Enhanced immunostimulatory effects of DNA-encapsulated peptide hydrogels

Abstract

DNA that encodes tumor-specific antigens represents potential immunostimulatory agents. However, rapid enzymatic degradation and fragmentation of DNA during administration can result in limited vector expression and, consequently, poor efficacy. These challenges have necessitated the use of novel strategies for DNA delivery. Herein, we study the ability of cationic self-assembling peptide hydrogels to encapsulate plasmid DNA, and enhance its immunostimulatory potential in vivo. The effect of network charge on the gel's ability to retain the DNA was assessed employing three gel-forming peptides that vary systematically in formal charge. The peptide HLT2, having a formal charge of +5 at neutral pH, was optimal in encapsulating microgram quantities of DNA with little effect on its rheological properties, allowing its effective syringe delivery in vivo. The plasmid, DNA(TA), encapsulated within these gels encodes for a melanoma-specific gp100 antigen fused to the alarmin protein adjuvant HMGN1. Implantation of DNA(TA)-loaded HLT2 gels into mice resulted in an acute inflammatory response with the presence of polymorphonuclear cells, which was followed by infiltrating macrophages. These cellular infiltrates aid in the processing of encapsulated DNA, promoting increased lymphoproliferation and producing an enhanced immune response mediated by CD4+/IFNγ+ expressing Th1 cells, and complemented by the formation of gp100-specific antibodies.

Biodegradable Poly(Amino Ester) with Aromatic Backbone as Efficient Nonviral Gene Delivery Vectors

“…Gene therapy affords a promising way to treat congenital and acquired diseases [ 1 , 2 ]. Safe and efficient delivery of genetic material into target cells remains a challenging aspect of gene therapy [ 3 ].…”

A Powerful CD8+ T‐Cell Stimulating D‐Tetra‐Peptide Hydrogel as a Very Promising Vaccine Adjuvant

“…Self‐assembling peptides have been widely used as the extracellular matrix for regenerative medicine and as platforms to understand biological process and to screen important analytes . Pioneering work has also demonstrated that self‐assembling peptides can be used as self‐adjuvated vaccines through the covalent conjugation of peptide or protein antigens . However, the reported self‐assembling peptides, including L‐ and D‐peptides, cannot elicit strong CD8 + T‐cell responses.…”

Synthesis and evaluation of the biostability and cell compatibility of novel conjugates of nucleobase, peptidic epitope, and saccharide

“…Supramolecular hydrogels [ 18 – 24 ] formed by self-assembly of small molecules in water, as demonstrated previously by us and other researchers, have numerous potential applications, such as encapsulation and delivery of DNA [ 25 ] and microRNA [ 26 ], delivery of therapeutic agents [ 27 – 29 ], scaffolds for cell culture [ 30 – 31 ] and spinal arthrodesis [ 32 ], sensor for detection of hyperuricemia disease [ 33 ] and diabetes [ 34 ], and matrix for the electrophoresis of acidic native proteins [ 35 ]. After obtaining the pure conjugates 1 – 8 , we tested their gelation properties.…”