Enhancing intratumoral biodistribution and antitumor activity of nab-paclitaxel through combination with a vascular disrupting agent, combretastatin A-4-phosphate

摘要

Nanomedicines can generally only reach cancer cells at the edges of tumors, leaving most tumor cells in the central regions untreated. Previous studies showed that treatment with the vascular disrupting agent combretastatin-A4-phosphate (CA4P) can disrupt tumor vasculature, causing vascular shutdown and leading to massive necrosis in the tumor core. In this research, 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. The iodine 131 isotope was used for tracing and biodistribution analysis of nab-paclitaxel uptake. Liquid chromatography coupled with tandem mass spectrometry was performed to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging (MRI) was used to evaluate the effect of tumor treatment. Biodistribution results demonstrated that the tumor accumulations of both nab-paclitaxel and paclitaxel in the I-131-nab-paclitaxel + CA4P group were much higher than those in the I-131-nab-paclitaxel group. Nab-paclitaxel in combination with CA4P inhibited tumor growth significantly more potently compared with the CA4P group, nab-paclitaxel group and PBS group. Our results demonstrate that co-administration of CA4P increased the intratumoral accumulation of nab-paclitaxel and improved its therapeutic effect compared with single treatments.