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Enzymatic protection and biocompatibility screening of enzyme-loaded polymeric nanoparticles for neurotherapeutic applications.

ABSTRACT: Polymeric nanoparticles provide a non-invasive strategy for enhancing the delivery of labile hydrophilic enzymatic cargo for neurological disease applications. One of the most common polymeric materials, poly(lactic-co-glycolic acid) (PLGA) copolymerized with poly(ethylene glycol) (PEG) is widely studied due to its biocompatible and biodegradable nature. Although PLGA-PEG nanoparticles are generally known to be non-toxic and protect enzymatic cargo from degradative proteases, different formulation parameters including surfactant, organic solvent, sonication times, and formulation method can all impact the final nanoparticle characteristics. We show that 30s sonication double emulsion (DE)-formulated nanoparticles achieved the highest enzymatic activity and provided the greatest enzymatic activity protection in degradative conditions, while nanoprecipitation (NPPT)-formulated nanoparticles exhibited no protection compared to free catalase. However, the same DE nanoparticles also caused significant toxicity on excitotoxicity-induced brain tissue slices, but not on healthy or neuroinflammation-induced tissue. We narrowed the culprit of toxicity to specifically sonication of PLGA-PEG polymer with dichloromethane (DCM) as the organic solvent, independent of surfactant type. We also discovered that toxicity was oxidative stress-dependent, but that increased toxicity was not enacted through increasing oxidative stress. Furthermore, no PEG degradation or aldehyde, alcohol, or carboxylic acid functional groups were detected after sonication. We identified that inclusion of free PEG along with PLGA-PEG polymer during the emulsification phases or replacing DCM with trichloromethane (chloroform) produced biocompatible polymeric nanoparticle formulations that still provided enzymatic protection. This work encourages thorough screening of nanoparticle toxicity and cargo-protective capabilities for the development of enzyme-loaded polymeric nanoparticles for the treatment of disease.

SUBMITTER: Liao R

PROVIDER: S-EPMC7442737 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPoultry vaccine has limited choices of adjuvants and is facing severe threat of infectious diseases due to ineffective of widely used commercial vaccines. Thus, development of novel adjuvant that offers safe and effective immunity is of urgent need.Materials and methodsThe present research engineers a novel chicken adjuvant with potent immune-potentiating capability by incorporating avian toll-like receptor 21 (TLR21) agonist CpG ODN 2007 with a poly(lactic-co-glycolic acid) (PLGA)-based hollow nanoparticle platform (CpG-NP), which subsequently assessed ex vivo and in vivo.ResultsCpG-NPs with an average diameter of 164 nm capable of sustained release of CpG for up to 96 hours were successfully prepared. With the ex vivo model of chicken bone marrow-derived dendritic cells (chBMDCs), CpG-NP was engulfed effectively and found to induce DC maturation, promoting dendrite formation and upregulation of CD40, CD80 and CCR7. In addition to enhanced expression of IL-1β, IL-6, IL-12 and IFN-γ, 53/84 immune-related genes were found to be stimulated in CpG-NP-treated chBMDCs, whereas only 39 of such genes were stimulated in free CpG-treated cells. These upregulated genes suggest immune skewing toward T helper cell 1 bias and evidence of improved mucosal immunity upon vaccination with the CpG-NP. The CpG-NP-treated chBMDCs showed protective effects to DF-1 cells against avian influenza virus H6N1 infection. Upon subsequent coupling with infectious bronchitis virus subunit antigen administration, chickens were immunostimulated to acquire higher humoral immune response and protective response against viral challenge.ConclustionThis work presents a novel hollow CpG-NP formulation, demonstrating effective and long-lasting immunostimulatory ability ex vivo and in vivo for chickens, as systemically compared to free CpG. This enhanced immune stimulation benefits from high stability and controlled release of internal component of nanoparticles that improve cellular delivery, lymphoid organ targeting and sustainable DC activation. CpG-NP has broad application potential in antiviral and vaccine development.

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Enzymatic protection and biocompatibility screening of enzyme-loaded polymeric nanoparticles for neurotherapeutic applications.

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