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A poly(beta-amino ester) activates macrophages independent of NF-?B signaling.

ABSTRACT: Nucleic acid delivery vehicles are poised to play an important role in delivering gene therapy for vaccines and immunotherapies, and in delivering nucleic acid based adjuvants. A number of common polymeric delivery vehicles used in nucleic acid delivery have recently been shown to interact with immune cells and directly stimulate immunogenic responses, particularly in particle form. Poly(beta-amino esters) were designed for nucleic acid delivery and have demonstrated promising performance in a number of vaccine and therapeutic studies. Yet, little work has characterized the mechanisms by which these polymers activate immune cells. Here we demonstrate that a poly(beta-amino ester) activates antigen presenting cells in soluble and particulate forms, and that these effects are independent of TLR signaling pathways. Moreover, we show the polymers induce activation independent of NF-?B signaling, but do activate IRF, an important innate inflammatory pathway. New knowledge linking physicochemical features of poly(beta-amino esters) or other polymeric carriers to inflammatory mechanisms could support more rational design approaches for vaccines and immunotherapies harnessing these materials. SIGNIFICANCE STATEMENT:The last several years have brought exciting work exploring biomaterials as delivery vehicles for immunotherapies, vaccines, and gene therapies. However, a gap remains between the striking finding that many biomaterials exhibit intrinsic immunogenic features, and the specific structural properties that drive these responses. The results in the current study indicate PBAEs cause macrophage activation by pathways that are distinct from pathways activated by common vaccine and immunotherapies components, such as toll-like receptor agonists. Thus, the work reveals new mechanistic details that can be exploited in investigating other materials, and to support more rational design of future biomaterial vaccines and immunotherapy carriers.

SUBMITTER: Dold NM

PROVIDER: S-EPMC6292427 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A poly(beta-amino ester) activates macrophages independent of NF-κB signaling.

Dold Neil M NM Zeng Qin Q Zeng Xiangbin X Jewell Christopher M CM

Acta biomaterialia 20171230

Nucleic acid delivery vehicles are poised to play an important role in delivering gene therapy for vaccines and immunotherapies, and in delivering nucleic acid based adjuvants. A number of common polymeric delivery vehicles used in nucleic acid delivery have recently been shown to interact with immune cells and directly stimulate immunogenic responses, particularly in particle form. Poly(beta-amino esters) were designed for nucleic acid delivery and have demonstrated promising performance in a n ...[more]

PMID: 29292166

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Project description:Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. STATEMENT OF SIGNIFICANCE:In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Dataset Information

A poly(beta-amino ester) activates macrophages independent of NF-?B signaling.

Publications

A poly(beta-amino ester) activates macrophages independent of NF-κB signaling.

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