**4. Targeted drug delivery**

It is necessary to ensure that the nanomaterials are carefully delivered only to the infected region of the body without affecting the surrounding healthy tissues.

When drugs or gene-loaded nanoparticles are injected into bodies, they can circulate in the blood vessels by crossing the epithelial barriers before reaching the target site. Escape of nanoparticles from the vascular circulation occurs in either continuous or fenestrated tissues. Nanoparticles can escape from the bloodstream at continuous vascular endothelium through paracellular pathway, intracellular process or transcellular pathway. It is different; the space between the fenestration sites on the endothelium is between 100 nm and 2 μm, which is longer than in healthy tissues that are normally 2–6 nm. Therefore, nanoparticles can penetrate fenestrations thus increase the drug concentration in target/tumor site which is called "enhanced permeation and retention effect (EPR effect)" [32–34]. Particle shape, surface charge, and feature are playing important roles in intercellular delivery [35, 36]. Quantity and type of polymers, particle size, solubility, biodegradability, and surface properties are having important role in release of bioactive drugs into the target site [37]. Drug entries through transcellular and paracellular pathways are shown in **Figure 1**.

**Figure 1.** Drug entry through transcellular and paracellular pathways.

Targeted drug delivery is classified into two categories. They are

**1.** Passive targeting

Hence, more attention has been paid to develop non-viral vectors as an alternative one for gene

Nonviral delivery systems have advantages like easy to prepare, amenable to synthetic manipulations of polymer properties, cell/tissue targeting, less immunogenic and oncogenic, no potential of virus recombination and limitation on the size of a transferred gene, virtually no limitation on the unrestricted plasmid size that can be delivered and the cost of production is relatively low [25]. Moreover, they can be consigned readily to carry genetic materials to target cells by virtue of their size, charge and structurally modifying the vectors [26]. Difference between viral and nonviral gene delivery is based on the various gene transfer and its complementary mechanisms. The mechanism includes in the viral gene delivery is the ability of virus to circulate in the blood, bind to cell surface receptors, gain entry into the cell, avoid lysosomal destruction, survive degradation in the cytosol, and deliver genetic material to the nucleus. In the nonviral gene delivery overcoming biological barriers in the circulation or inside the target cell and transferring the gene vector is based on the molecular weight of the vector, ratio between the vector nitrogens and the DNA phosphates (termed the N:P ratio) and

Nonviral gene delivery systems are typically composed of plasmid DNA condensed into

Nonviral vectors are categories into lipid- and polymer-based one. Whereas the polymeric based nonviral vectors have the advantage over lipid-based one due to its modification

**•** DNA/polymer complexation: Nanosize complex forms when cationic polymer neutralizes

**•** DNA/polymer complex: Also referred as polyplex, which passes through cell membrane by

**•** It is free to be encoded into a therapeutic protein or to be inserted into the genome [6, 8–10].

It is necessary to ensure that the nanomaterials are carefully delivered only to the infected

When drugs or gene-loaded nanoparticles are injected into bodies, they can circulate in the blood vessels by crossing the epithelial barriers before reaching the target site. Escape of nanoparticles from the vascular circulation occurs in either continuous or fenestrated tissues.

delivery [6, 8–10, 24].

16 Advanced Technology for Delivering Therapeutics

the salt concentration of the buffer solution. [27–30].

The steps involved in the polymeric gene delivery are given below:

charged phosphate with negatively charged cell membrane.

**•** Endosome: Complex enters into cytoplasm through endosome.

region of the body without affecting the surrounding healthy tissues.

a nonspecific or receptor-mediated endocytosis.

**•** Transportation to nucleus.

**4. Targeted drug delivery**

nanoparticles by a cationic polymer [31].

property.

**2.** Active targeting

## **4.1. Passive targeting**

Passive targeting involves the cells that are to be targeted migrate toward the drug-carrying vehicles. This system is widely used in the delivery of cells like neutrophils, macrophages, dendritic cells for vaccination purposes. In this system, it is not necessary the drug-carrying vehicles in nanometer regime [38].

## **4.2. Active targeting**

Active targeting involves rational design of nanosytems with suitable surface engineering performed with acceptable chemical linking strategies to specifically target the cell receptors of a target tissue. Furthermore, the targeting operates at two levels; first, the targeting of tissue/ system in order to enrich the concentration of the carriers at the infected site [9, 39].
