Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery

Abstract

Nanomedicines including liposomes, micelles, and nanoparticles based on the enhanced permeability and retention (EPR) effect have become the mainstream for tumor treatment owing to their superiority over conventional anticancer agents. Advanced design of nanomedicine including active targeting nanomedicine, tumor-responsive nanomedicine, and optimization of physicochemical properties to enable highly effective delivery of nanomedicine to tumors has further improved their therapeutic benefits. However, these strategies still could not conquer the delivery barriers of a tumor microenvironment such as heterogeneous blood flow, dense extracellular matrix, abundant stroma cells, and high interstitial fluid pressure, which severely impaired vascular transport of nanomedicines, hindered their effective extravasation, and impeded their interstitial transport to realize uniform distribution inside tumors. Therefore, modulation of tumor microenvironment has now emerged as an important strategy to improve nanomedicine delivery to tumors. Here, we review the existing strategies and approaches for tumor microenvironment modulation to improve tumor perfusion for helping more nanomedicines to reach the tumor site, to facilitate nanomedicine extravasation for enhancing transvascular transport, and to improve interstitial transport for optimizing the distribution of nanomedicines. These strategies may provide an avenue for the development of new combination chemotherapeutic regimens and reassessment of previously suboptimal agents.

Keywords: extracellular matrix; interstitial fluid pressure; nanomedicine; tumor microenvironment; tumor nanomedicine delivery; tumor perfusion.

Figure 1

The transport barriers for tumor nanomedicine delivery imposed by a complicated tumor microenvironment including poor blood perfusion, IFP, dense ECM, and a large number of stromal cells. The nanomedicines have to cross the blood vessel walls, penetrate the extravascular space, and eventually reach tumor cells to exert their therapeutic effects.

Figure 2

The effects of IMA treatment on tumor nanoparticle delivery. (A) In vivo fluorescence imaging of A549 xenograft-bearing mice (the upper row) treated with IMA or water as a control, ex vivo fluorescence imaging of their corresponding tumor xenografts (the lower row), and (B) the relative signal intensity of tumor tissue 24 h post the injection of DiR-labeled nanoparticles or micelles. ^*p < 0.05, compared with Control+NP group. ^**p < 0.01 compared with IMA+Micelles group. (C) In vivo distribution of micelles and nanoparticles in tumor slices from A549 tumor xenograft-bearing mouse models treated with IMA or water at 24 h after i.v. injection of a mixture of DiD-labeled nanoparticles and coumarin-6-labeled micelles. The oral dose of IMA was 50 mg/kg/d for 3 weeks. The dose of both coumarin-6 and DiD was 0.05 mg/kg. The bar indicated 100 μm. Reprinted from reference with permission by copyright holder, Zhiqing Pang.

Figure 3

Characterizations of NPs and effects of rtPA treatment on tumor nanoparticle delivery. TEM photograph (A) and size distribution (B) of NPs. Bar: 100 nm. In vivo (C) and ex vivo imaging (D,E) of A549 xenograft-bearing mice treated with 2 weeks of rtPA (25 mg/kg/d) or saline 24 h after the injection of DiR-labeled NPs. ^**p < 0.01 rtPA vs. saline group. In vivo distribution of NPs in tumor tissues. (F) Original magnification: 120 ×. Reprinted from reference with permission, Copyright Elsevier, 2016.