Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health’economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer’drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease.
Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting’strategies that might constitute the platform for the next generation of RA therapeutics
Trojan horse’ approaches for drug delivery.
Liposomes (1), are able to harbour therapeutic payloads such as biologic agents, siRNA or small-molecule drugs (2), limiting systemic activation and degradation as well as adverse effects. Nanoparticles (4) can be generated with polymers such as HA, PLA and PLGA (6), which have encapsulated therapeutic payloads
successfully (2) for tissue drug delivery. The surface of liposomes and nanoparticles can be functionalized to confer specific targeting or therapeutic properties (3). The presence of RGD in a methotrexate-loaded PLGA’Au nanoparticle32 provided active targeting of ??V??3-expressing endothelial cells (5).
Functionalization of a nanoparticle surface with folic acid37 drives selective internalization of a methotrexate-conjugated dendrimer (5). Surface functionalization can also introduce a second therapeutic activity, such as in the conjugation of tocilizumab with an HA’Au nanoparticle74 combining anti-IL-6R activity to VEGF binding (5). Abbreviations: HA, hyaluronic acid; MTX, methotrexate; PEG, polyethylene glycol; PLA, polylactic acid; PLGA, poly(lactic-co-glycolic) acid; RGD, Arg’Gly’Asp peptide; siRNA, small interfering RNA. Guided missile’ approaches for drugdelivery.
Antibodies, antibody derivatives and targeting peptides can be used to guide drugs to tissues. b | Several formats have been developed, including bispecific antibodies fusing a targeting domain (for example L19 or scFv A7) to an anti-TNFdrug.
Therapeutic antibodies can also be fused to target peptides and achieve active tissue delivery, as demonstrated in the fusion of the anti-C5 antibody derivative to the synovium-targeting peptide.A novel class of therapeutic agents named immunocytokines, characterized by targeting antibody derivatives (such as Dekavil and Tetravil,66 [Philogen, Italy]) or targeting peptides fused to cytokines (such as IL-10 or IL-4, to increase cytokine delivery in the tissue of interest and reduce the risk of systemic activation. Abbreviations: EDA, extra domain A of fibronectin; EDB, extra domain B of fibronectin; scFv, single-chain variable fragment. TREG’s Anti-Rheumatoids. Data obtained over the last years, however, have shed new light on the role of T cells in regulation of the inflammatory response. This line of research started almost 15 years ago with the discovery of so-called regulatory T cells (Treg). This exciting discovery raised expectations for novel ways of treating arthritis by targeting these Treg.
Direct approaches to enhance Treg function There are several methods available to directly target Treg for the treatment of autoimmune disease. These include expansion and induction of Treg in vitro followed by reinfusion into the patient, or in vivo by immune modulatory compounds. Methods of enhancing Treg function in arthritis patients. Treg can be enhanced in arthritis patients via different methods: (A) isolation and ex vivo expansion of natural Treg or (B) in vitro induction of Treg from non-Treg (n-Tr), followed by reinfusion into the patient; (C) in vivo induction and expansion of Treg by anti-CD3 antibodies.(aCD3), HADC inhibitors (HADCi) and neuropetides, such as VIP; (D) mucosal tolerization with self-antigen, preferably HSP; (E) indirect improvement of Treg function by enhancing the responsiveness of effector cells to suppression and blocking pro-inflammatory cytokines. In order to overcome the systemic effects of DMRD drugs, they can be directly targeted to the synovial capsule of the affected joint through intravenous route, especially when the disease manifests only in limited number of joints However, the rapid clearance of drugs from the synovial cavity into the blood stream defeats the purpose of their intra-articular administration.
Antigen-specific induction of Treg by mucosal tolerization with self-antigen Mucosal tolerization with self-antigen could work in human disease as well, as long as an immunogenic antigen is used that is presented at the same location as the self-antigens driving the immune response. A special class of proteins, termed heat shock proteins (HSPs), are promising antigens for this Treg induction via mucosal tolerization. HSPs HSPs are a set of evolutionarily conserved chaperones that are up-regulated under conditions of cellular stress for instance during infection and inflammation.
As a result, they are abundantly present at the site of inflam mation in RA and JIA and, because of their unique features HSPs are very immunogenic. Therefore, these antigens are good candidates for mucosal tolerization in autoimmune disease, since they trigger T-cell responses and are highly present at the site of inflammation.
Moreover, studies with cells from JIA patients suggest that HSPs might have a natural role in controlling inflammation via the induction of regulatory responses . Several HSP family members have been shown to be protective upon mucosal administration in experimental arthritis, even in already established disease, probably via the induction of Treg. Moreover, nasal administration of a mycobacterial HSP peptide inhibited adjuvant arthritis, but also arthritis induced by an unrelated, non-microbial stimulus. Thus, HSPs suppress experimental arthritis irrespective of the initial trigger and are effective in already established disease.
This makes them suitable for therapeutic application in human arth- ritis. Studies with OM-89, an extract of Escherichia coli used for the treatment of RA, provide the first evidence that HSP could be effective in the treatment of human arthritis.
Significance of Use of Liposomes in the Delivery of Anti Rheumatoid.
In this regard, liposomes have proven to be the most suitable delivery systems for retaining the drug in the synovial cavity by virtue of their size and chemical composition. The clearance of intrasynovially administered drugs can be overcome through liposomes by virtue of the size of multilamellar vesicles (MLVs).
This facilitates the uptake of drug by the target synovial cells and reduces the exposure to nontarget sites, eliminating the undesirable side effectsThe rationale for the use of liposomes in rheumatoid arthritis is Technology GAGomers: GAGomers are lipidated glycosaminoglycan (Gag) particles based on the technology invented by Prof Rimona Margalit and Prof Dan Peer at the lab of Rimona Margalit at the Department of Biochemistry, Tel Aviv University in Israel.
These particles are used to encapsulate a wide variety of cargo including nucleic acids and insoluble small molecules. The anionic, non-sulfated and large Gag used, Hyaluronic Acid (HA), is natural to the body, distributed widely throughout connective, epithelial, and neural tissues.
HA primary receptors are CD3 and CD25. CD44 is a cell surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration and is expressed in many cells. CD44 has many isoforms due to alternative splicing with different affinities to HA. High affinity forms of activated CD44 splice variants (CD44v) are highly expressed in cancer cells and in inflammation.
Having this HA as a shell, the GAGomers are naturally targeted to cells expressing these specific activated receptors and HA confers a stealth coating to these particles. GAGs are natural sulfated glycopolymers that have various sulfation patterns on the co-polymer of particular disaccharide units. GAGs are also involved in the interaction with Hsp-FL,the Type II complex was obviously observed in the presence of heparin, heparan sulfate and dermatan sulfate. However, the complex formation was not detected with chondroitin, chondroitin sulfate A and C, keratan sulfate, keratin polysulfate, and hyaluronic acid. Hsp70 superfamily, to be a sialicacid-bindingprotein.
SBP binds in a sialic acid-dependent manner to the major di-sialylated gangliosides that are enriched in the lipid rafts of sea urchin sperm plasma membrane. To characterize the glycolipid binding property of the Hsp70 family in detail, we surveyed various acidic and neutral glycolipids for the interaction with Hsp70, and showed that acidic, but not neutral glycolipids induce the high molecular-weight complex formation with Hsp70 in solution, despite the fact that Hsp70 has an activity to bind both neutral and acidic lipids on the solid surface. Recently the Hsp70-acidic lipid interaction has also been demonstrated by other group using liposome-based binding assay.
These results suggest that Hsp70 directly interacts with the acidic glycan moiety of glycolipids. Extracellular acidic glycans are also linked to glycosaminoglycans (GAGs) and sialylated glycoproteins. Therefore, the acidic glycan units of GAG and glycoproteins may also be involved in the interaction with Hsp70, which enables the retention of membrane-free Hsp70 outside cells. Artificial glycopolymers containing sulfated and Sialylated glycans on the polyacrylamide (PAA) backbone and natural GAGs for the interaction with Hsp70.
Challenge: The use of DMRD drugs to treat Rheumatoid arthritis is greatly has non-specific cytotoxic effects these on healthy tissues, as well dose limiting toxicities and often very severe side effects. Many of the most potent cytotoxic drugs have limited solubility and are therefore difficult to administer intravenously.
GAGomers: Since GAG has no solubility barrier. In terms of efficacy and safety and to extend the life, Studies needed to show foxp3 coated GAG nano particles in nasal or oral administration in targeted delivery of Rheumatoid arthritis Patients.
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