ReviewPolymeric micro/nanoparticles: Particle design and potential vaccine delivery applications
Introduction
Vaccination is the most effective and economic way to prevent infection and severe outcomes caused by bacterial, viruses, or other pathogen. Owing to hundred kinds of vaccines, global death has decreased, along with cost for treatment for infectious diseases. The development of vaccine products was accompanied with rapid advancement of biotechnology, immunology, and biomaterials. The first generation of vaccine was dated from 1796, when Edward Jenner inoculated healthy people with attenuated live cowpox virus, opening the era of vaccination in its modern form. By the 1940s, the vaccines were developed when passage in cell culture permitted the selection of attenuated mutants. Following that era, heat or chemical inactivation was applied to pathogens (e.g. typhoid, plague, and so on) to reduce the toxicity while maintaining the immunogenicity [1]. Although live or inactivated vaccines are capable of eliciting robust immune response with the assist of endogenous adjuvant (nonspecific pathogenic component), the safety concerns has limited their clinic use, especially when extremely dangerous pathogens, such as human immunodeficiency virus (HIV) and hepatitis virus, are involved [2]. Therefore, the modern generation of genetically engineered vaccine or subunit vaccine, which have defined components, good stability and high safety, emerged from the recombinant hepatitis B virus vaccine in 1986. However, most of the new generation vaccines suffer from shortcoming of poor immunogenicity, and the exploration of high-performance adjuvant has become a rapidly expanding research area [3].
In addition to the progress of preventive vaccines for healthy people, vaccine-based treatments of chronic infected diseases and malignant tumors have attracted tremendous interests in the recent decades [4], [5]. Compared with conventional chemotherapy or radiotherapy, vaccines strategy possesses relatively higher specificity and lower side effect. For example, the first Food and Drug Administration (FDA)-approved tumor vaccine (Provenge) could suppress metastatic castration-resistant prostate cancer by activating the power of the patient's own immune system [6]. A crucial requirement for therapeutic vaccine is to elicit sufficient cellular immune responses against the target cells, thus not only the strength but also the polarization of the immune response should be considered in adjuvant design, making it even more challenging [7].
Development of vaccines requires safe and efficient adjuvant or antigen delivery systems. Although being pursued, ideal adjuvants remain out of reach for now. Alum salt is the most commonly used adjuvant approved by FDA (in 1926), which can be found in diphtheria–tetanus–pertussis, human papillomavirus or hepatitis vaccines [8]. Alum salt induces the antibody related immune response by a depot effect and activation of antigen presenting cells (APCs). Nevertheless, the preventive effect was not satisfactory for some subunit vaccine (e.g. H5N1 split vaccine). Moreover, its incapacity in eliciting cellular response hindered its therapeutic application in treatment of infected or cancerous cells. In the following 80 years, adjuvants like water-in-oil emulsion (e.g. Freund's adjuvant), microorganism component (lipopolysaccharide, LPS), and cytokines (Interleukine-2) were developed to induce higher immune response. Albeit effective in animal models, these adjuvants were reported to induce adverse effects like fever, lethargy, and even shock. Their clinic applications were thus stagnated until MPL-A (Monophosphoryl Lipid A, a derivate of LPS) was adopted as an adjuvant in FDA approved cervical cancer vaccine in 2009. In this regard, there is still an unfulfilled need for a safe and potent adjuvant.
Compared with traditional adjuvant, the micro/nanoparticles (MP/NP) possess a particular advantage as they have similar size and structure as that of a pathogen, leading to a preferred interaction with antigen presenting cells (APCs). MP/NP, such as polymeric particles, liposomes and micelle, have shown promising signs owing to their attributes in bio-application [9], [10], [11], [12], [13]. Firstly, antigens that loaded in the particles can be protected from enzymatic degradation and rapid denaturation. Secondly, particles can improve the antigen uptake by APCs, promoting subsequent antigen process and cellular mediated response. Thirdly, the fine-tuned characteristics (e.g. size, surface charge or structure) of particles allow them to fulfill a prolonged antigen release for long-lasting humoral response, or targeted delivery and controllable release for specific cellular immunity [14], [15], [16]. Last but not least, the particulate vaccines can be administrated via alternative routes like oral, rectal, or nasal administration, rather than subcutaneously injection.
The potential of polymeric particulate vaccine delivery systems has been widely recognized [17], [18], [19]. However, owing to the prevalent use of non-uniform sized particles, discrepant and even contradictory outcomes were often present in biological or immunological evaluations. This situation has kept compromising the progress in establishing reliable theoretical guidance for particle design [20]. Moreover, wide size distribution may lead to an uncontrollable tissue distribution of the adjuvant particles, magnifying the concern on safety. To resolve these problems, our research group has developed a special MP/NP fabrication method on the basis of microporous membrane emulsification and has achieved successes in preparing bio-degradable (e.g. polylactide PLA) and polysaccharide (e.g. chitosan) MP/NP with controllable and uniform size (Fig. 1) [21], [22], [23], [24]. Particles at a range of 100 nm to 100 μm have been successfully prepared by choosing membrane with specific pore size. In addition, the scale-up equipment (40 L/h when pore size is 5.2 μm) has been established in our group, which can be applied for scaling-up test. Based on this kernel technique, MP/NP of different structure or physiochemical properties for specific characteristics and functions can be obtained (see our previous review [25]). The polymeric MP/NP with defined sizes and properties thus facilitated to exploring the relationship between the particle properties and immunomodulatory effects, providing enlightening paradigms in vaccine development.
Herein, we provide a review on the correlation of the particle physiochemical properties and antigen loading mode with the resultant biological/immunological outcomes, mostly based on the study of using the aforementioned uniform MP/NP. The underlying mechanisms of how the particles-based vaccine functioned in the immune system were also discussed. On the basis of particle design concept, potential applications of polymeric MP/NP were implicated not only for prophylactic vaccine (against e.g. Influenza and Anthrax), but also for therapeutic vaccine (against e.g. chronically infected hepatitis and malignant tumor).
Section snippets
Particle property design for vaccine delivery
The requirements of immune responses vary for specific antigen type and vaccination purpose. Antibody mediated humoral response is critical in the defense against extracellular pathogens for the preventive vaccine, while antigen specific cytotoxic T cells is mostly wanted for therapeutic vaccine. As APCs are pivots that translate the vaccine stimulation to immune system, their responses to MP/NP are very important for regulating the subsequent immune response. The major APCs responses include
Conclusions
This article reviewed the recent insight and practical progress of MP/NP based adjuvant/antigen delivery system in our research group, emphasizing on the uniform-sized polymeric particles. In-depth understandings of particle–bio interactions make an important contribution to support the rapid expanding researches on particle adjuvants. However, it is not an easy task to draw an uncontested conclusion due to the complexity originated from the particle fabrication. By using a unique microporous
Author contribution
Both authors have (1) screened relevant literature and discussed the review outline, (2) drafted the article or revised it critically for important intellectual content, and (3) approved the final version submitted.
Conflict of interest statement
The authors have no conflict of interest to declare.
Acknowledgments
This work was supported by Youth Innovation Promotion Association, Chinese Academy of Sciences (2013033), National Natural Science Foundation of China (51302265), National High Technology Research and Development Program of China (2014AA093604), and Major Project of the Ministry of Science and Technology of China (2014ZX09102045).
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