**2. Drug loading, targeting and releasing**

#### **2.1 Drug loading**

Drug loading is an important property of a drug delivery system, and it is defined as the process of incorporating a drug into a carrier. The therapeutic agents can be introduced into gel-carriers by ionic interaction, dipole interaction, hydrogen

#### *Hydrogel Biomaterials for Drug Delivery: Mechanisms, Design, and Drugs DOI: http://dx.doi.org/10.5772/intechopen.103156*

bonding, physical encapsulation, covalent bonding, precipitation, or surface absorption. It's common that more than a loading mechanism is used in drug delivery systems, and the ideal loading strategies are determined based on the compatibility between the physicochemical properties of the drug and the carrier.

The drug-loading process can take place during the formation of the carriers, or by incubating carriers into a concentrated drug solution to allow the loading through adsorption on their surface area [21]. However, this method has limited loading capacity, and the incubation time can influence the drug loading efficacy [22, 23]. In general, the entrapment and loading of drug molecules into polymer carriers depend on several characteristics: polymer and crosslinker concentrations, molecular weight of the polymer, and drug-polymer interactions [24–26]. The higher the polymer concentration the more efficient the drug entrapment is; at a high concentration, the polymer viscosity is increased, which delays the drug diffusion within the polymer particles [27]. Similarly, the high concentration of the crosslinker yields tangible increase in the loading efficiency [28]. Conversely, Fu et al., 2004 reported that the encapsulation efficiency decreases when the molecular weight of the polymer increases [29]. In protein based drugs, the interaction between the polymer and the drug molecules contribute to the entrapment efficiency; it increases if the protein molecules are entrapped into hydrophobic polymers, moreover, ionic interaction between the molecules and the polymer particles increase the efficiency of encapsulation, specifically, in polymers that belongs to carboxylic end groups [30].

### **2.2 Targeting**

The delivery of therapeutics by nanocarriers can be passive: transport of drugcarrying nanoparticles through permeable vessels due to the enhanced permeability and retention (EPR) effect; or active: based on molecular recognition in which peripherally targeting moieties that interact with specific cell receptors [31].

In localized cancer therapy, the mechanism of passive targeting relies heavily on the tumor characteristics; tumor hypoxia causes rapid growth of leaky vessels, which increases the permeation of nano-delivery systems into the tumor, the lack of lymphatic filtration allows for the retention of these systems on the tumor's interstitial space [32]. Moreover, this targeting strategy also depends on the carriers' size; delivery systems larger than 50 kDa permeate through leaky vessels and retained in the tumor, smaller molecules are washed out quickly (very short circulation time) from the tumor [33]. The charge and the surface chemistry affect the circulation time of carriers; mononuclear phagocyte system (MPS) cells tend to opsonize largely hydrophobic and charged systems. Thus, water-soluble and neutral (or slightly anionic) compounds (e.g., Polyethylene Glycol) are used to coat the nanocarriers surface [31, 32, 34]. Active targeting also depends on the EPR effect to accumulate the delivery nanocarriers in the tumor region, however, the efficacy of this strategy capitalize on equipping the nanocarriers' surface with ligands that bind to specific receptors of cancer cells, thus, enhancing the penetration and efficiency of the chemical therapeutics. **Figure 1** illustrates passive and active targeting strategies.

#### **2.3 Drug releasing**

Biodegradation of the nanocarriers is essential for the release of the drug molecules over extended periods of time (days or weeks). It is also crucial for the removal of delivery systems from the body [35]. The carrier size has an effect on the efficacy

#### **Figure 1.**

*Schematic illustration of active and passive delivery of drug molecules.*

of the releasing process; drug molecules loaded at or in proximity to the surface of small particles are released at a fast rate due to the large surface-to-volume ratio. On the other hand, slower release rates are associated with larger particles, nevertheless, more drug molecules can be loaded. Modulation of the drug release can also be controlled by the molecular weight of the gel composition; higher molecular weight tends to exhibit slower release rates [36, 37]. In general, the mechanism of releasing drugs is dependent on three main parameters: drug diffusion and dissolution, gel matrix design, and interaction between the drug and the gel matrix.

The transport of the therapeutic molecules out of the gel matrix is a complex process that depends on the dissolution and diffusion of the drug [38]. Several studies have been conducted to develop mathematical models that describe this process [39–41]. The basic equation of the dissolution rate as a function of diffusion can be described as [42].

$$\frac{d\mathbf{M}}{dt} = \frac{\mathbf{DA}}{\mathbf{h}} (\mathbf{C}\_s - \mathbf{C}) \tag{1}$$

Where dM/dt is the rate of dissolution, A is the surface area of solid in contact with the dissolution milieu, D is the diffusion coefficient, Cs is the drug solubility, and C is the drug concentration at time t, and h is the diffusion boundary layer thickness at the solid's surface. This equation shows that the dissolution rate is directly dependent on the surface area of the particle and the solubility of the drug. Conversely, larger thickness of the diffusion boundary layer reduces the dissolution rate. When the size of the nanocarriers is reduced from the micro-domain to nanodomain, the surface area increases resulting in a higher rate of dissolution as reported in [43].

There are several mechanisms to release the drug, most common strategies are diffusion and swelling controlled. In diffusion-controlled delivery systems, drug molecules diffuse from a region of high drug concentration (reservoir) through the gel matrix or membrane. The design of these systems is commonly available as spheres, cylinders, slabs, or capsules. These systems can have a constant rate of release as described by Eq. (1), or their release rate can be proportional to the square *Hydrogel Biomaterials for Drug Delivery: Mechanisms, Design, and Drugs DOI: http://dx.doi.org/10.5772/intechopen.103156*

**Figure 2.** *Schemes of drug release systems: (a) from a reservoir system; (b) from a matrix system.*

root of time. In the latter case, the drug is usually dispersed or dissolved uniformly through the matrix of the hydrogel [10]. In swelling controlled systems, the drug is dispersed within carriers made of a glassy gel, and upon contact with biofluids, they swell beyond their boundary which results in the diffusion of the drug during the relaxation of the gel chains, this process is known as anomalous transport [10, 44]. Illustrations of the two releasing mechanisms provided in **Figure 2**. The structure of the nanocarriers' controls the release of the drugs; using hydrogels alone in synthesizing the nanocarriers can result into fast premature release of drugs and poor tunability [45]. Therefore, using additives can enhance the control of the drug delivery process; using Polydopamine (PDA) as an additive to the hydrogel materials in making the nanocarriers provides an on-demand capability to release the drug. In high glutathione (GSH) and acidic condition, the bond between the drugs and PDA experience weakening. This is a useful property to release the drugs in inflammatory areas or tumor cites where pH levels are low. While at neutral pH levels such as in normal tissues, the bond between the PDA and the therapeutic dugs is not affected [46–50]. Furthermore, PDA generates heat upon exposure to near infrared (NIR) laser, which makes it ideal for NIR triggered drug delivery [51].
