Tissue Factor-Targeted "O2-Evolving" Nanoparticles for Photodynamic Therapy in Malignant Lymphoma.

Ziying Li,Han Yan,Huafang Wang,Tao Guo,Bo Zhang,Yu Hu,Heng Mei,Yanxue Yin,Weiwei Jin,Wei Shi

doi:10.3389/fonc.2020.524712

Abstract

Vascular-targeted PDT (vPDT) has produced promising results in the treatment of many cancers, including drug-resistant ones, but little is known about its efficacy in lymphoma. Unfortunately, the lack of a specific therapeutic target and a hypoxic microenvironment for lymphoma jeopardizes the efficacy of vPDT severely. In this study, we designed a lymphoma tissue factor-targeted “O2-evolving” strategy combining PDT with catalase and HMME-encapsulated, EGFP-EGF1-modified PEG-PLGA nanoparticles (CENPs) to boost PDT efficiency; this combination takes advantage of the low oxygen tension of lymphoma. In our results, CENPs accumulated effectively in the vascular lymphoma in vivo and in vitro, and this accumulation increased further with PDT treatment. Per positron emission tomography imaging, combining CENPs with PDT inhibited lymphoma glucose metabolism significantly. The expression of hypoxia-inducible factor (HIF)-1α in the entrapped catalase groups reduced markedly. These data show that the combined administration of PDT and CENPs can prompt tissue factor-cascade-targeted and self-supply of oxygen and that it has a good therapeutic effect on malignant lymphoma.

Highlights

Despite the development of new therapies, patients with partial non-Hodgkin’s lymphoma (NHL) are still treatment-resistant; the hypoxia attributed to malformed vasculature and rapid tumor growth may be the real problem [1, 2]
In the process of PDT, tissue factor (TF) could abundantly generate at vascular sites due to the damage of reactive oxygen species (ROS) to endothelial cells, so more PS could be recruited through the positive feedback effect
There was no significant change in TF expression with CENPHMME concentrations of 100 and 500 ng/mL (Figure 3A vs B), possibly because the excessive ROS production during PDT damaged Human umbilical vein endothelial cells (HUVECs). These findings demonstrate that combining CENPs with PDT could increase TF expression in HUVECs

Summary

Introduction

Despite the development of new therapies, patients with partial non-Hodgkin’s lymphoma (NHL) are still treatment-resistant; the hypoxia attributed to malformed vasculature and rapid tumor growth may be the real problem [1, 2]. Anti-Lymphoma Targeted Photodynamic Therapy System many tumors in the preclinic and clinic [5,6,7], but it has never been used to treat NHL, except cutaneous T-cell lymphoma [8]. The most important step in the killing ability of PDT is the tumor gathering of PS and local ROS production [9]. In the process of PDT, TF could abundantly generate at vascular sites due to the damage of ROS to endothelial cells, so more PS could be recruited through the positive feedback effect. The system, composed of a factor VII-derived EGFP-EGF1 fusion protein and PEG-PLGA nanoparticle-loaded hematoporphyrin monomethyl ether (HMME), combined with PDT to exhibit efficient TF-cascade-targeting ability in vitro and in vivo [12]

Methods

Results

Conclusion