Identification of an Aptamer With Binding Specificity to Tumor-Homing Myeloid-Derived Suppressor Cells.

Shaohui Tian,Haifa Shen,Junhua Mai,Yongbin Liu,Thomas Welte,Maricela Ramirez

doi:10.3389/fphar.2021.752934

Shaohui Tian, Haifa Shen + Show 4 more

Open Access

https://doi.org/10.3389/fphar.2021.752934

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Abstract

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor growth and metastasis. Since they constantly infiltrate into the tumor tissue, these cells are considered as an ideal carrier for tumor-targeted drug delivery. We recently identified a DNA-based thioaptamer (T1) with tumor accumulating activity, demonstrated its potential on tumor targeting and drug delivery. In the current study, we have carried out structure-activity relationship analysis to further optimize the aptamer. In the process, we have identified a sequence-modified aptamer (M1) that shows an enhanced binding affinity to MDSCs over the parental T1 aptamer. In addition, M1 can penetrate into the tumor tissue more effectively by hitchhiking on MDSCs. Taken together, we have identified a new reagent for enhanced tumor-targeted drug delivery.

Highlights

Multiple physical and biological barriers block drug molecule penetration in the tumor tissue, rendering most therapeutic agents ineffective (Blanco et al, 2015; Rosenblum et al, 2018)
To assess aptamer binding on Peripheral blood mononuclear cells (PBMCs), cells were first incubated with fluorescently labeled antibodies, and stained with DAPI before flow cytometry analysis on an LSRII Flow Cytometer or a BD FACS Fortessa (Bronte et al, 2016)
Cell type analysis revealed that most T1 aptamers were associated with the CD45+CD11b+Ly6C+Ly6G− monocytic Myeloid-derived suppressor cells (MDSCs) (M-MDSCs) and CD45+CD11b+ Ly6C−Ly6G+ polymorphonuclear MDSCs (PMN-MDSCs)

Summary

INTRODUCTION

Multiple physical and biological barriers block drug molecule penetration in the tumor tissue, rendering most therapeutic agents ineffective (Blanco et al, 2015; Rosenblum et al, 2018). Compared with other immune cells, most of which preferentially migrate to lymphoid organs or livers, MDSCs show more specific tumor tropism (Eisenstein et al, 2013). Both the abundance and high mobility make circulating MDSCs an ideal vehicle for transporting drug molecules or particles from bloodstream into the neoplastic lesion (Chandra and Gravekamp, 2013). Aptamers are single-stranded oligonucleotides folded into unique three-dimensional structures They can bind to both small and macro-molecules with high affinity and specificity (Zhang et al, 2013). The T1 aptamer could bind to both MDSCs and cancer cells, serving as an affinity moiety for tumor-targeted drug delivery. We have identified a new aptamer (M1) with enhanced MDSC-binding ability

MATERIALS AND METHODS

Hunter Application

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT

ETHICS STATEMENT