Essay Example on Understanding the molecular mechanism of engineered Nanoparticles

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Understanding the molecular mechanism of engineered nanoparticles would help in the developing the new nanoparticles The immune activity of the nanoparticles may be attributed to following mechanisms 1 Depot effect 2 activation of the NLR pyrin domain containing 3 NLRP3 inflammasome 3 delivery of antigens to draining lymph nodes 4 pattern presenting receptor PPR dependent immune activation 5 repetitive antigen presentation T cell differentiation However often it's difficult to isolate one mechanism as each nanoparticle might act as adjuvant using multiple mechanisms 2 4 1 Depot affect The nanoparticles can persist at the site of injection for long period of time thus enhancing the immune response this effect is called as Depot effect Zhang et al42 studied the persistence of the soluble antigen OVA antigen loaded PLGA nanoparticles antigen and nanoparticles physical mixtures and the combination of antigen loaded and physically mixed nanoparticles The showed that the OVA loaded PLGA had highest depot effect as compared to the soluble protein They further relate it to the immune response and suggested that the high immune response in the PLGA loaded nanoparticles as compared to soluble OVA was a result of the depot effect Figure 2 3 Depot formation of encapsulated OVA when OVA was encapsulated in PLGA Reproduced with permission from reference 42 42 2 4 2 Delivery of the antigens into the draining lymph node 



The major site for the most of the immune cells and interactions is the lymph node The targeting of the lymph node has been a major mechanism by which most of the small nanoparticles enhance the immune response For example Mueller and co authors synthesised different size of NPs using print technology and targeted the draining lymph nodes using various molecular weight polyethylene glycol In order to enhance the immune response and OVA was used as an antigen They showed that 80X180 nm nanoparticle with 500 kDa PEG showed the highest targeting to draining lymph nodes as compared to the soluble OVA and also showed the highest antibody titres 43 2 4 3 NLRP3 inflammasome activation NLRP3 is a main determinant in the activation of the innate immune response NLRP 3 triggers the high dose of ATP which leads to down activation of IL 1 β Nanoparticles like silica titanium dioxide have shown to have excellent adjuvant response through the NLRP 3 pathway 44 2 4 4 Pattern recognition receptors PRR agonist PRRs play a crucial role in the innate immune response They recognise the conserved pathogen associated molecular patterns PAMPs which are distinctive to each pathogen PRRs can detect various microbial pathogens like bacteria viruses parasites fungi and protozoa PRRs are not only expressed by antigen presenting macrophage and dendritic cells but also by other cells both immune and non immune cells The PRRs are localized on the cell surface within the endosomes and cellular matrix 



They are involved in activating pro inflammatory signalling pathways stimulating phagocytic responses macrophages neutrophils and dendritic cells or binding to micro organisms as secreted proteins There are various types of PRRs depending on the localisation 2 4 4 1 Membrane bound PRRs 2 4 4 1 1 Toll like receptors TLRs 2 4 4 1 2 TLRs are transmembrane receptors which detect various types of infecting pathogens The TLRs located on the surface of the cell like TLR 1 2 4 5 6 and 11 while TLR3 TLR4 TLR7 TLR8 and TLR9 are expressed on endosomal or lysosomal compartments and endoplasmic reticulum ER TLR3 7 and 8 recognize viral RNA TLR9 recognizes bacterial DNA and TLR5 and 10 recognize bacterial or parasite proteins After the first detection of the pathogens the TLR further initiates the activation of signalling pathways such as NF kappa B pathway that helps in secretion of inflammatory signals like cytokines 45 Figure 2 4 Localisation of TLR Reproduced with permission from reference 45 45 2 4 4 1 3 C type lectin receptors CLR CLR are carbohydrate binding receptors through carbohydrate recognition domains CRDs There are 17 groups of CLRs The pathogen recognised by CLRs are summarised in table no 1 46 2 4 4 2 Cytoplasmic PRRs 2 4 4 2 1 Nucleotide oligomerization NOD like receptors NLR The NODs NOD1 and NOD2 can recognize bacterial peptidoglycan motifs and NALPs which also recognize microbial pathogens These NLRs are involved in the regulation of inflammation and apoptosis Table 2 1

Type of CLRs and its ligands Reproduced with permission from reference 46 46 CLR Ligand Ligand origin References Group II Calcium dependent CRD Dectin 2 α mannans O linked mannobiose rich glycoprotein S mansoni C albicans M tuberculosis 47 50 Group VI Calcium dependent multiple CRD Mannose Receptor MR High mannose Omega 1 ManLam schistosoma egg antigen Trichuris muris Mesocestoides corti 51 52 DEC 205 CD205 plasminogen activator Y pestis 53 Group V Calcium independent non CRD Dectin 1 β glucans L infantum C albicans Mycobacterium spp 54 55 2 4 4 2 2 Retinoic acid inducible gene I RIG I like receptors RLR RIG 1 melanoma differentiation associated gene 5 MDA5 and DDX3 help recognize viral RNA 2 4 4 3 Secreted PRRs Peptidoglycan recognition proteins PGRs and the leucine rich repeat receptor LRR can recognise the invading microorganisms directly Taking advantage of these receptors researchers are developing new nanoparticles with could enhance the receptor activity by strategies like mannose receptor targeting on dextran particles 56 Gausse and co authors synthesised muramyl dipeptide tagged particles which by itself could enhance the NOD2 receptor and loaded CPG an agonist for TLR9 They showed that these particles induced both adaptive and innate immune response 38


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