Co-Delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-Responsive Star Polymer that Forms Unimolecular Micelles in Water.

Wenjing Lin,Hongru Li,Chun Wang,Lijuan Zhang,Na Yao,Wenqing Han,Samuel Hanson

doi:10.3390/polym8110397

Wenjing Lin, Hongru Li + Show 5 more

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https://doi.org/10.3390/polym8110397

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Abstract

Dual functional unimolecular micelles based on a pH-responsive amphiphilic star polymer β-CD-(PLA-b-PDMAEMA-b-PEtOxMA)21 have been developed for the co-delivery of imiquimod and plasmid DNA to dendritic cells. The star polymer with well-defined triblock arms was synthesized by combining activator regenerated by electron-transfer atom-transfer radical polymerization with ring-opening polymerization. Dissipative particle dynamics simulation showed that core-mesophere-shell-type unimolecular micelles could be formed. Imiquimod-loaded micelles had a drug loading of 1.6 wt % and a larger average size (28 nm) than blank micelles (19 nm). The release of imiquimod in vitro was accelerated at the mildly acidic endolysosomal pH (5.0) in comparison to physiologic pH (7.4). Compared with blank micelles, a higher N:P ratio was required for imiquimod-loaded micelles to fully condense DNA into micelleplexes averaging 200–400 nm in size. In comparison to blank micelleplexes, imiquimod-loaded micelleplexes of the same N:P ratio displayed similar or slightly higher efficiency of gene transfection in a mouse dendritic cell line (DC2.4) without cytotoxicity. These results suggest that such pH-responsive unimolecular micelles formed by the well-defined amphiphilic star polymer may serve as promising nano-scale carriers for combined delivery of hydrophobic immunostimulatory drugs (such as imiquimod) and plasmid DNA with potential application in gene-based immunotherapy.

Highlights

With advances in genomics and proteomics, many new potential antigens have been identified and can be developed into subunit vaccines in the forms of recombinant proteins and synthetic peptides, as well as genetic vaccines based on DNA
More specific and potent molecular adjuvants based on ligands of toll-like receptors (TLRs) have attracted much attention in recent years—some of the well-known ones include CpG oligodeoxynucleotides (TLR9 ligand), imidazoquinolines (TLR7/8 ligand), polyinosinic-polycytidylic acid (poly(I:C), TLR3 ligand), and monophosphoryl lipid A (MPL, TLR4 ligand), just to name a few [7]
The objective of this study is to develop unimolecular micelles as nanocarriers for combined delivery of IMQ and plasmid DNA to dendritic cells

Summary

Introduction

With advances in genomics and proteomics, many new potential antigens have been identified and can be developed into subunit vaccines in the forms of recombinant proteins and synthetic peptides, as well as genetic vaccines based on DNA. Compared with traditional vaccines comprised of attenuated or deactivated pathogens, subunit- and gene-based antigens are much safer in humans but can be poorly immunogenic. Vaccine adjuvants are capable of enhancing immunogenicity of antigens either through exerting immunostimulatory effects or by altering the process of antigen delivery. Major categories of adjuvants include killed bacteria, bacterial components, aluminum salt, oil-based emulsions, polysaccharides, and liposomes [1,2,3,4,5]. These highly specific immunostimulatory molecules require new and better carriers to deliver them—along with antigens—to their respective cellular and molecular targets. Emulsions, and polymeric nanoparticles are some of the current types of delivery systems that have shown much promise in enhancing the efficacy of molecular adjuvants and vaccines [8,9,10,11]

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