analyze tumor vasculature in different treatment groups.Terminal transferase d UTP nick end labeling was used to assess cellular apoptosis.Results:Gamma counting and phosphor screen autoradiography showed that the radioactive accumulation of ¹³¹I-nab-paclitaxel in the tumor site was significantly higher in the ¹³¹I-nab-paclitaxel+CA4P group 24 hours after administration than in the ¹³¹I-nab-paclitaxel group.The results of liquid chromatography coupled with tandem mass spectrometry demonstrated that the concentration of intratumoral paclitaxel was higher in the ¹³¹I-nab-paclitaxel+CA4P group than the ¹³¹I-nab-paclitaxel group.Magnetic resonance imaging results indicated that 21 days after treatment,co-administration of nab-paclitaxel and CA4P had smaller tumor volume and larger tumor necrosis rate compared with the phosphate buffer saline group,CA4P group and nab-paclitaxel group.Immunohistochemical analysis of CD31 and terminal transferase d UTP nick end labeling showed that co-administration of nab-paclitaxel and CA4P had a lower microvessel density and higher tumor cell apoptosis compared with the other treatment groups.Conclusion:Co-administration of CA4P increased the intratumoral accumulation of nab-paclitaxel and improved its therapeutic effect compared with single treatments.