Novel Complex of PD-L1 Aptamer and Holliday Junction Enhances Antitumor Efficacy in Vivo.

Ting Li,Xian-Da Yang,Fengjiao Yao,Jinhong Duan,Yacong An,Xundou Li

doi:10.3390/molecules26041067

Ting Li, Xian-Da Yang + Show 4 more

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https://doi.org/10.3390/molecules26041067

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Abstract

Blocking the PD-1/PD-L1 pathway can diminish immunosuppression and enhance anticancer immunity. PD-1/PD-L1 blockade can be realized by aptamers, which have good biocompatibility and can be synthesized in quantity economically. For in vivo applications, aptamers need to evade renal clearance and nuclease digestion. Here we investigated whether DNA nanostructures could be used to enhance the function of PD-L1 aptamers. Four PD-L1 aptamers (Apt) were built into a Holliday Junction (HJ) to form a tetravalent DNA nanostructure (Apt-HJ). The average size of Apt-HJ was 13.22 nm, which was above the threshold for renal clearance. Apt-HJ also underwent partial phosphorothioate modification and had improved nuclease resistance. Compared with the monovalent PD-L1 aptamer, the tetravalent Apt-HJ had stronger affinity to CT26 colon cancer cells. Moreover, Apt-HJ markedly boosted the antitumor efficacy in vivo vs. free PD-L1 aptamers without raising systemic toxicity. The results indicate that multiple aptamers attached to a DNA nanostructure may significantly improve the function of PD-L1 aptamers in vivo.

Highlights

Cancer is a leading cause of mortality in the 21st century
The results indicate that the PD-L1 aptamer has great potential for future development as an immune checkpoint blockade (ICB) agent
Previous studies have shown that a PD-L1 aptamer can generate an anti-tumor effect in vivo [23]

Summary

Introduction

Cancer is a leading cause of mortality in the 21st century. There are four main treatments for cancer: surgery, radiotherapy, chemotherapy, and immunotherapy. Unlike the first three treatments that directly target the cancer cells, immunotherapy attacks the tumor through mobilization of the host s immune system [1]. Clinical data have shown that blocking the PD-1/PD-L1 pathway can enhance antitumor immunity, produce a lasting clinical response, and prolong patient survival [8]. Increasing numbers of clinical studies indicate that antibodies targeting PD-1 or PD-L1 can achieve promising results in multiple tumor types [2,9], including melanoma, prostate cancer, and non-small cell lung cancer (NSCLC) [10,11,12]. In patients with advanced squamous cell NSCLC, PD-1 antibody can significantly improve overall survival, response rate, and progression-free survival [14]. The development of PD-1/PD-L1 inhibitors as a form of cancer immunotherapy has gained unprecedented attention

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