Sublingual Boosting with a Novel Mucoadhesive Thermogelling Hydrogel Following Parenteral CAF01 Priming as a Strategy Against Chlamydia trachomatis.

Chlamydia trachomatis is the most prevalent sexually transmitted disease of bacterial origin. The high number of asymptomatic cases makes it difficult to stop the transmission, requiring vaccine development. Herein, a strategy is proposed to obtain local genital tract immunity against C. trachomatis through parenteral prime and sublingual boost. Subcutaneous administration of chlamydia CTH522 subunit vaccine loaded in the adjuvant CAF01 is combined with sublingual administration of CTH522 loaded in a novel thermosensitive and mucoadhesive hydrogel. Briefly, a ternary optimized hydrogel (OGEL) with desirable biological and physicochemical properties is obtained using artificial intelligence techniques. This formulation exhibits a high gel strength and a strong mucoadhesive, adhesive and cohesive nature. The thermosensitive properties of the hydrogel facilitate application under the tongue. Meanwhile the fast gelation at body temperature together with rapid antigen release should avoid CTH522 leakage by swallowing and increase the contact with sublingual tissue, thus promoting absorption. In vivo studies demonstrate that parenteral-sublingual prime-boost immunization, using CAF01 and OGEL as CTH522 vaccine carriers, shows a tendency to increase cellular (Th1/Th17) immune responses when compared to mucosal or parenteral vaccination alone. Furthermore, parenteral prime with CAF01/CTH522 followed by sublingual boosting with OGEL/CTH522 elicits a local IgA response in the genital tract.

Design of novel orotransmucosal vaccine-delivery platforms using artificial intelligence.

The linings of the oral cavity are excellent needle-free vaccination sites, able to induce immune responses at distal sites and confer systemic protection. However, owing to the mucosal tissues' intrinsic characteristics, the design of effective antigen-delivery systems is not an easy task. In the present work, we propose to develop and characterize thermosensitive and mucoadhesive hydrogels for orotransmucosal vaccination taking advantage of artificial intelligence tools (AIT). Hydrogels of variable composition were obtained combining Pluronic® F127 (PF127), Hybrane® S1200 (HS1200) and Gantrez® AN119 (AN119) or S97 (S97). Systems were characterized in terms of physicochemical properties, adhesion capacity to mucosal tissues and antigen-like microspheres release. Additionally, polymers biocompatibility and their immune-stimulation capacity was assessed in human macrophages. Interestingly, cells treated with HS1200 exhibited a significant proliferation enhancement compared to control. The use of AIT allowed to determine the effect of each polymer on formulations properties. The proportions of PF127 and Gantrez® are mainly the factors controlling gelation temperature, mucoadhesion, adhesion work and gel strength. Meanwhile, cohesion and short-term microsphere release are dependent on the PF127 concentration. However, long-term microsphere release varies depending on the Gantrez® variety and the PF127 concentration used. Hydrogels prepared with S97 showed slower microsphere release. The use of AIT allowed to establish the conditions able to produce ternary hydrogels with immune-stimulatory properties together with adequate mucoadhesion capacity and antigen-like microspheres release.

New tools to design smart thermosensitive hydrogels for protein rectal delivery in IBD.

Local treatment of Inflammatory Bowel Disease (IBD) has been pointed out to be a novel therapeutic approach with several advantages when compared to conventional therapies. However, the development of systems able to fulfil the requirements of this administration route is not an easy task. The present work suggests the utilization of Artificial Intelligence Tools (AIT) as an instrument to understand polymer-polymer interactions towards obtaining thermosensitive hydrogels suitable for protein rectal administration in IBD. Enemas composed by Pluronic® F127 and F68 and Methocel® K4M were developed and characterised. Two experimental designs were carried out in order to determine the effect of each polymer on their texturometric and rheological behaviour. Using the results of the first experimental design we can justify the inclusion of each raw material PF127, PF68 and MK4M in the formulation and conclude that a compromise solution is necessary to obtain thermosensitive hydrogels of the required properties. The results of the second experimental design allowed concluding that PF127 ruled mainly syringeability and bioadhesion work. On the other hand, PF68 modulated principally gelation temperature, viscosity and protein release from hydrogel matrix. Finally, MK4M influenced bioadhesiveness and mostly determined viscosity. AIT also allowed delimiting the design space to produce easy administrable and highly bioadhesive enemas that undergo fast sol-gel transitions at body temperature.