الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
A common term to describe joint disorders is arthritis which means joint inflammation associated with pain, swelling andstiffness.
There are more than 100 types of arthritis.
The most common type of arthritis is osteoarthritis, while rheumatoid arthritis (RA) is the most disabling type as its effects may extend to affect other body organs like heart, lung andspleen.
The most characteristic RA symptom is polyarthritis accompanied with joint swelling in a symmetrical pattern.
We focused onthis thesis on RA treatment. RA inflammatory process beginsin the synovium.
Hyperplasia and inflammation of synovial tissue occuras a result of the effect of the chemical mediators produced by inflammation associated cells like activated macrophages and fibroblast-like synoviocytes (FLS).
RA degenerative effectsextend to subchondral bone and periarticular soft tissues resulting in irreversible functional disabilities.
Several conventional treatments were used for RA treatment including non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifyinganti-rheumatics andbiological agents.
Conventional RA therapeutic agents are associated with numerous side effects such as immune suppression, gastrointestinal problems andliver toxicity.
Nanocarriers have emerged a promising alternative for conventional RA treatments. Nanocarriers can passively target inflamed rheumatic joints as a result of increased permeability of affected joints due to inflammation.
Passive accumulation of nanocarriers in joints affected by RA may involve a new retention mechanism thatresembles the classical enhanced permeability and retention (EPR).
This retention mechanism is appreciationis “ELVIS” which stand for extravasation through the leakyvasculature and subsequent inflammatory cell-mediated sequestration.
Targeting nanocarriers to inflamed rheumatic joints will reduce side effects associated with systemic administration of drugs.
Also, nanocarriers can provide sustained release behavior which may decrease the frequency of drug administration and hence improve patient compliance.
Numerous receptors are overexpressedin inflamed joints, for example, CD44, folic acid, scavenger receptor type A and notch 1 receptor. Targeting these receptors showed very promising results for suppression of RA progression.
Local targeting for RA can be achieved by intra-articular administration of drugs.
Intra-articular injections suffer from some drawbacks including the need for repetitive injections to achieve the desired therapeutic outcome.
Intra-articular injections of nanocarrierscan overcome this drawbackas functionalization of nanocarriers surface with functional groups that can target the overexpressed joint receptors may increase the drug residence time in the joints.
In addition to passive, active, and local targeting approaches, another approach has appeared which is synergistic targeting that 123 depends on incorporating materials with therapeutic potential for RA treatment within the nanocarriers composition.
The aim of this thesis is the development of nanocarriers that can passively, actively and/or synergistically target RA inflamed joints.
We prepared plain and leflunomide (LEF) loaded nanostructured lipid carriers (NLCs) and coated them with differentcoatings.
We coated LEF loaded NLCswith chondroitin sulfate (CHS), chitosan (CS) and hyaluronic acid (HA).
We investigated the potential of LEF loaded particles for both oral and intra-articular delivery.
Pharmacokineticstudy was conducted for uncoated, CHS and CS coated NLCs.
For intra-articular delivery NLCs were incorporated in CS and HA thermo-sensitive hydrogels.
In order to investigate the anti-arthritic ability of different formulations in for oral and intra-articular delivery, we developed RAin rats by adjuvantarthritis model.
We evaluated the improvementof different clinical parameters associated with RA progression.