**3. Rationale of SDDS**

Enhancement of therapeutic efficiency by 'intelligent/smart' carriers that release drugs in a controlled manner at the site of action to achieve minimal side effects are categorized as "Smart Drug delivery system" (SDDS). Maintaining optimum size and surface properties, the materials can be engineered to create nanoparticles that can maneuver the microenvironment and respond to endogenous stimuli, like increased concentration of some enzymes, redox gradient-enhanced level of glutathione, or variations in interstitial pH [26] and/ or exogenous stimuli that include temperature changes, applying magnetic field or light, and giving high energy radiation.

#### **3.1 pH-responsive**

pH, an important parameter linked to pathophysiological conditions, like inflammation can be exploited for enhanced therapeutic efficiency [27]. Reports priori give clarity that pH in normal tissue and blood is maintained around 7.4, but in arthritic microenvironment, extracellular pH values are intrinsically acidic, usually pH 6.8 [28]. The acidic pH can be attributed to the excess infiltration and activation of proinflammatory cells in the synovium, causing increased demand for oxygen and energy. Augmented consumption of glucose *via* glycolysis consequently enhances production of lactic acid, that causes local acidosis [29, 30]. Hence, the nanoparticles should be strategically designed to sensitively distinguish pH changes in inflammatory area where high disease activity and joint destruction correlates with low synovial pH. These pH-responsive nanoparticles encapsulating therapeutic molecules like NSAIDs, DMARDs etc. can be promising for RA treatment. Even at the cellular level, pH-sensitive SDDS can either stimulate drug release into lysosomes, or the late endosomes or may even trigger the escape of nanoparticles from lysosomes into the cytosol [31]. Appropriate size will enable efficient penetration in the inflamed joints, facilitated by angiogenesis during RA progression, that causes endothelial cell discontinuity leading to enhanced vascular permeability [32].

Two strategies are rationally used to design of pH-sensitive SDDS, one using materials with acid-sensitive bonds, that can be cleaved by low pH conditions allowing the release of encapsulated molecules from the nanoparticles; and secondly, using polymers (polyacids or polybases) that have ionizable groups, that undergo pH-dependent transformation and change in solubility [33]. Researchers have engineered a dual-strategy by attributing targeting abilities by surface functionalization and simultaneously using pH responsiveness to enhance therapeutic selectivity in RA.

#### **3.2 Redox-responsive**

Intracellular microenvironment can be exploited using redox responsive NPs. Reactive oxygen species (ROS) is generated primarily during oxidative phosphorylation(OXPHOS), but can further be produced by oxidative burst of activated phagocytic cells [34]. Polymers with ROS-sensitive thioketal moiety, or selenium (Se), tellurium (Te), B-based linkers in their monomeric backbone can be utilized as building blocks for the synthesis of stimuli- responsive nanoparticles. Hence, ROS can easily be monitored as an intracellular indicator [35] as chronic inflammation induces continuous production of ROS [36].

ROS concentrations in inflammatory tissues ranges 10- to 100- fold higher than normal tissues [36], thus, promising accuracy and specificity to develop the redox stimuli-responsive DDSs.

#### **3.3 Temperature-responsive**

Temperature is another crucial factor essential for release of drug [38], as the normal physiological conditions have lower temperatures compared to the inflamed RA microenvironment [39]. Therefore temperature-responsive functionalized NPs can be used to trigger the release of drug at the inflammatory site. They are designed and fabricated to retain their payloads at physiological temperature (37°C), and quick release it when the temperature is increased around 40–45°C, attributing a more efficient targeted SDDS [40]. Phase-transition behavior of the materials that are thermosensitive are used to design NPs, based on the lower critical solution temperature (LCST) of polymers/lipids whose solubility varies with changes in temperature. All excipients in a mixture are totally miscible in all amounts in LCST. In materials with transitional behavior, increased solubility is observed below LCST; and polymeric constituents are prone to swelling due to the hydrogen bonds being formed between the polymer functional groups with water molecules enabling drug loaded molecules. When temperature is raised above the LCST, a hydrophobic-hydrophilic conversion takes place, that leads to a morphological transformation from a random coil-to-globular form. Because of alterations in temperature, the hydrogen bonds breaks causing the network to collapse, and the polymer becomes insoluble, causing shrinkage in the volume and oozing-out of water molecules from inside. This transition initiates release of the entrapped payload of drugs. The application of thermo-responsive SDDS is based on the concept of exploiting the temperature difference between healthy and diseased tissues [40]. Thermal energy can be given directly, or external utilizing heat sources like NIR that may be indirectly applied in RA, that elicits a thermo-responsive behavior based on the thermo-sensitivity of nanomaterials. Typically, the requisite range of temperature fluctuates from 38–43°C [37]. The temperature-stimuli can originate from within the body, or by localized hypothermia, or hyperthermia, may provoke a response based entirely on the thermosensitivity of used nanomaterials. Additional advantages of thermo-sensitive NPs may be attributed to reduction in use of toxic organic solvents during fabrication, the capacity to entrap both lipophilic and hydrophilic molecules, controlled and sustained release properties. A plethora of reports using several polymers have been established for the synthesis of temperature-responsive systems, that include derivatives of poly(N-isopropylacrylamide (PNIPAAm), pluronics (poly(ethylene oxide)- poly(propylene oxide) (PEO-PPO)), poly(N vinyl caprolactam), polysaccharide spinoffs, and derivatives of phosphazene [41–43]. Researchers are making concerted efforts on achieving temperature-responsive NPs stimulated by magnetic action coupled with thermo-responsive effect by light absorption instead of temperature alone.

#### **3.4 Light and magnetic responsive**

Light-responsive systems rely on an external stimulus to activate the drug release preferably at the target site using light irradiation. NPs respond to 'on–off drug' release, as it may close/open when stimulated using light radiation. Also termed as photodynamic therapy, SDDS based on magnetic stimuli represents another external way to trigger drug release at the target site under programmable *Smart Drug-Delivery Systems in the Treatment of Rheumatoid Arthritis: Current, Future… DOI: http://dx.doi.org/10.5772/intechopen.99641*

exposure of magnetic field [37]. Iron-oxide NPs have excellent potential for smart drug delivery, as it exhibits a significant response to both light and magnetic stimuli, it can be exploited for triggering a burst release of drug at the inflamed sites of RA termed as the magneto-calorific effect and photothermal effects. Thermal properties of magnetic NPs might be conveniently modulated by modifying their own viscosity in the endo-cellular environment. Photodynamic therapy (PDT) and photothermal therapy (PTT) use photosensitizers as therapeutic molecules. Moreover, near infrared(NIR) light can efficiently infiltrate the inflamed RA joints. Cu7.2S4 nanoparticles triggered with NIR irradiation (808 nm, 1 W cm−2) was suggested to accomplish improved bone mineral density (BMD) and bone structure and volume. It further impedes invasion to synovial tissue, erosion of cartilage and bone *in vivo*.

Huo et al. have prepared optical nanoparticles induced PTT and PDT and documented probable pathways for cell toxicity [44]. During PTT cell necrosis can be induced by NIR laser light irradiation (wavelength:1064 nm), however when given as combination therapies (PTT + PDT), evidence of both necrosis and apoptosis pathways are indicated. Furthermore, PTT-PDT combination given simultaneously, can account for immunogenic cell-death, while fluorophores can be used for optical imaging as a diagnostic tool that can be applied for RA too.

#### **3.5 Enzyme responsive**

Specific enzymes like phospholipases, proteases, or glycoside are often overexpressed in different pathological conditions, like inflammation, and can be exploited for enzyme triggered release and accumulation of drugs at the targeted site of interest [37]. Nevertheless, nature of cleavable units, the sensitivity of the delivery system can significantly influence the pharmacokinetics of entrapped payload. Further, it must be ensured that the metabolites or the degraded moieties are non-toxic and biocompatible and are cautiously eliminated from the body. Therefore, in future, enzyme-responsive nanoparticles offer tailor-made therapy according to variations in levels of disease expression. Redox- and enzyme-responsive nanoparticles are coming up as promising therapies in RA treatment.

#### **3.6 Energy upconversion NPs**

Nanomaterials with exceptional physico-chemical properties targeting the lesions can be supplemented with precise external stimuli, such as light, microwave, ultrasound, and radiation. Upconversion nanoparticles (UCNPs) synthesized from rare-earth elements that are capable of translating NIR photons that have low-energy to high-energy ultraviolet or visible photons [45]. These extraordinary NIR excitation based optical properties of UCNPs allows penetration to deep tissues with minimum auto-fluorescence background, reinforcing a wide array of diagnostic applications alongwith biomedical imaging system [46, 47]. SDDS can translate the external stimuli and equivalent energy input into beneficial effects or release the payload *via* an energy-upconversion process [48]. Ultrasound-based, photo-dynamic-based, radiation-based and microwave-based, energy-UPNPs have been widely explored in RA treatment as an alternative therapy (**Figure 2**). These developing technologies induce death of synovial fibroblasts and other inflammatory cells by generating hyperthermia, cellular ROS, mechanical and photoelectric effects [49]. Synovial cells can be directly targeted by nanoparticles to decrease bone erosion (**Table 1**)[50].

#### **Figure 2.**

*Schematic representation of stimuli-responsive polymers for nanotherapeutics of rheumatoid arthritis (RA).*



*Smart Drug-Delivery Systems in the Treatment of Rheumatoid Arthritis: Current, Future… DOI: http://dx.doi.org/10.5772/intechopen.99641*

#### **Table 1.**

*List of stimuli-responsive nanoparticles for the treatment of RA.*
