**2. Targeted drug delivery**

Very few drugs bind selectively to the desired therapeutic target, and hence, some targeting approaches are required to destine the drug in desired tissue or organ to reduce efficacy and dose-related toxicity. The concept of targeted drugs is not new, but dates back to 1960 when Paul Ehrlich first postulated the concept of "magic bullet," and this continues to be a challenge to implement in the clinic. The challenges include the selection of proper target for a particular disease, drug for effective treatment and stable, biodegradable drug carriers while avoiding the immunogenic and nonspecific interactions that efficiently clear foreign material from the body. Moreover, the preparation of the delivery system should be easy or reasonably simple, reproductive, and cost-effective. Nanoparticles (NPs) are potentially useful as carriers of active drugs and, when coupled with targeting ligands, may fulfill many attributes of a "magic bullet." Furthermore, the NPs offer several potential advantages including increased efficacy and therapeutic index, improved pharmacokinetic effect, reproducible sizes with opportunity for surface functionalization, ability to entrap both hydrophilic and lipophilic drug, increasing stability of drug from enzymatic degradation, thereby delivering entrapped drug intact to various tissue and cells for site-specific and targeted delivery and thus decreasing drug toxicity. The size and other characteristics can be manipulated depending on the drug and intended use of the product [6]. The drug targeting strategies must meet two basic requirements to achieve effective drug delivery. The drugs should reach the desired sites after administration, with minimal loss of the dose and activity in blood circulation. Second, the drugs should act only on target cells without harmful effects to healthy tissue [7]. Two strategies have been adopted for drug targeting: *passive targeting* and *active targeting*.

## **2.1. Passive targeting**

Passive targeting exploits natural conditions of the target organ or tissue to direct the drug to the target site. For example, passive targeting takes advantage of the unique pathophysiological characteristics of tumor vessels, that is, leaky vasculature with 100–800 nm pores enabling nanodrugs to accumulate in tumor tissues. Typically, tumor vessels are highly disorganized and dilated with a high number of pores, resulting in enlarged gap junctions between endothelial cells and compromised lymphatic drainage. The leaky vascularization, coupled with poor lymphatic drainage, serves to enhance the permeation and retention of NPs within the tumor region. This is often called enhanced permeability and retention (EPR) effect [8]. The drug-loaded NPs are preferentially accumulated in tumor tissue than normal cells, solely due to their small particle size rather than binding. The NPs cannot readily cross the blood capillaries of normal tissues because they are held up with tight junctions. Therefore, passive targeting approach can assist in depositing a higher amount of drug in solid tumors than that of free drug.

In addition to the EPR effect, the passive targeting is supported by microenvironment surrounding tumor tissue that is different from that of healthy cells. The fast-growing tumor cells require more oxygen and nutrients to maintain high metabolic rate. Consequently, glycolysis is stimulated to acquire more energy and creates an acidic environment [9]. This advantage can be exploited to target chemotherapeutic agents to the tumor cells. The pH-sensitive NPs have been prepared that remain stable at physiological pH 7.4 but degrade at the acidic pH of the tumor and liberate the drug molecules. In case of cancer treatment, the size and surface properties of drug delivery NPs must be controlled specifically to avoid uptake by the reticuloendothelial system (RES) to maximize circulation times and targeting ability [10].

## **2.2. Active targeting**

allow self-administration of the dosage forms. Moreover, the pharmaceutical quality of the delivery systems must be ensured in accordance with the regulatory specifications to facilitate reproducible drug release from the system and minimize the influence of the body such as food effects on drug release. It is also necessary to investigate the feasibility of the developed

However, controlled release systems do not exclusively deliver the drug to the target organ. For this reason, the target-specific drug delivery systems must be designed in order to control biodistribution of the drug. Consequently, various novel concepts have been emerged to meet the specific needs of an ideal drug delivery system. This chapter introduces a brief description of targeted drug delivery mechanism along with some of the novel-targeted drug delivery

Very few drugs bind selectively to the desired therapeutic target, and hence, some targeting approaches are required to destine the drug in desired tissue or organ to reduce efficacy and dose-related toxicity. The concept of targeted drugs is not new, but dates back to 1960 when Paul Ehrlich first postulated the concept of "magic bullet," and this continues to be a challenge to implement in the clinic. The challenges include the selection of proper target for a particular disease, drug for effective treatment and stable, biodegradable drug carriers while avoiding the immunogenic and nonspecific interactions that efficiently clear foreign material from the body. Moreover, the preparation of the delivery system should be easy or reasonably simple, reproductive, and cost-effective. Nanoparticles (NPs) are potentially useful as carriers of active drugs and, when coupled with targeting ligands, may fulfill many attributes of a "magic bullet." Furthermore, the NPs offer several potential advantages including increased efficacy and therapeutic index, improved pharmacokinetic effect, reproducible sizes with opportunity for surface functionalization, ability to entrap both hydrophilic and lipophilic drug, increasing stability of drug from enzymatic degradation, thereby delivering entrapped drug intact to various tissue and cells for site-specific and targeted delivery and thus decreasing drug toxicity. The size and other characteristics can be manipulated depending on the drug and intended use of the product [6]. The drug targeting strategies must meet two basic requirements to achieve effective drug delivery. The drugs should reach the desired sites after administration, with minimal loss of the dose and activity in blood circulation. Second, the drugs should act only on target cells without harmful effects to healthy tissue [7]. Two strategies have been adopted for drug targeting: *passive targeting* and *active targeting*.

Passive targeting exploits natural conditions of the target organ or tissue to direct the drug to the target site. For example, passive targeting takes advantage of the unique pathophysiological characteristics of tumor vessels, that is, leaky vasculature with 100–800 nm pores enabling nanodrugs to accumulate in tumor tissues. Typically, tumor vessels are highly disorganized

DDS to be scaled up from the laboratory to the production scale.

options.

**2. Targeted drug delivery**

4 Advanced Technology for Delivering Therapeutics

**2.1. Passive targeting**

One way to overcome the limitations of passive targeting is to attach ligands such as antibodies, peptides, vitamins, aptamers, or small molecules by a variety of conjugation chemistries to the surface of the nanocarriers that only bind to specific receptors on the cell surface [11]. For high specificity, however, the receptors need to be highly expressed on tumor cells rather than on normal cells. The targeting conjugates are internalized by receptor-mediated endocytosis mechanism. The targeting ligands bind with the receptors first, followed by endosome formation with the enclosure of the ligand-receptor complex by plasma membrane. The endosome is then transferred to specific organelles, and drugs are released by acidic pH or enzymes.
