Docetaxel-Mediated Uptake and Retention of Gold Nanoparticles in Tumor Cells and in Cancer-Associated Fibroblasts.

Abdulaziz Alhussan,Perry L Howard,Kyle Bromma,Abraham S Alexander,Wayne Beckham,Devika B Chithrani,Monica Mesa Perez

doi:10.3390/cancers13133157

Abdulaziz Alhussan, Perry L Howard + Show 5 more

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https://doi.org/10.3390/cancers13133157

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Abstract

Simple SummaryCurrently, radiotherapy and chemotherapy are the most commonly used options, in addition to surgery, to treat cancer. There has been tremendous progress in interfacing nanotechnology to current cancer therapeutic protocols. For example, nanoparticles are used as drug carriers in chemotherapy and as radiation dose enhancers in radiotherapy. However, most of the work to date has been focused on tumor cells. To make significant progress in this field, we need to consider the tumor microenvironment, especially cancer-associated fibroblast cells that promote tumor growth. Our study shows the potential of targeting both tumor cells and cancer-associated fibroblasts to reap the full benefits of cancer nanomedicine.Due to recent advances in nanotechnology, the application of nanoparticles (NPs) in cancer therapy has become a leading area in cancer research. Despite the importance of cancer-associated fibroblasts (CAFs) in creating an optimal niche for tumor cells to grow extensively, most of the work has been focused on tumor cells. Therefore, to effectively use NPs for therapeutic purposes, it is important to elucidate the extent of NP uptake and retention in tumor cells and CAFs. Three tumor cell lines and three CAF cell lines were studied using gold NPs (GNPs) as a model NP system. We found a seven-fold increase in NP uptake in CAFs compared to tumor cells. The retention percentage of NPs was three-fold higher in tumor cells as compared to CAFs. Furthermore, NP uptake and retention were significantly enhanced using a 50 nM concentration of docetaxel (DTX). NP uptake was improved by a factor of three in tumor cells and a factor of two in CAFs, while the retention of NPs was two-fold higher in tumor cells compared to CAFs, 72 h post-treatment with DTX. However, the quantity of NPs in CAFs was still three-fold higher compared to tumor cells. Our quantitative data were supported by qualitative imaging data. We believe that targeting of NPs in the presence of DTX is a very promising approach to accumulate a higher percentage of NPs and maintain a longer retention in both tumor cells and CAFs for achieving the full therapeutic potential of cancer nanotechnology.

Highlights

Radiotherapy (RT), chemotherapy, and surgery are the most widely used approaches to treat cancer
(1) Is there a difference in NP uptake between tumor cells and cancer-associated fibroblasts (CAFs)? (2) What is the ability of tumor cells and CAFs to retain NP? (3) Can we improve the NP uptake in both tumor cells and CAFs using DTX? How significant is the effect in both tumor cells and CAFs? (4) Can we significantly improve the retention of NPs in tumor cells and in CAFs using DTX? (5) Is there a significant difference in the NP behavior in tumor cells and in CAFs based on our study?
The addition of the RGD peptide requires a stabilizing agent to avoid aggregation; pentapeptide is most used for this purpose, we instead used polyethylene glycol (PEG) because an RGD/PEG combination (Figure 2a) allows better translation of this work to future in vivo studies and clinical trials

Summary

Introduction

Radiotherapy (RT), chemotherapy, and surgery are the most widely used approaches to treat cancer. The major limitation to attaining a curative RT dose in high-risk (locally advanced) non-metastatic tumors is the high susceptibility of normal tissues to damage from radiation. We are nearing the limit of the RT dose given to patients, which creates a need for novel methods that enhance the effective dose to the tumor, while mitigating side effects. Enhancing the targeted delivery of radiotherapy by incorporating NPs with high atomic number material such as gold has tremendous potential to maximize the radiation dose given to the tumor and minimize doses delivered to normal tissue [1,2,3,4,5]. The use of NPs has shown promising results in overcoming some chemotherapeutic issues, where an increase of up to 5% of the injected chemotherapeutic dose within the tumor was observed [6]. Recent advances in nanotechnology can be exploited to overcome challenges in current cancer therapies

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