Brain targeted drug delivery

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Chapter: Pharmaceutical Drugs and Dosage: Organ-specific drug delivery

Drug delivery to the brain, or the central nervous system (CNS), in general, is indicated in several clinical situations that include tumors, Alzheimer’s disease, epilepsy, migraine, infections, inflammatory dis-eases, and conditions that are etiologically based on neurotransmitter imbalance.


Brain targeted drug delivery

Drug delivery to the brain, or the central nervous system (CNS), in general, is indicated in several clinical situations that include tumors, Alzheimer’s disease, epilepsy, migraine, infections, inflammatory dis-eases, and conditions that are etiologically based on neurotransmitter imbalance.


1. Blood–brain barrier

Drug delivery to the brain and the CNS is particularly challenging because of the BBB. The BBB is a term that denotes the special nature of the blood vessels that carry blood to the brain and the spinal cord. The tight junc-tions of endothelial cells lining these blood vessels are highly impervious to substances in the blood, with electrical resistivity ≥ 0.1 Ωm. The BBB selectively allows the passage of water, certain gases, and lipophilic mol-ecules that can diffuse through the cell membranes (paracellular route), and through active transport (through the transcellular route) of certain mol-ecules that are important to neuronal function such as glucose and amino acids (Figure 15.3). Thus, drugs that are present in the bloodstream are not able to permeate as readily into the CNS tissue as they can into the tissue of other organs.


Figure 15.3 Routes of drug transport across the endothelial cell lining of the blood–brain barrier (BBB) that has tight junctions. Hydrophilic molecules, such as essential nutrients, can cross the cellular membranes through endocytosis or tranport-ers. Lipophilic molecules cross the membrane through diffusive transport. Presence of efflux transporters and metabolizing enzymes can reduce the total amount of drug crossing over to the other side.


2. Drug delivery strategies to the brain

Drug delivery strategies to the brain include the following:

1. Drug encapsulation in liposomes or nanoparticles

·  Drug encapsulation in liposomes provides colloidal particles with lipophilic and membranous exterior that can fuse with the endo-thelial cell membranes and enable transcellular drug transport. Commercially available liposome encapsulated drugs include amphotericin B (AmBisome) and doxorubicin (Caelyx)

·  Commercially available nanoparticulate drugs that target the CNS include colloidal gold nanoparticles (Aurimmune) and gold-coated silica nanoparticles (AuroShell).

2. Drug modification, for example, by preparation of a lipophilic prodrug

·  Small-molecule drugs that are generally low molecular weight (<500 Da), nonionizable at physiologic pH, low hydrogen bond capa-bility, and high lipophilicity can readily cross the BBB through passive diffusion. Examples of such compounds include benzodiazepines, alcohol, and nicotine. The lipophilicity of a drug can be increased through structural modification and/or by preparation of a lipophilic prodrug. Examples of drugs that can diffuse across the BBB include levodopa, γ-Aminobutyric acid (GABA), and valproic acid.

3. Drug conjugation with an active transport substrate to achieve recep-tor-mediated active transport

·  Drug conjugation with a moiety that has endothelial cell recep-tors for active transport across the BBB can increase drug uptake in the brain. For example, drug conjugation with the angio-pep-2 peptide, which targets the low-density lipoprotein (LDL) receptor, has been utilized to target drugs and nanoparticles to the brain.

4. Transnasal route of administration

Nasal mucosa is a highly permeable and vascularized site. The olfactory region in the nasal passage is a small patch of tissue that contains olfactory nerve endings and is considered a port of entry of external chemicals into the brain. In addition, the characteris-tics of the drug that influence its permeation through the transcel-lular route, a key challenge in utilizing the nasal route for brain drug delivery is the ability to present the drug to this region of absorption in sufficient concentration and for a long enough dura-tion that can enable the delivery of therapeutic dose. Compounds such as insulin-like growth factor I (IGF-I) have been delivered to the brain through the nasal route.

5. Direct intrathecal or intracerebroventricular injection or placement of DDS during invasive surgery (implant)

·  Intracerebroventricular (ICV) injection of chemotherapy agents, morphine, and antibiotics used in the treatment of meningitis is achieved through a subcutaneously implanted reservoir in the scalp (Ommaya reservoir) that connects to the cerebrospinal fluid (CSF) in a lateral ventricle through an implanted catheter.

·   Biodegradable SR wafers loaded with chemotherapy agents have been used as implants in the brain. These DDSs can be placed directly at the site of tumor following surgery.

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