Need for organ specific and targeted drug delivery

Need for organ specific and targeted drug delivery

Most new chemical entities (NCEs), including molecularly targeted agents, do not present compelling efficacy and safety in terms of the benefit-to-risk ratio in human clinical trials due to either efficacy or toxicity concerns. The toxicity profile of an agent includes general toxicity and effects explained by its mechanism of action. Although the toxicity profile usually remains largely unpredictable and difficult to modify, the safety and efficacy of these agents usually benefits from targeted delivery to either the physiologi-cal regions of where their molecular receptors are present in high concen-tration, or to avoid drug exposure to organs and tissues where significant toxicities exist.

Targeted drug delivery is a method of delivering drug in a manner that selectively increases drug concentration to a biological target. Targeted drug delivery is different from target-based drug development or drug tar-gets that are defined as the molecular targets that the drugs modulate for their pharmacological action. Drug therapy that aims to utilize drug mol-ecules 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 to improve the 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 nontarget organs, tissues, 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 and/or prevents its undesired toxicities in other tissues or organs. In addition, sometimes targeted strategies are intended to avoid drug expo-sure to nontarget organs or tissues.1 This can help avoid specific drug-related toxicities in particular organs, such as the kidney. For example, intravenously injected liposomal doxorubicin has lower nephrotoxicity and cardiotoxicity than intravenous (IV) injection of doxorubicin solution.

Advantages of targeted drug delivery

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 tis-sue. For example, prodrugs of doxorubicin have been prepared with folate receptor conjugated through bovine serum albumin or polyethylene glycol (PEG), that enable drug targeting to tumors that express folate receptors. Two important design elements of targeted DDS are (a) the selection of the target organ or tissue and (b) the selection of the targeting strategy.

·           The selection of the target organ or tissue is governed by the phar-macological need of the disease state and the drug substance. For example, drugs are targeted to the 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 after systemic administration. In addition, expression of specific receptors on the cell surface of tumor tissues can be utilized for active targeting of the DDS to tumor cells.

Examples of established drug targeting strategies

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 clinical practice include the following:

·           Enteric coating of oral solid dosage forms to overcome chemical insta-bility against acidic pH of the 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.1

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 Targeted Delivery of Small and Macromolecular Drugs.2 In this chapter, we will describe different organ-specific drug targeting strategies.

Pulmonary drug delivery

The respiratory tract includes the nasal mucosa, hypopharynx, and large and small airway structures including the trachea, bronchi, bronchioles, and alveoli. This tract provides a larger mucosal surface for drug absorp-tion. Pulmonary drug delivery refers to drug delivery to the local or sys-temic circulation through the alveoli.

Advantages of pulmonary drug delivery

Lung epithelium is highly permeable and has low enzymatic/metabolic activity compared to the liver and intestine. With a large surface area (~100 m²) and a highly permeable membrane (~0.2–0.7 mm thickness), alveolar epithelium permits rapid drug absorption into the systemic circu-lation. There are 200–600 million alveoli in a normal human lung. This route of administration is useful for treating pulmonary conditions and for drug delivery to other organs via the circulatory systems. In general, lipid-soluble molecules are absorbed rapidly from the respiratory tract, and thus, an increasing number of drugs are being administered by this route, including bronchodilators (e.g., beclomethasone dipropionate), cor-ticosteroids, antibiotics, antifungal agents, antiviral agents, and vasoactive drugs.

Lung alveoli can also permit systemic absorption of macromolecules, such as proteins, peptides, oligonucleotides, and genes. For example, DNase alpha (Pulmozyme®, Genentech), an enzyme used to reduce the mucus viscosity in the airways of cystic fibrosis patients, is most effective when administered by inhalation. This protein is delivered directly to its site of action by nebulization. The recent approval of inhaled human insulin by the FDA for use in diabetes mellitus stands as a major advancement in the field of pulmonary delivery of macromolecules and systemically acting drugs.

Barriers to pulmonary drug delivery

The lung has evolved to maintain sterility of its pathways and to avoid undesired airborne pathogens and particles through mechanisms such as (a) airway geometry, (b) localized high humidity, (c) mucociliary clearance, and (d) the presence of alveolar macrophages. These mechanisms also pres-ent themselves as barriers to pulmonary drug delivery.