Targeted drug delivery

Targeted drug delivery

Drug delivery in a selective manner to a biological target, such as organ, tissue, cells, or intracellular organelles, is called targeted drug delivery. Targeted drug delivery is differentiated from target-based drug develop-ment or drug targets, which are defined as the molecular targets that the drugs modulate for their pharmacological action. Drug therapy that aims to utilize drug molecules that target a specific protein or receptor for their action is called targeted drug therapy. Targeted drug delivery, on the other hand, refers to the science and technology of presenting a drug to its site of action. The overall goal of all drug-targeting strategies is the improvement of efficacy and/or safety profile of a drug substance.

Targeted drug delivery can involve either drug delivery to a specific organ or tissue or avoiding drug delivery to a specific organ, tissue, or cells. Targeted drug delivery to a particular physiological location can bring the drug to its primary site of action. Thus, it can help improve the efficacy of a drug or prevent its undesired toxicities in other tissues or organs. In addi-tion, sometimes, targeted strategies are intended to avoid drug exposure to a specific organ or tissue.1 This can help avoid specific drug-related toxici-ties in particular organs, such as the kidney. For example, intravenous (IV) injection of liposomal doxorubicin has lower nephrotoxicity and cardio-toxicity than IV injection of doxorubicin solution.

The most significant advantages of targeted drug delivery are realized in acute disease states, for example, targeting cytotoxic anticancer drugs to a specific organ (e.g., brain, lungs, liver, kidney, and colon) or the tumor tissue. For example, prodrugs of doxorubicin have been prepared with folate ligand conjugated through bovine serum albumin or polyethylene glycol (PEG), which enable targeting of the drug to the tumors that express folate recep-tors. Two important design elements of targeted DDSs are (a) the selection of the target organ or tissue and (b) the selection of the targeting strategy.

·           The selection of target organ or tissue is governed by the pharmacologi-cal need of the disease state and the drug substance. For example, drugs are targeted to the blood–brain barrier (BBB) for drug delivery to the brain for neurodegenerative diseases such as Alzheimer’s disease.

·           The selection of the targeting strategy for the DDS is governed by the pathophysiology of the target tissue and how it can be utilized to impart stimuli-responsive physicochemical property changes in the DDS. For example, leaky vasculature of the tumor tissue can be uti-lized for passive drug targeting by designing a DDS that is smaller in particle size and thus can extravasate to the tumor site. In addition, expression of specific biochemical receptors on cell surface of tumor tissues can be utilized for active targeting of the DDS to tumor cells.

Several drug-targeting approaches have successfully transitioned from the proof of concept to the clinical application and have become a state of the art. Examples of targeted drug delivery platforms that have become well accepted in the clinical practice include the following:

·           Enteric coating of oral solid dosage forms to overcome chemical insta-bility against acidic pH of the gastrointestinal (GI) tract or adverse effects of the drug in the gastric environment

·           Pulmonary drug delivery by dry powder inhalation

·           Ocular inserts for drug delivery to the surface of the eye

·           Transdermal and implantable DDSs for sustained systemic absorp-tion or local drug delivery.

In addition, several drug delivery strategies being explored are at different preclinical and clinical stages of advancement. Targeted delivery of small and macromolecular drugs has been discussed in depth in a recent book.2 In this chapter, we will describe different drug-targeting strategies and the role of physicochemical properties of the DDS, combined with the disease mechanism and tissue physiology, in the identification of target as well as a targeting strategy and vehicle.

The design and development of targeted drug delivery agents are based on the biological principles of physiological differences in target tissues compared with other organs or tissues that can be utilized for targeting approaches. These biological differences are matched to the physicochemi-cal principles of drug release from the DDS that targets its drug cargo to a specific organ or tissue. Such a DDS can be exemplified by the drug carriers that include stimuli-responsive polymers that demonstrate a signif-icant change in their properties with relatively minor change in an environ-mental physicochemical stimulus. The environmental physicochemical or mechanical stimuli that can cause response in the stimuli-responsive DDSs are exemplified by the following:

·           pH

·           Ionic strength or osmolarity

·           Light

·           Heat

·           Electricity

·           Ultrasound

·           Oxidation–reduction (redox) potential