Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

Bo Zhang,Zhiqing Pang,Wei Shi,Heng Lu,Yu Hu,Lanting Wang,Ting Jiang,Heng Mei

doi:10.18632/oncotarget.11546

Abstract

Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

Highlights

Nowadays nanomedicines have become the mainstream for tumor therapy [1], owning to their unique superiorities to small molecules [2]
These results agreed with other tumor microenvironment modifiers as previously documented including losartan, chloroquine, rapamycin, etc [17, 25, 26], indicating the dose of imatinib mesylate (IMA) used in the present study might be safe for animal models without significant therapeutic effects or adverse responses
Tumor microenvironment modification by IMA treatment was investigated by immunofluorescence staining (Figure 2)

Summary

Introduction

Nowadays nanomedicines have become the mainstream for tumor therapy [1], owning to their unique superiorities to small molecules [2]. To achieve improved nanomedicine delivery to tumor tissues, both nanomedicine properties and the tumor microenvironment could be optimized. Nanomedicines could be elaborately designed to achieve improved tumor delivery by the size shrink strategy [12, 13] or the tumor microenvironment-responsive strategy [14, 15]. These advanced nanomedicines still could not conquer the resistance of drug delivery from the complex tumor microenvironment [3]. To the best of our knowledge, few studies highlighted the necessity to optimize both nanomedicine properties and the tumor microenvironment simultaneously to achieve a pronounced improvement in tumor therapy

Methods

Results

Conclusion