Two Antibody-Guided Lactic-co-Glycolic Acid-Polyethylenimine (LGA-PEI) Nanoparticle Delivery Systems for Therapeutic Nucleic Acids.

Jian-Ming Lü,Bin Zhan,Dongliang Liu,Changyi Chen,Qizhi Yao,Zhengdong Liang

doi:10.3390/ph14090841

Abstract

We previously reported a new polymer, lactic-co-glycolic acid-polyethylenimine (LGA-PEI), as an improved nanoparticle (NP) delivery for therapeutic nucleic acids (TNAs). Here, we further developed two antibody (Ab)-conjugated LGA-PEI NP technologies for active-targeting delivery of TNAs. LGA-PEI was covalently conjugated with a single-chain variable fragment antibody (scFv) against mesothelin (MSLN), a biomarker for pancreatic cancer (PC), or a special Ab fragment crystallizable region-binding peptide (FcBP), which binds to any full Ab (IgG). TNAs used in the current study included tumor suppressor microRNA mimics (miR-198 and miR-520h) and non-coding RNA X-inactive specific transcript (XIST) fragments; green fluorescence protein gene (GFP plasmid DNA) was also used as an example of plasmid DNA. MSLN scFv-LGA-PEI NPs with TNAs significantly improved their binding and internalization in PC cells with high expression of MSLN in vitro and in vivo. Anti-epidermal growth factor receptor (EGFR) monoclonal Ab (Cetuximab) binding to FcBP-LGA-PEI showed active-targeting delivery of TNAs to EGFR-expressing PC cells.

Highlights

Cancer was the second leading cause of death, while the heart disease was the first leading cause of death in the United States (US) in 2018 [1]
We extended our previously developed new lactic-co-glycolic acid-polyethylenimine (LGA-PEI) polymer as an improved NP platform for delivering therapeutic nucleic acids (TNAs) to active-targeting delivery systems by covalent conjugation of MSLN scFv Ab fragment or fragment crystallizable region-binding peptide (FcBP) for binding any full Ab (IgG)
We used an FDA-approved humanized anti-epidermal growth factor receptor (EGFR) monoclonal Ab (Cetuximab, Eli Lilly and Company, Indiana, USA), binding to our new FcBP-lactic-co-glycolic acid (LGA)-PEI polymer, which effectively loads TNAs, forms functionalized NPs, and targets pancreatic cancer (PC) cell lines with high expression of ERGR in vitro and in vivo. These results demonstrate that two Ab-guided NP delivery platform technologies built up from our novel LGA-PEI polymer may have great potential for clinical applications of the active-targeting therapy with TNAs for PC and other types of cancers with unique and specific cell surface markers

Summary

Introduction

Cancer was the second leading cause of death, while the heart disease was the first leading cause of death in the United States (US) in 2018 [1]. Cancer emerged recently as the leading cause of death in many states in the US [2]. It is estimated that the total new cancer cases and cancer deaths in US are 1,898,160 and 608,570, respectively, in. New cases and death from pancreatic cancer (PC) in the US are estimated to be 60,430 and 48,220, respectively, in 2021. PC is the third leading cause of cancer death following lung cancer (131,880 deaths) and colorectum cancer (52,980 deaths) [3]. The 5-year relative survival rate is the lowest for PC (9%) among all cancer types

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