Targeting tumor microenvironment with PEG-based amphiphilic nanoparticles to overcome chemoresistance

Abstract

Multidrug resistance is one of the biggest obstacles in the treatment of cancer. Recent research studies highlight that tumor microenvironment plays a predominant role in tumor cell proliferation, metastasis, and drug resistance. Hence, targeting the tumor microenvironment provides a novel strategy for the evolution of cancer nanomedicine. The blooming knowledge about the tumor microenvironment merging with the design of PEG-based amphiphilic nanoparticles can provide an effective and promising platform to address the multidrug resistant tumor cells. This review describes the characteristic features of tumor microenvironment and their targeting mechanisms with the aid of PEG-based amphiphilic nanoparticles for the development of newer drug delivery systems to overcome multidrug resistance in cancer cells.

From the clinical editor: Cancer is a leading cause of death worldwide. Many cancers develop multidrug resistance towards chemotherapeutic agents with time and strategies are urgently needed to combat against this. In this review article, the authors discuss the current capabilities of using nanomedicine to target the tumor microenvironments, which would provide new insight to the development of novel delivery systems for the future.

Keywords: Amphiphilic nanomaterials; Cancer microenvironment; Multidrug resistance; Poly(ethylene glycol); Tumor targeting.

Figure 1

(a) Molecular structures of DSPE-PEG₂₀₀₀ and NPAPF and scheme for preparation of M-NPAPF-Au. (b) Viability of CT26, HepG2, L02 cells incubated with different concentrations of M-NPAPF-Au for 24 h. (c) Non-invasive fluorescence image of CT26 tumor-bearing mice and their dissected tumors and organs 6, 12 and 24 h after intravenous injection. The white arrows indicate tumor sites and the red circles indicate dissected tumors. 1-Liver, 2-Spleen, 3-Kidney, 4-Heart, 5-Lung, 6-Tumor, 7-Brain, 8-Intestine. (d) Semi-quantitative biodistribution of M-NPAPF-Au in mice determined by the averaged fluorescence intensity of each tumor and organ. Error bars are based on three mice per group. (e) Blood circulation curved of free NPAPF (black) and M-NPAPF-Au (red) determined by measuring the fluorescence intensity of NPAPF in blood at different time points post-injection. (f) CT images of CT26 tumor-bearing mice before and after intravenous injection M-NPAPF-Au (6, 12 and 24 h). The white circles indicate tumor regions, the upper row shows stereo images and the bottom row shows sectional images. (g) Biodistribution of Au by ICP-MS in tumor tissues and major organs. Reprinted from Liang et al. with permission of Elsevier.

Figure 2

(a) Schematic illustration of the structure of multimodality treatment nanoparticles (MMNPs). (b) and (c) CLSM images of MMNPs without Herceptin and MMNPs for 2 h incubation in SK-BR-3 cells respectively. (d) SK-BR-3 cell viability of different treatment methods at various concentrations of nanoparticles after 24 h incubation and recovered in fresh medium for 12 h. Reprinted from Feng et al. with permission of Elsevier.

Figure 3

The scheme of DOX-loaded Tf-conjugated biodegradable PEG-PCL polymersomes for glioma chemotherapy. Reprinted from Jiang et al. with permission of American Chemical Society.

Figure 4

(a) Scheme of cRGD/m for for targeted delivery of platinum anticancer drugs to glioblastoma. IVCLSM observations of 20% cRAD/m (green) and 20% cRGD/m (red) in blood vessels and tumors at (b) 5 min and (c) 5 h after intravenous coadministration. Their colocalization is shown in yellow. Scale bars represent 100 μm in all images. (d) Comparison of tumor growth inhibition with 20% cRGD/m and 20% cRAD/m. Five days after tumor cell transplantation, the mice were injected intravenously with micelles. Data represent mean ± SEM (n=12). Two-way ANOVA was used to analyze differences in the tumor mass volume, and **p < 0.001 and *p < 0.01 were considered significant. Reprinted from Kataoka et al. with permission of American Chemical Society. (e) Scheme of CRGDK modified micelles for drug delivery of cancer therapy in vitro and in vivo. Reprinted from Liang et al. with permission of American Chemical Society.

Figure 5

(a) Illustrative preparation of FA-targeted and PTX and QD loaded micelle and pH-tunable drug release. (b) In vivo QD fluorescent images showing FA-enhanced tumor targeting of the QD-loaded targeted micelles after tail vein injection into nude mice bearing Bel-7402 subcutaneous xenograft. (c) Tumor growth inhibition in nude mice (n=20) bearing Bel-7402 tumor after tail vein injection of different formulation. Reprinted from Shuai et al. with permission of John Wiley and Sons.

Figure 6

Illustration of ligand-directed, reduction-sensitive, shell-sheddable, biodegradable micelles based on PEG-SS-PCL and Gal-PEG-PCL copolymers actively delivering DOX into the nuclei of asialoglycoprotein receptor-overexpressing hepatocellular carcinoma cells. Reprinted from Zhong et al. with permission of American Chemical Society.

Figure 7

(a) The schematic drawing shows solid tumor organization with the characteristic acidic front, vascularized circumference, hypoxic region and necrotic core. (b) Representation of different mechanisms involved in MDR.

Figure 8

Schematic illustration of stimuli-response drug delivery systems based on amphiphilic nanostructure. (a) pH responsive, (b) Photo irradiation-responsive, (c) Redox-responsive, (d) Rox-responsive. Reprinted from Wang et al. with permission of Elsevier, Li et al. with permission of John Wiley and Sons, Zhang et al. with permission of American Chemical Society, and Zhang et al. with permission of Elsevier.