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Basics of Targeted Drug Delivery

Kshama A. Doshi

Sutro Biopharma, 111 Oyster Point Blvd, South San Francisco,, CA, 94080, United States

1.1 Introduction

Biological effects conferred by drugs are associated with drug mechanism of action, and drug pharmacological and physicochemical properties. To elicit pharmacological response, drugs are commonly designed to bind to a target and activate or inhibit them, for example, chemotherapy drug belonging to the class of topoisomerase-2 inhibitors binds to and stabilizes enzyme topoisomerase-2 in cells to induce cell death, antidiabetic medication exenatide binds to and activates good lab practices (GLP)-1 to increase insulin secretion. Further, depending upon the route of drug administration, drugs undergo four main processes - absorption (absorption of drug from site of administration into blood), distribution (distribution of drug to different tissues from bloodstream), metabolism (breakdown of drug), and excretion (elimination out of the body) which are predominantly affected by the physicochemical properties of the drug. These factors largely account for the rate and extent of drug efficacy and overall potency.

In addition to the above-mentioned processes, pharmacological response and efficacy induced by the drug are also governed by its delivery to the site of action, the selective delivery to the target, and associated safety. To facilitate safe and effective drug transport, various drug-delivery systems (formulations, dosage forms, drug-device combinations, etc.) have been developed thus far. During the last several decades, multiple technologies and formulations, including controlled-release drug-delivery technology, oral and transdermal drug-delivery systems, nanotechnology-based products, have significantly improved patient outcomes [1]. While significant improvements have been made in multiple disease indications, there continue to remain areas that require attention to fulfill the unmet need in terms of increasing drug efficacy by improving patient compliance, reducing side effects, and reducing dosing frequency. Targeted drug-delivery systems have gained wide attention in recent years to selectively target the drug at the site of action and thereby facilitate site-specific delivery to ensure high safety, efficacy, and patient compliance. This chapter introduces some basic concepts followed by the rationale for development of targeted drug-delivery approaches, different approaches to achieve this, commercial success to date, and challenges associated with this approach.

Figure 1.1 (a) Bioavailability of an agent administered intravenously (in red) and orally (in blue). (b). Therapeutic index (TI) of an agent as defined by the ratio of ED50 to TD50. ED50: Effective dose for 50% response points, TD50: Toxic dose for 50% response points.

1.1.1 Concept of Bioavailability and Therapeutic Index

Bioavailability (BA) is the rate and extent to which the drug is absorbed from the drug product and becomes available at the site of action [2]. BA of an agent administered intravenously is high as compared to oral administration. This is a result of instant entry of the agent in the systemic blood circulation following intravenous dosing as compared to absorption from the Gastrointestinal (GI) tract followed by entry into systemic circulation with oral dosing (Figure 1.1a). Therapeutic index (TI) is an indicator of relative safety of a drug. TI is defined as the ratio of maximally tolerated toxic dose to minimum effective dose. A common method used to calculate TI of an agent is to calculate ratio of dose that induces toxic effects in 50% response points (TD50) to the dose that induces therapeutic effects in 50% response points (ED50) (Figure 1.1b).

1.2 Targeted Drug Delivery

The terms "targeted drug delivery" and "targeted drug therapy" are frequently used in drug discovery research; however, both these terms are distinct from one another and cannot be used interchangeably. Targeted drug therapy refers to specific interaction between drug and a certain protein or moiety on target/disease cells [3]. Targeted drug delivery, on the other hand, refers to predominant accumulation of the drug/drug formulation in the target/disease zone [4]. Effective drug-delivery system design, for all kinds of formulation, requires four key requirements - retain, evade, target, and release.

Retain: The delivery system should remain intact in its original form throughout the course of formulation development, processing, and administration.

Evade: Upon administration, it should be retained in the form such that it evades body defense mechanisms, stays protected from the body's immune system attacks, and reaches desired target zone in an optimal time frame.

Target: Drug-delivery system should be designed to result in exclusive drug accumulation at the intended site of action, i.e. disease area, while avoiding healthy tissues and drug-associated toxicity.

Release: Once at the desired site of action, the system should be capable of releasing drug from the formulation for the agent to confer its therapeutic effect.

The goal of targeted drug-delivery system is to increase TI of a drug over a nonspecific drug-delivery system. A delivery system that results in preferential accumulation of drug at the disease site while sparing nondisease sites in the body and limiting overall toxicity is considered to have a higher TI as compared to a system that results in equal accumulation of the drug in both disease and nondisease sites [5]. A general rule is delivery system that confers higher drug TI is clinically safer as compared to lower TI.

1.3 Strategies for Drug Targeting

Over the last few decades, multiple ideas have evolved ranging from identification of different materials to invention of novel concepts to potentiate and improve delivery of drugs to intended target region. Strategies for drug targeting are often classified into three main categories - passive targeting, active targeting, and physical targeting (Figure 1.2).

Figure 1.2 Schematic representing different directed drug-delivery-targeting techniques.

1.3.1 Passive Targeting

Often referred to as "no targeting," passive targeting utilizes the principle to accumulate drugs into specific regions of the body due to inherent features and characteristics of the said tissue. Passive targeting makes use of differences in anatomical features between target tissue and nontarget tissue to ensure preferential accumulation of drug. Common examples of passive targeting include accumulation of drugs via the reticuloendothelial system (RES), increased accumulation of drugs due to enhanced permeability and retention (EPR) effect, and localized delivery.

1.3.1.1 Reticuloendothelial System (RES) System

RES is an essential part of the immune system that lines organs, including liver and spleen. RES consists of phagocytic immune cells, including monocytes and macrophages, that can recognize and uptake foreign moieties. Biological function of monocytes and macrophages includes opsonization or capturing foreign substances that reach the systemic circulation. Thus, the RES system enables preferential uptake of nanoparticles by organs, including liver and spleen. For example, nanoparticles with strong hydrophobic surfaces are preferentially taken up by the liver followed by spleen and lungs.

1.3.1.2 Enhanced Permeability and Retention (EPR) Effect

Tumor vasculature is highly leaky and discontinuous as compared to normal tissue vasculature. Unlike normal vasculature, which is lined with endothelial cells tightly held together, tumor vasculature is more heterogeneous in size and permeability. Depending on the stage of tumor progression and anatomical location, gaps between endothelium range in size from 100 to 780?nm [6, 7]. Additionally, elevated expression of proteins, including vascular epithelial growth factor (VEGF), epithelial growth factor (EGF), and basic fibroblast growth factor (bFGF), enhances vasodilation and extravasation of drugs from the leaky vasculature in tumors [8]. These characteristics of tumor vasculature enable enhanced delivery and retention of high-molecular-weight drugs in the target region. Augmented therapeutic effect achieved as a result of this phenomenon is associated with EPR effect. EPR effect is commonly used for passive targeting of agents >40?kDa in molecular weight. Additionally, low-molecular-weight agents that are administered in drug carriers, including conjugates, nanoparticles, and liposomes, can also be delivered preferentially to the tumor by leveraging the EPR effect.

Examples of commercially available formulations that target drug to tumor region leveraging the EPR effect include DaunosomeT and DoxilT, clinically used anticancer agents. Both Daunsosome and Doxil are liposomal formulations that efficiently accumulate in the tumor cells minimizing the frequency...