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Influence of different chitosan derivatives on the immunogenicity of PLGA nanoparticles

Vaccines based on recombinant protein antigens often require immunostimulants. Both nanoparticles and chitosan and its derivatives can enhance immunogenicity. For this reason, in the presented studies, PLGA nanoparticles were functionalized with different chitosan derivatives and optimized as effect enhancers for the pneumococcal protein antigen PspA4Pro.

Tags: chitosan, nanoparticles, chitosanderivative, Vaccines, pneumococci, PLGA

EVALUATION OF POLYMER CHOICE ON IMMUNOGENICITY OF CHITOSAN COATED PLGA-NANOPARTICLES WITH SURFACE-ADSORBED PNEUMOCOCCAL PROTEIN ANTIGEN PSPA4PRO

Kan Kaneko, Eliane N. Miyaji, Viviane M. Gonçalves, Daniela M. Ferreira, Carla Solórzano, Ronan MacLoughlin, Imran Saleem, Evaluation of polymer choice on immunogenicity of chitosan coated PLGA NPs with surface-adsorbed pneumococcal protein antigen PspA4Pro, International Journal of Pharmaceutics, Volume 599, 2021, 120407, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2021.120407

Novel pathogens and the growing number of microbial resistances continue to be the main drivers for the development of new vaccines. Often these are based on recombinant protein antigens, which offer high safety and precision. However, they are often limited by weak intrinsic immunogenicity, which necessitates the use of immunostimulants.

Nanoparticles (NPs) can enhance the immunogenicity of vaccines through improved targeting, uptake, and transport of antigens and adjuvants. Poly(lactic-co-glycolic acid) (PLGA) is considered a particularly biocompatible polymer for NPs that has been successfully used in numerous therapeutics. Through electrostatic interactions, the recombinant antigens can be placed on the surface of the NPs in a relatively uncomplicated process. Immunogenicity of the vaccines can also be enhanced by encapsulating the antigen NPs with chitosan (CS). CS has enhanced immunogenicity due to the positive charges of the amino groups. It is also able to elicit an immune response through the TLR pathway as well as the cGAS staining pathway. In addition, CS can enhance the presentation and residence time of antigens on mucosa through its mucoadhesive properties, which also has a positive effect on the immunogenicity of NPs. To obtain the optimal immune response of vaccines by CS-PLGA-NPs, different PLGA polymers and chitosan derivatives were synthesized and characterized into CS-PLGA-NPs in the presented study. In addition, the immunogenicity of the NPs was investigated using a JAWSII dendritic cell model. In addition to PLGA polymers with different lactic and glycolic acid ratios (50:50, 75:25), terminal end groups (acid, ester) and molecular weights (7-17 kDa, 24-38 kDa, 4-15 kDa), the following chitosan derivatives from Heppe Medical Chitosan GmbH were tested:

Chitosan derivative

Molecular weight (Mw)

Deacetylation degree (DA)

Viscosity

Chitosan HCl

30-400 kDa

88,7 %

3,5 mPas

Carboxylmethylchitosan (CMC)

30-500 kDa

94,1 %

12 mPas

Oligomer

5 kDa

78 %

2 mPas

Glutamate

30–200 kDa

88,6 %

22 mPas

In addition, low molecular weight chitosan (LMW, 50-190 kDa, DA: 75-85%), trimethyl chitosan (TMC, 50-190 kDa, DA: NA) and chitosan glycol (400 kDa) were investigated as well.

RESULTS

  • REF-PLGA (lactic and glycolic acid ratio 50:50, terminal acid group, MW: 7-17 kDa) was used for CS encapsulation
  • 55-70% CS absorption on PLGA-NP surface for CS HCl, TMC, CMC and glycol CS, for LMC, oligomer and CS glutamate it was only below 45%
  • Large variation in zeta potential of CS-PLGA-NPs from -30 mV (glycol CS) and +30 mV (CMC).
  • Large differences in absorption efficiency of PspA4Pro depending on CS: below 10% for CMC and oligomer, above 90% for CS HCl, glutamate, and glycol CS
  • Different expressions of CD40 and CD86 in JAWSII cells: greatest increase for CS HCl compared to PLGA-only NPs, little difference for CMC and oligomer → presumably a lower intrinsic immunogenicity
  • Depending on CS initial concentration (0.2 - 2 mg/mL), there was no change in particle size for CS HCl, TMC and up to 120 nm increase for LMC, glycol CS, comparable observations with respect to PDI
  • CS HCl showed the highest absorption efficiency, as well as the highest CS level at each concentration used
  • CD40/86 expression mixed dependent on CS concentration used, only LMC proportional dependent on concentration, plateauing occurs with CS HCl

Summary: In this study, PLGA-NPs with negatively charged chitosans and chitosan derivatives were found to have generally poorer immunogenicity than those with a positive charge. Large variations between the chitosans and chitosan derivatives were seen in both CS absorption on the PLGA-NP surface, the absorption efficiency of PspA4Pro, and the expression of CD40 and CD86 in JAWSII cells. Overall, CS HCl was found to be the most immunogenic, and also had high adsorption efficiency and PspA adsorption.

Link to article: Evaluation of polymer choice on immunogenicity of chitosan coated PLGA NPs with surface-adsorbed pneumococcal protein antigen PspA4Pro - ScienceDirect

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