Acidified sucralfate encapsulated chitosan derivative nanoparticles as oral vaccine adjuvant delivery enhancing mucosal and systemic immunity

Oral vaccines are generally perceived to be safe, easy to administer, and have the potential to induce both systemic and mucosal immune responses. However, given the challenges posed by the harsh gastrointestinal environment and mucus barriers, the development of oral vaccines necessitates the employment of a safe and efficient delivery system. In recent years, nanoparticle-based delivery has proven to be an ideal delivery vector for the manufacture of oral vaccines. Hence, considering the above, the sucralfate acidified (SA) encapsulated N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC)/N,O-carboxymethyl chitosan (CMCS) nanoparticles (SA@N-2-HACC/CMCS NPs) were prepared, and the BSA was used as a model antigen to investigate the immune responses. The SA@N-2-HACC/CMCS NPs had a particle size of 227 ± 7.0 nm and a zeta potential of 8.43 ± 2.62 mV. The NPs displayed slow and sustained release and high stability in simulated gastric juice and intestinal fluid. RAW 264.7 macrophage-like cell line demonstrated enhanced uptake of the SA@N-2-HACC/CMCS/BSA Nps. The vaccine via oral administration markedly enhanced the residence time of BSA in the intestine for more than 12 h and elicited the production of IgG and sIgA. The SA@N-2-HACC/CMCS NPs developed here for oral administration is an excellent technique for delivering antigens and provides a path of mucosal vaccine research.

Introduction

The most effective strategy for administering large-scale highly pathogenic virus epidemics lies in the widespread deployment safe and effective vaccines. Currently, the majority of licensed vaccines present limitations, such as the need for injecting immunization. The injecting immunization has many drawbacks, including the need for professional staff, unresolved biosafety concerns, and the potential for pain and discomfort during the procedure [1]. Considering these clinical needs and the limitations of traditional injectable vaccines, vaccination via the mucosal route has shown its potential advantages as a new specific delivery method [2]. The mucosal immune system constitutes the first line of defense against invading pathogens [3], and mucosal immunity is effective in promoting rapid and durable immune protection compared to systemic immunity [4]. More importantly, mucosal immunity can induce immune protective responses at the distant mucosal sites through the common mucosal immune system (CMIS). Mucosal vaccine can be classified as oral, nasal, vaginal, or rectal based on the route of administration, of which oral administration is the easiest and most ideal route of vaccination. Oral administration can confer antibodies by inducing both mouth and intestinal mucosal immune responses [5]. Specifically, oral vaccine can induce mucosal and systemic immunity responses by activating antigen-presenting cells (APCs) within the intestinal mucosa [6]. Thus oral immunization induces the local production of secretory IgA antibodies that are essential for the induction of a protective humoral immune response [7]. In previous studies, oral immunization with the canine distemper virus (CDV) vaccine has been demonstrated to elicit a significant immune response in mice, a finding that provides a reference for immunizing wildlife with CDV vaccines [8]. Oral immunization with the Clostridium perfringens vaccine can significantly increase the expression of specific anti-α antibodies and protect chickens from necrotic enteritis disease [9], and oral immunization with the Bacille Calmette-Guérin (BCG) and ovalbumin vaccine produce more IgG2a and improve immunity to pathogen infections [10]. A variety of oral vaccines, including those for cholera, rotavirus, and polio, have received regulatory approval and are now available for public health use [11]. Despite the numerous benefits of oral immunization over traditional parenteral injection methods, it is worth emphasizing that a mucosal delivery system via oral immunization is essential to protect the vaccine from gastric degradation, enhance antigen absorption in the gastrointestinal (GI) tract, trigger adaptive immune responses [12], and cross the intestinal epithelial barrier [13]. As a result, there is an urgent need for innovative vaccination formulations and delivery systems that can improve efficacy and safety.

Nanomaterials have emerged as a superior class of vaccine delivery vectors, with polymeric nanoparticles (NPs) standing out as a highly proficient platform for oral drug delivery [14]. Hence, nanotechnology-based delivery systems hold great potential for the development of oral vaccines [15]. For this reason, many effective NPs delivery systems have been reported to address the above problems. However, the poor residence time in the intestine and the weak protective effect of gastric degradation are still the bottlenecks of oral vaccine research. Sucralfate has been widely used as a mucosal protective material and for the treatment of peptic ulcers and GI discomfort [16]. It forms a protective barrier to shield the gastric wall from ulcers or damage [17]. Experimental evidence exists to suggest that sucralfate acidified (SA) can form a thick protective film in the stomach and small intestine [18]. Thus, we hypothesize that supplementation of the SA into nanomaterials not only helps to resist the complex environment of the stomach but also delivers NPs to the GI tract to prolong the residence time of NPs in the intestine.

Nanocomposite materials based on chitosan have become attractive in recent years due to their biocompatibility, low toxicity, and biodegradability [19]. Our lab has synthesized N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) based on the quaternized modification of chitosan, N,O-carboxymethyl chitosan (CMCS), and N-2-HACC/CMCS NPs as a nano delivery system [20]. It was demonstrated in our previous studies that N-2-HACC/CMCS NPs as a delivery system enhanced mucosal immune response with intranasal administration [21,22], suggesting that the N-2-HACC/CMCS NPs have tremendous promise for mucosal delivery of vaccines. However, it is necessary to connect the functionalized materials with N-2-HACC/CMCS NPs to achieve oral immunization.

To improve the ability of the delivery system to resist stomach acid and enhance the residence time of antigens in gut lymphoid tissues, we constructed an oral vaccine delivery system based on SA and N-2-HACC/CMCS NPs (SA@N-2-HACC/CMCS NPs). The SA@N-2-HACC/CMCS/BSA NPs were formulated to incorporate bovine serum albumin (BSA) to verify the immune effect. In the present study, we evaluate the adhesion, antigen presenting ability, antigen sustained release and stability in the simulated GI, residence time in the intestine, and immunogenicity of the SA@N-2-HACC/CMCS/BSA NPs in a guinea pig model. This work reveals the great potential of chitosan derivative-based nanomaterials as a mucosal vaccine delivery system, providing new opportunities for the future development and clinical application of oral vaccines.

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Zhi Zhao, Shuai Qiao, Zheng Jin, Heqi Li, Haitao Yu, Chunjing Zhang, Tan Hui Yin, Kai Zhao, Acidified sucralfate encapsulated chitosan derivative nanoparticles as oral vaccine adjuvant delivery enhancing mucosal and systemic immunity, International Journal of Biological Macromolecules, Volume 279, Part 3, 2024, 135424, ISSN 0141-8130, https://doi.org/10.1016/j.ijbiomac.2024.135424.

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Video: Chitosan as a natural excipient