Introduction: Nanosized anticancer drug delivery systems hold great promise for safe, simple and effective therapies against malignant solid tumors. Due to the enhanced permeability and retention (EPR) effect of solid tumor tissues, nanoparticles can passively accumulate in tumors, and this resulted in more than ten nanocarrier-based drugs been marketed for the treatment of cancers. However, a main barrier for further improving the therapeutic efficiency of nanomedicines lies in the poor permeability of solid tumors. Especially in the tumor central regions, low penetration of nanoparticles results in low contact probability of drugs to reach a majority of tumor cells and limited therapeutic outcomes. Aiming at this problem, in this study, we proposed a novel strategy for enhancing the treatment efficacy of nanomedicines within the central regions of solid tumor by combining nanomedicines with vascular disrupting agents (VDAs). As shown in Figure 1, nanomedicines mainly act on the tumor periphery, while VOAs eradicate tumor cells in the central regions of a solid tumor. Therefore, the combination is expected to eradicate the entire tumor. Materials and Methods: A typical small-molecule VDA, combretastatin A4 disodium phosphate (CA4P), which is in phase Ⅰ/Ⅱ clinical trials was applied here. Cis-diamminedichloroplatinum loaded nanoparticles (CDDP-NPs) prepared from CDDP and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG), which was previously reported and optimized by us was applied here as the model nanomedicine. For in vivo studies, Balb/C mice bearing murine colon carcinoma C26 tumors was applied. Results and Discussion: The effect of CA4P, CDDP-NPs and the combination on tumor necrosis after a single intravenous injection was compared by H-E staining. As shown in Figure 2, in contrast to CDDP-NPs or CA4P alone, the combination of CDDP-NPs+CA4P caused necrosis in both the central and peripheral regions, and resulted in a necrosis rate of 92.8±3.0%. In the following in vivo anticancer efficacy test, the combination group exhibited significant tumor growth suppression without significant bodyweight loss. Conclusion: Our work supports the notion that coadministration of nanomedicines plus vascular disrupting agents will serve as a promising strategy for the treatment of solid tumors with high efficacy and low side effects.
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