**4. Principle of SDDS**

Presently, the conventional treatments exhibit escalation in dose and systemic toxicity upon administration of drug. Most anti-inflammatory therapeutic drugs are equitoxic to both the normal cells and inflamed cells. SDDS has been well recognized in the past few decades owing to its potential for site-specific and targeted delivery [66]. Encapsulation of anti-inflammatory drugs in nanoparticles can enhance the site-specificity, reduce the dose, curtail the systemic toxicity and improve the biodistribution to targeted disease site [67]. To overcome the disadvantage of conventional delivery of drugs, selective delivery whether passive or active can be used for targeting drug to the site of action as SDDS in RA therapy.

#### **4.1 Passive targeting**

Passive targeting can be accomplished by targeting the physiological and anatomical changes in inflamed tissues, that occurred due to RA. For passive targeting, NPs do not require any surface modification, either by conjugation or by attaching a surface ligand. Various studies have shown the enhanced permeability and retention (EPR) mechanism for passive accumulation in inflamed tissues [68]. In the inflammatory RA milieu, there is evidence of angiogenesis but no evidence of displaying an abnormal lymphatic drainage [69]. The long-circulating delivery vehicles have been evidenced to specifically accumulate within the pannus of the inflamed synovium [70]. The hyperplasia in pannus exhibits a leaky vasculature due to high vascular permeability comparable to solid tumors. Consequently, taking advantage of leaky vasculature may for passive targeting is a promising option [71]. EPR allows NPs in size range from 20 to 200 nm to selectively accumulate in pannus and display on the surface of inflamed tissue. In addition to the EPR effect, hypoxic and acidic environment of inflamed joint also favors passive targeting [70]. Arthritic inflamed joint has poor oxygen delivery and increased metabolic rate due to meager perfusion into the diseased synovial joint. Therefore, the two conditions can easily be used as method of passive drug targeting in less oxygen and acidic microenvironment of RA affected inflamed tissue. NPs administrated in blood stream with hydrophobic surface are easily recognized by reticuloendothelial system (RES) such as spleen and liver, and engulfed by macrophages, consequently quickly eliminated from systemic circulation.

## **4.2 Active targeting**

Targeted delivery involves active targeting to specific cells in the microenvironment of arthritic joints. Overexpressed receptors on particular immune cells can be targeted with its complimentary ligand that is decorated on nanoparticle surface. Several receptors are expressed by different cells, we shall be discussing a few including CD44, folate and beta-3 integrins. Targeting angiogenic vascular endothelial cells are also under investigation, with E-selectin as a promising target molecule [72]. Receptor mediated endocytosis is responsible for efficient uptake of the ligand decorated carrier molecule (ligand-receptor interaction) (**Figure 3**).

#### **Figure 3.**

*Outline of the targeting strategies for nanoparticulate drug delivery systems used in RA.*
