Thermo-responsive hydrogel loading hypericin induces pro-inflammatory response against Trichinella spiralis infection via toll-like receptor 3 activation.

BACKGROUND

Trichinella spiralis can cause animal and human trichinellosis, which is fatal for human beings. Study demonstrated that toll-like receptor 3 (TLR3) agonist was effective in reducing trichinella infections. Hypericin (Hyp) has great potential in activating TLR3 and may be a favorable choice for immunotherapy of trichinellosis. However, its applications are hampered by poor water solubility and dose-dependent phototoxicity.

PURPOSE: This study aimed to overcome the disadvantage of Hyp by using thermo-responsive hydrogel, better exert its immunotherapeutic efficacy against T. spiralis by activating TLR3.

STUDY DESIGN AND

METHODS

We used P(NIPAM-co-AM) hydrogel prepared by acrylamide (AM) and N-isopropylacrylamide (NIPAM) to load Hyp, and named P(NIPAM-co-AM)/Hyp. Subsequently, its lower critical solution temperature (LCST) characterization, biocompatibility, immunomodulatory activity via TLR3 signaling pathway, and therapeutic efficacy against T. spiralis were evaluated.

RESULTS

The study showed that the controllable drug release rate of P(NIPAM-co-AM)/Hyp owed to its remarkable temperature sensitivity. P(NIPAM-co-AM)/Hyp exhibited exceptional efficacy in activating the TLR3 signaling pathway and significantly promoting DC cells maturation. P(NIPAM-co-AM)/Hyp effectively elicited a robust pro-inflammatory immune response with up-regulation of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-2 (IL-2), interleukin-12 (IL-12) in T. spiralis-infected mice. Compared to Hyp and albendazole (ABZ), P(NIPAM-co-AM)/Hyp exhibited a significant decrease in the encysted muscle larvae number and histopathological destruction. The muscle larvae burden was dropped from 58,733 to 32,833 per mice at a dose of 10 mg/kg, with a reduction rate of 42.8 %. Moreover, the reduction rate increased to 64.30 % at a dose of 20 mg/kg.

CONCLUSIONS

This study confirms the therapeutic efficacy of P(NIPAM-co-AM)/Hyp as a TLR3 agonist and provides a new study direction for immunotherapy strategy and vaccine development by targeting parasites.