Functional Nanoparticles for Tumor Penetration of Therapeutics

Abstract

Theranostic nanoparticles recently received great interest for uniting unique functions to amplify therapeutic efficacy and reduce side effects. Despite the enhanced permeability and retention (EPR) effect, which amplifies the accumulation of nanoparticles at the site of a tumor, tumor heterogeneity caused by the dense extracellular matrix of growing cancer cells and the interstitial fluid pressure from abnormal angiogenesis in the tumor inhibit drug/particle penetration, leading to inhomogeneous and limited treatments. Therefore, nanoparticles for penetrated delivery should be designed with different strategies to enhance efficacy. Many strategies were developed to overcome the obstacles in cancer therapy, and they can be divided into three main parts: size changeability, ligand functionalization, and modulation of the tumor microenvironment. This review summarizes the results of ameliorated tumor penetration approaches and amplified therapeutic efficacy in nanomedicines. As the references reveal, further study needs to be conducted with comprehensive strategies with broad applicability and potential translational development.

Keywords: composites; controlled release; drug delivery; functional materials; nanomedicine.

Figure 1

The barriers of functional nanoparticles for penetrated delivery into the tumor. (a) The path to the cancer cells. (b) Heterogeneity of the tumor decreases the penetration of drug/nanoparticles unevenly. (c) The dense extracellular matrix hinders nanoparticle distribution. (d) Low blood perfusion causes the nanomedicine supply to be insufficient. Reprinted from Reference [3] with permission from Springer Nature, 2013.

Figure 2

The scheme of different strategies of functional nanoparticles for the penetrated delivery of drugs and energy molecules in recent years.

Figure 3

Size-changeable function for tumor penetration. Li et al. reported a tumor-microenvironment-responsive nanoparticle that possessed a switchable size in weakly acidic conditions. (a) Structure of drug-loaded polymeric nanoparticles composed of dendrimers and a functional polymer. (b) Schematic illustration displaying the functions and self-assembly of polymeric nanoparticles, and pH-sensitive cluster of particles at neutral pH exhibiting a size transition at tumor acidic condition. (c) The size transition of drugs/particles overcame tumor barriers in poorly permeable tumor tissue. Reprinted from Reference [23] with permission from the American Chemical Society, 2013.

Figure 4

Ligand functionalization for tumor penetration. Wang et al. revealed that after intravenous injection of targeted HDL, iRGD was guided to tumors through three main processes: iRGD targets α_v integrins on the endothelium of tumors and undergoes proteolytic cleavage; and subsequently, it achieves tumor penetration. While applying the NIR laser irradiation, rapid drug release is actuated intracellularly, and the photothermal conversion leads to the ROS generation of ICG. Reprinted from Reference [33] with permission from John Wiley and Sons, 2018.

Figure 5

Combinational strategies for tumor penetration. Our group developed tumor penetration with two steps. First, the SCNAs transported drug-loaded GQD to the tumor, and the size of the SCNAs increased in the weakly acidic tumor environment to enhance local accumulation. Second, light-actuated delivery of GQDs and drug-enhanced tumor penetration. Reprinted from Reference [53] with permission from John Wiley and Sons, 2017.

Figure 6

Combinational strategies for tumor penetration. He et al. demonstrated their TCM-legM as functional nanoparticles: (i) specific activation targeting by the highly expressed legumain protease to the tumor; (ii) improving tumor penetration and cell internalization; (iii) actuating the weak acid-responsive drug release to achieve antimetastatic therapy. Reprinted from Reference [54] with permission from John Wiley and Sons, 2018.