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    Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines
    Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines
    Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines
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    Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines

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    Emerging Nanotechnologies in Immunology aims to deliver a systematic and comprehensive review of data concerning the nature of interaction and nano-related risks between the nanophamaceuticals currently in the pipeline of S&T development for skin, ocular, and nasal drug delivery, including absorption, toxicity, and the ability to distribute after systemic exposure.The scientific development of manufactured nanomaterials for drug delivery is increasing rapidly. One of the most prominent applications is topical drug delivery, where cutaneous, ocular, and nasal exposure becomes even more relevant. These targets are the first barrier that nanoparticles encounter when in contact with the human body.The contributors addresses a representative set of the broad spectrum of nanopharmaceuticals currently being used, including cationic lipid nanoparticles, polymeric PLGA, PLA nanoparticles, biomacromolecules-based nanoparticles, and other scaffolds tissue engineered skin substitutes. Regulation and risk is also covered, since the safety of these nanophamaceuticals still represents a barrier to their wide innovative use.
    • Provides the reader with a thorough knowledge of the safety aspects of nanopharmaceuticals which are currently under research
    • Focuses on the characterization and quantification of the nanopharmaceuticals
    • Allows readers to understand the correlation between the nature of the materials and their potential nanotoxicological effects
    • Includes an overview of regulatory aspects related to the R&D of nanopharmaceuticals
    LanguageEnglish
    PublisherElsevier Science
    Release dateMay 17, 2018
    ISBN9780323401135
    Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines

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      Book preview

      Emerging Nanotechnologies in Immunology - Ranjita Shegokar

      (www.ebsouto.pt).

      Preface

      Ranjita Shegokar¹ and Eliana B. Souto², ¹Berlin, Germany, ²Coimbra, Portugal

      Nanotechnologies have always fascinated human since several decades and are now widely explored in biomedical field. Diverse types of nanoparticles are being explored around the world, some examples include biodegradable nanoparticles, green nanoparticles, polymeric nanoparticles, lipid nanoparticles, metal nanoparticles, graphene, carbon nanotubes, and several others.

      Innovation in process engineering, chemical synthesis, diverse collaborations across various fields of science expertise, it is possible to modify in vitro and in vivo properties of nanoparticles with various chemical functional groups, ligands, and antibodies. These multipotential and multifunctional aspects of nanotechnology provides platform for treatment of diverse health problems and diseases. These nanosized particles improve communications with biomolecules on the cell surfaces and within the living cells in a way that can be decoded and designated to various physiochemical responses of cells to exhibit desired diagnostic and/or therapeutic response.

      In short, nanotechnologies play key role and have enormous potential in immunology. The present book titled Emerging Nanotechnologies in Immunology: The Design, Applications, and Toxicology of Nanopharmaceuticals and Nanovaccines aims to deliver a systematic and comprehensive review of data concerning the nature of interaction and nano-related risks between the nanopharmaceuticals currently in the pipeline of scientific developments in skin, ocular and nasal targeted drug delivery, including absorption, toxicity, and the ability to distribute after systemic exposure. The book’s contributors address a representative set of the broad spectrum of nanopharmaceutics presently being used, including cationic lipid nanoparticles, polymeric nanoparticles, biomacromolecules-based nanoparticles, and other. In addition, regulation and risk are also covered since the safety of these nanopharmaceuticals still represents a barrier to their wide and innovative use. Benefits of natural compound like curcumin is discussed as potential candidate. Nano-antibiotic is another area to explore potential of nanotechnologies covered to give new insights from research across the world.

      The book is very useful for pharmacologists, microbiologists, biotechnologists, nanotechnologists, and medical experts. Students and researchers would as well as postgraduates, developing their research in topical drug delivery; policy makers and pharmaceutical companies and learned societies, associations, and research groups working in nanopharmaceuticals.

      Key Features

      • Provides a thorough knowledge of the safety aspects of nanopharmaceuticals currently under research.

      • Focuses on the characterization and quantification of nanopharmaceuticals to allow readers to understand the correlation between the nature of the materials and their potential nanotoxicological effects.

      • Includes an overview of regulatory aspects related to the R&D of nanopharmaceuticals.

      Chapter 1

      Nanopharmaceuticals in immunology

      What’s new in research?

      Ranjita Shegokar¹, Ana R. Fernandes² and Eliana B. Souto³,    ¹Freie Universität Berlin, Department of Pharmaceutics, Biopharmaceutics & NutriCosmetics, Kelchstr, Berlin, Germany,    ²Universidade de Coimbra, Coimbra, Portugal,    ³Department of Pharmacutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra, Portugal

      Abstract

      In last few decades, nanomedicines have emerged as an innovative promising approach for the delivery of several compounds of pharmaceutics relevance. The developed pharmaceutics offer new opportunities both at academic and industrial levels, as well as to regulators, with an ultimate aim of better treatment of patients. The market of nanopharmaceuticals is expected to increase at an annual growth rate of 12.5%, reaching a value of $130.9 billion in the coming years. Nowadays, there are several formulations approved by Food and Drug Administration and other regional authorities for the treatment of many diseases, such as cancer, immunotherapy, HIV/AIDS, and malaria. This chapter discusses new therapeutic options on the use of nanopharmaceuticals in the field of immunology. There is an urgent need to conduct new studies, because the risk of bioaccumulation in body organs still is a problem. In the future, with the help of multidisciplinary efforts, in a few years nanopharmaceuticals will cover major portion of drug delivery market and will be used as standard in the drug industry.

      Keywords

      Nanoparticles; drug delivery; immunology; cancer; formulation; HIV/AIDS; malaria; tuberculosis

      Chapter Outline

      1.1 Introduction 1

      1.2 Application of Nanopharmaceuticals for Disease Treatment 4

      1.3 Evolution of Nanopharmaceuticals for Disease Treatment 4

      1.3.1 Cancer 4

      1.3.2 Immunotherapy 8

      1.3.3 Vaccines 9

      1.3.4 HIV/AIDS 11

      1.3.5 Tuberculosis and Malaria 15

      1.4 Conclusion 15

      References 16

      1.1 Introduction

      Nanomedicines are emerged in pharmaceutical research since last few decades, offering new challenges and opportunities to research community, industry, and regulators to serve patient better. Fast development of scientific and technological tools to surplus the need of medical field in creating better human health care and life quality is in demand. The field of nanopharmaceuticals requires expertise from several area of science, from the traditional research to biotechnology, to offer new solutions for unmet healthcare challenges [1]. In this global context, nanomedicine emerges as a promising tool also to optimize the therapy of pediatric diseases. An expression of this potential and vision was the development of the pioneering NanoPediatrics Program [2]. The introduction of innovative nanopharmaceuticals has shown potential impact on disease treatment and global healthcare. Various effective nanopharmaceuticals such as dendrimers, lipid nanoparticles, polymer-lipid complexes, nanocrystals, liposomes, viruses, virus-like materials, polymeric particles, hydrogels, emulsions, and inorganic materials, are being explored in the field of immunology, which is of interest to both, for industry and academia [3]. Nanopharmaceuticals are known to have specific interactions with the immune cells and blood proteins, depending on the size range and physicochemical properties. This makes biocompatibility and immunotoxicity the critical aspects when developing nanopharmaceuticals. Adjuvate dosage regimen and therapeutic index, appropriate administration route and disease environment are the main factors influencing the optimum delivery of nanopharmaceuticals [4]. Literature confirms that nanomedicines loading drugs are safe, biocompatible and have ability to decrease the toxicity of conventional drugs. Despite various formulation issues, a considerable number of nanomedicines have been approved by regulatory authorities, as the Food and Drug Administration (FDA) and other regional authorities (Table 1.1).

      Table 1.1

      Nanopharmaceuticals have transformed clinical medicine, in the area of drug delivery and vaccines. Various nanometer sized carriers are being tested for the effective delivery of drugs, antigens, or adjuvants to antigen presenting cells or lymph nodes, in order to promote or suppress immune responses against disease and autoimmunity [5]. The main advantages of nanopharmaceuticals for immunological drug delivery include protection of drug from premature enzymatic and proteolytic degradation, to control pharmacokinetics, and to enhance absorption by target cells and tissues in order to exhibit immune-stimulatory effect [6].

      Nanocrystals and self-nanoemulsifying drug delivery systems (SNEDDS) resulted already in numerous marketed drug products. They offer a prolonged gastrointestinal-residence time, permeation enhancing properties and oral absorption can be strongly improved. As nanocrystals consist of 100% of drug there is no matrix in which the drug is loaded. Due to the tremendous increase in surface area generated by the use of drug nanocrystals, its solubility and saturation velocity are strongly increased. Sirolimus (Rapamune), aprepitant (Emend), fenofibrate (Tricor, Triglide), and megestrol acetate (Megace ES) are examples of marketed drug nanocrystals [7].

      As a way to increase the surface area, porous materials are emerging as a new category of drug delivery systems. Various types of pores allow them to adsorb drugs and release them in a more reproducible and predictable way. Pharmaceutically explored porous adsorbents include silica, calcium silicate, magnesium aluminometa silicate, zeolites, activated carbon, silicon dioxide, ceramics, calcium carbonate, iron oxides, titanium dioxide, bauxite, and zirconium oxide. The advantages of such nanopores material includes: DNA sequencing using nanopores requires the ability of moving a DNA strand and reading sequence information at each position; 2D materials have their extraordinary electrical, chemical, optical, mechanical, and structural properties; benefit from the rapid development of nanotechnology [8].

      1.2 Application of Nanopharmaceuticals for Disease Treatment

      Attempts are being made to target nanopharmaceuticals not only to cells but also to organelle at more precise dose level. This type of approach is highly required in diseases like tuberculosis (TB), human immunodeficiency virus (HIV), and malaria [9,10] in which immune cells are infected. Among organelles, mitochondria and nucleus are the most studied targets besides lysosomes for stimuli-responsive delivery. The challenges of organelle based delivery rely on the need to cross cellular and intracellular membranes. These challenges confirm the need of further understanding of optimum nanopharmaceuticals formulation design (with or without surface modifiers), of intracellular trafficking mechanisms, endosomal escape ability of nanoparticles for intracellular transport, endosome–lysosome degradation resistance of nanoparticles and the complexity of the cellular. Another possible strategy is to target multiple organelles at the same time for effective delivery. Mallick et al. targeted the mitochondria and nucleus simultaneously using 200 nm nanoparticles [11]. Stepwise membrane fusion, as well as targeting of mitochondria and nucleus, was achieved using endosome- and organelle-fusogenic lipid enveloped multicoated nanoparticles [12]. Currently, the mechanism involved in organelle targeting is not yet fully understood; it is expected that the use of nanopharmaceuticals may contribute to clarify the pathways that drugs follow to reach intracellular targets [13].

      1.3 Evolution of Nanopharmaceuticals for Disease Treatment

      1.3.1 Cancer

      The application of nanopharmaceuticals in the treatment of cancer is vast and widely studied. Nanoparticles make use of enhanced permeability and retention (EPR) effect via leaky junctions in tissue which lead to extravasation of nanoparticles from blood flow [14] (Fig. 1.1).

      Figure 1.1 Nanoparticles can extravasate into the tumors through the gaps between the defective endothelial cells. These particles can accumulate in the tumors due to poor lymphatic drainage.

      The pattern of protein adsorption on nanoparticles and its influence on bioavailability and biodistribution must be studied to establish useful clinical use of nanopharmaceuticals. Drug delivery via EPR effects is mainly by passive accumulation while approaches for active targeting includes nanoparticle surface decoration with bioactive molecules such as transferrin, engineered antibodies, enzymes, and folic acid, which recognize and interact with cancer-specific targets overexpressed on the surface of cells [15]. Ideally external aids like heat, light, ultrasound, or magnetic fields stimulate release of bioactive content from nanoparticles to exert pharmacological effect in the pathological tissue.

      Thermosensitive liposomes decorated with engineered antibody mimicking the human epidermal growth factor receptor 2 (HER2) have been used to deliver paclitaxel to HER2-positive cancers [16]. Tumor cells were targeted by nanoparticles coupled with tumor-homing peptides, e.g., CREKA peptide which recognizes clotted plasma proteins in tumor vessels and tumor stroma, and the cell-penetrating peptide Lyp-1 [17].

      The majority of nanomedicines used in chemotherapy on the market are liposomes and polymer-based nanoformulations. Several others are in the pipelines including polymer-lipid complex, dendrimers, functional liposomes, micelles, polymeric nanoparticles, and metal nanoparticles [18].

      Nanopharmaceuticals in cancer treatment mainly cover nanomaterials or nanoparticles as carriers for drug, diagnostics, theranostic or as medical devices.

      Recently, cholesterol bearing pullulan (CHP) nanogels have been used as carriers for long peptide antigens (LPAs) as cancer vaccines. After subcutaneous administration in mice nanogel significantly inhibited tumor growth (Muraoka, Harada et al. 2014). In another study, CHP nanogels were explored to encapsulate and deliver NY-ESO-1 antigens, which are originally found in esophageal cancer (Hasegawa, Noguchi et al. 2006).

      Qian et al. used silica based nanoparticles of mean size between 70 and 80 nm surface-decorated with gold nanoparticles (6 nm) for the photothermal ablation of SK-N-BE(2)-C neuroblastoma cells. This approach enabled to localize the destruction of the tumor and restrict the adverse effects [19].

      Lee et al. assessed the effect of Au(III) porphyrin loading noncoated and coated polyethylene glycol (PEG) lipid nanoparticles composed of cetyl alcohol and Brij 78 in the NA2 neuroblastoma model. Encapsulation substantially reduced the systemic toxicity of the drug and prolonged the survival of tumor-bearing mice. To reduce accumulation in the liver and associated hepatotoxicity, nanoparticles were coated with PEG-chains of molecular weight 750 and 2000 g/mol. The surface modification reduced the hepatic uptake to minimal levels, while it increased the accumulation in the tumor by means of EPR effect [20].

      Makky et al. synthesized glycodendrimeric porphyrins that are recognized by the mannose receptor in retinoblastoma cells. Studies conducted in a biomimetic model and in a subcutaneous xenograft model of human retinoblastoma showed inhibition of tumors in orthotopic location. Similar rationale was used by Gary-Bobo et al., who developed silica mesoporous nanoparticles for one photon photodynamic therapy (PDT) (containing the porphyrin PS) loaded with the antitumoral camptothecin and modified with mannose or galactose for the active targeting of the nanoparticles to retinoblastoma Y79 cell line in vitro. The combined approach led to greater cell death in vitro [21,22].

      Curcumin-loaded nanoparticles composed of N-isopropylacrylamide, vinylpyrrolidone and acrylic acid (NanoCurc) showed a dose-dependent decrease in the growth of Daoy and D283 Med cell lines in vitro. Moreover, nanocurcumin downregulated the expression of IGF-1, STAT3 and Gli1 in Daoy cells, [23]. Excellent antitumoral activity of a curcumin/2-hydroxypropyl-γ-cyclodextrin complex encapsulated within liposomes was observed against KHOS osteosarcoma cell line in vitro and in a xenograft osteosarcoma model in vivo was studied by Dhule et al. [24].

      Zabaleta et al. demonstrated via in vivo studies with paclitaxel nanoparticles that PEGylation of nanoparticles either with PEG 2000 or PEG 6000 yielded carriers of lower mucus interactions than particles coated with PEG 10,000 [25,26].

      Long-circulating liposomes of doxorubicin [27], arabinofuranosylcytosine [28,29], adriamycin [30], and vincristine [31] have been reported in literature. Recent studies describe surface modification of Tf to PEG on PEGylated liposomes in order to combine long-term circulation and targetability properties [32], e.g., folate decorated cyanoacrylate-based nanoparticles via activated PEG blocks [33]. Vasoactive intestinal peptide (VIP) has been coupled to PEG-liposomes to target VIP-receptors of the tumor [34]. Antibody decorated pH-sensitive liposomes, i.e., immunoliposomes demonstrated cystolic drug for the delivery of fluorescent dyes, antitumor drugs, proteins, and DNA [35].

      Concurrent delivery of paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin from PEG-b-PLA micelles significantly increased the values of the area under the plasma concentration–time curves of paclitaxel and rapamycin in mice compared to the drugs delivered individually, while the pharmacokinetic parameters were the same for 17-AAG [36].

      Thermoresponsive gels are biodegradable, biocompatible gels that demonstrate reverse thermal gelation properties. ReGel is a triblock copolymer comprised of poly(lactic-co-glycolic acid) (PLGA) and PEG with the basic structure of (PLGA-PEG-PLGA). Preclinical studies of ReGel loaded with paclitaxel (OncoGel) demonstrated safety and efficacy in brain and esophageal cancers in vivo models [37,38].

      Park et al. developed polymer microneedles out of poly(L-lactide) (PLA), polyglutamic acid (PGA), and PLGA by mold fabrication and looked at the diffusion of compounds across the skin and showed that porous PLA microneedles, with a porosity of 75% lacked strength and were unable to penetrate the skin [39]. Various other applications of PLA are discussed by Tylor et al. [40].

      Thymoquinone derived from Nigella sativa plant has been shown to exhibit anti-inflammatory and anticancer activity. Thymoquinone nanoparticles prepared by nanoprecipitation have shown improved effectiveness and bioavailability [41]. Curcumin, e.g., has minimal systemic bioavailability, but its biologic activity and bioavailability have been tremendously increased via various nanoparticle formulations.

      Bisht et al. have developed nanoparticulate curcumin using cross-linked polymeric nanoparticles comprised of N-isopropylacrylamide, Nvinyl-2-pyrrolidinone, and PEG acrylate, which has been tested in various pancreatic cancer cell lines [42]. Nanoparticles showed superior cytotoxicity and downregulated multiple proinflammatory markers in a dose-dependent manner.

      To achieve a high bioavailability, ursolic acid phospholipid nanopowders have been prepared by solvent emulsification–evaporation and ultrasonic dispersion. However, limited biological testing of these particles has been reported. In another study, triptolide, a traditional Chinese medicine compound was incorporated in various nanoparticle systems, which could be used in various anti-inflammatory, immunosuppressive, antifertility, and antineoplastic medications [43]. Polyphenols are naturally occurring compounds which have proven anti-inflammatory properties and thus high potential for cancer therapy [44]. The concept of nanochemoprevention has been introduced aiming at using nanotechnology to enhance the outcome of chemoprevention. PLA-PEG nanoparticles containing epigallocatechin gallate (EGCG) exhibited a >10-fold dose increase over nonencapsulated EGCG [45].

      Cisplatin loaded thermal-sensitive poly-N-isopropylacrylamide modified gold nanoparticles efficiently triggered drug release and showed improved cytotoxicity in A875 melanoma cell [46].

      1.3.2 Immunotherapy

      Polysaccharide self-assembled nanogels (amphiphilic and cationic) were widely used in immunotherapy as molecular chaperones for intracellular protein delivery, nasal vaccines, and gene delivery. Various research examples include pullulan modified with alkyl chains, photoresponsive spiropyran, thermoresponsive poly(2-isopropyl-2-oxazoline), deoxycholic acid-modified pullulan, PLA-grafted pullulan, and alkyl chain-modified hydroxyethyl/vinyl methacrylate pullulan [47]. Pullulan can also be modified with functional groups, cationic or contained double bonds to form nanogel. Other examples include siloxane modified cholesteyl pollulan, Arg-Gly-Asp peptide-modified cholesteyl pollulan, imidazole-modified cholesteyl pollulan, and vitamin B6-modified pullulan. Other polymers than Pullulan used in nanogel formation studied are chitosan, heparin, dextran, mannan, cluster dextrin, hyaluronic acid, and glycogen (Hosseinkhani, Aoyama [48–52]). The core–shell type gel particles were prepared using diethyl amino ethyl methacylate as pH-sensitive units in the core and amino ethyl methacylate as cationic units in the shell. Cytosolic delivery of protein antigen and short interfering RNA (siRNA) via the proton sponge effect performed in dendritic cells (DCs) showed effective delivery and activation of CD8+ T-cells [53].

      Successful delivery of vascular endothelial growth factor (VEGF)-silencing siRNA (siVEGF) using unmodified CH-CA-self-nanogel or modified nanogel with diethylaminoethane (DEAE) has also been reported [54].

      Lipid bilayer-cross-linked multilamellar liposomes were also used to target antigens and release them for a few weeks thereby elicitating CD8+ T-cell responses [55]. On the other hand, to deliver antigens to the cytosol, pH-responsive polymers were used to surface modify liposomes for successful cancer immunotherapy [56].

      Red blood cell membrane-coated PLGA nanoparticles trapping toxins showed superior protective immunity compared with the heat-denatured toxin alone [57]. In another study, solid core nanoparticles, consisting of poly(propylene sulfide) (PPS) as a cross-linked core exhibited efficient transport of active to lymph nodes and activated DCs. Furthermore, the conjugation of oligonucleotide (ODN) adjuvants with these particles induced the activation of CD8+ T-cells and long-term cellular immunity [58,59].

      Chitosan is a cationic polysaccharide composed of glucosamine with or without N-acetyl modification. Chitosan formed gel-like submicrometer-sized particles after addition of tripolyphosphate, which exhibited antibody production. Subsequently, the surface modification of chitosan/tripolyphosphate particles using alginate as ODN adjuvants or recombinant NcPDI antigens carrier showed effective delivery at target site Chitosan-DNA nanoparticles are reported for nasal immunization [60–64]

      Gamma PGA (γ-PGA) nanoparticles loaded with antigen were internalized by DCs [65] and showed an antitumor effect via generation of both Th1 and Th2-type immune induction [66]. HER2 embedded nanogel was tested subcutaneously in mice showed protective and therapeutic effects, indicating antigen-specific cellular immune response against the protein delivering epitope [67].

      CHP (cholesterol bearing Pullulan) nanogels were successfully explored to deliver cytokines like IL-12 [68] to overcome degradation or clearance challenge thereby providing long-term delivery. In another study, raspberry-like NanoClik nanoparticles were also explored for long-term sustained delivery of IL-12 [69]. In addition amine-modified CHP (CHP-NH2) nanogels were complexed with quantum dots (QDs) and with protein through electrostatic interactions to target active intracellularly [70].

      1.3.3 Vaccines

      Nanoparticles are used for cancer vaccines to target the immune systems. Nanoparticles can imprison tumor antigens and adjuvants and be targeted to specific receptors expressed on the surface of DCs. After the uptake of nanoparticles starts the degradation and release of antigens and adjuvants, which promotes the initiation of DC maturation. In the maturation process, DCs regulate the expression of some cell surface molecules. These cells also release cytokines and after this process, there is the presentation of antigens to T-cells (through MHC-peptide complexes). To finalize, T-cells suffer clonal expansion and then promote the tumor destruction. This process involves the action of cytotoxic T lymphocytes (CTL) with T helper 1 cells (Th1) as well as effector cells, e.g., macrophages (Mph), natural killer T-cells (NK), and granulocytes (Gran) (M Silva, Videira et al. [71]) Fig. 1.2.

      Figure 1.2 Application of nanoparticles in the cancer vaccines.

      Nasal vaccines using pneumococcal surface protein A (PspA) as an antigen in CHP-NH2 nanogel (PspAnanogel) were studied in mice and in nonhuman primates. Both in vivo study confirmed improved active delivery of nanogel [72,73].

      Intranasal vaccination is one of the most attractive immunization strategies for delivering vaccine antigens directly onto the mucosa to induce a protective immune response. Intra nasal vaccine delivery using the CHP-NH2 nanogel of type-A neurotoxin subunit antigen Hc (BoHc/A), the recombinant nontoxic receptor-binding fragment of Clostridium botulinum showed effective delivery and retained in the nasal cavity for longer period compared to pure antigen BoHc/A, which disappeared within 6 h [74].

      Selfnanogels were used for the first time in cancer therapy as immunological drug delivery, particularly for cancer vaccines. These vaccines can be either prophylactic or therapeutic. Nonionic CHP nanogels are typically used as cancer vaccines and cytokine delivery, and cationic nanogels for nasal vaccines and intracellular delivery of proteins and nucleic acids.

      A recent clinical trial investigated the dose-dependent effects of CHP-NY-ESO-1 vaccines in advanced metastatic esophageal cancer patient, which showed a positive response thereby increasing the survival rate of patients at 200 μg/dose [75]. Similar observations were found for patient receiving vaccine containing MAGE-A4 in a CHP nanogel [76].

      Solid lipid nanoparticle (SLN) are also used as a carrier for DNA vaccine against visceral leishmaniasis. Enhanced protection effect was observed for DNA vaccine encapsulated SLN to mice are associated with high levels of IFN-γ and lower levels of IL-10 production resulting in a strong Th1 immune response

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