Drug Delivery to the Brain

Elizabeth CM de Lange

Drug Delivery to the Brain

Elizabeth CM de Lange

1997, Journal of Cerebral Blood Flow & Metabolism

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AI-generated Abstract

The delivery of pharmaceuticals to the central nervous system (CNS) is significantly hampered by the blood-brain barrier (BBB), which restricts most drugs from achieving therapeutic levels in the brain. Traditional drug discovery methods have not kept pace with innovations in drug delivery strategies, leading to a disproportionate focus on drug discovery over effective delivery mechanisms. New approaches that enhance drug transport across the BBB, whether through invasive, pharmacologic, or physiologic strategies, are imperative to address the increasing prevalence of CNS disorders and ensure effective treatment.

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FIG. 2. The only class of potential neuropharmaceuticals that has significant blood-brain barrier transport are small molecules that have the dual criteria of lipid solubility, and molecular weight less than a 400 to 600 d threshold. MW, molecular weight. illustrated with histamine, which has a molecular weight of 111 d Figure 4A is an autoradiogram of a mouse obtained 5 minutes after intravenous injection of ['*C]- histamine.This small molecule readily traverses the po- rous capillaries in all peripheral tissues but does not enter the brain or spinal cord because of the lack of transport through the BBB. Although in the early 1900s the BBB was believed to be localized at the choroid plexus, the cellular basis of the BBB is, in fact, localized to the brain vasculature, as depicted by the scanning electron micro- graph of a vascular cast of the human cerebellar cortex (Fig. 4B). The capillaries are spaced approximately 40 yzm apart in the brain and it takes a small molecule approximately 1 second to diffuse a distance of 40 wm. The plasma transit time is approximately | second in the brain. Therefore, the angioarchitecture of the brain has evolved to allow for instantaneous solute equilibration

FIG. 1. Flow chart comparing the pathways of two different meth- odologies for CNS drug development; the trial and error approach, and the rational drug design approach, wherein the latter is based on high throughput screening of thousands of molecules. The latter will invariably select drugs that have negligible blood-brain barrier transport properties. Therefore, in the absence of parallel prog- ress in the development of CNS drug delivery strategies, the CNS drug discovery program invariably ends in program termination.

FIG. 3. Strategies for brain drug delivery may be broadly classi- fied as being either neurosurgical-based (invasive), pharmaco- logic-based, or physiologic-based.

FIG. 4. (A) Sagittal section film autoradiogram of a mouse killed 5 minutes after intravenous injection of ['4C]-histamine, a small molecule that readily crosses the porous capillary beds in peripheral tissues, but does not cross the blood-brain barrier (BBB) in brain or spinal cord (Pardridge et al., 1986). (B) Scanning electron micrograph of a vascular cast of the human cerebellar cortex (Duvernoy et al., 1983). (C) Four cells comprising the cerebral microvasculature include the endothelium, which constitutes the permeability barrier of the BBB, the pericyte, the astrocyte foot process, and occasional neuronal innervation of the endothelial cell.

FIG. 5. In neurotrophin drug development, the limiting factor is brain drug delivery. The strategies presently in practice for brain dru delivery in humans are outlined. The top emphasizes that the products of neurotrophin CNS drug discovery programs cannot underg¢ clinical development for the treatment of CNS disorders in patients, unless the brain drug delivery bottleneck is navigated. The first attemp at brain drug delivery that is generally currently tried is intraventricular drug infusion. The figure shows an autoradiogram of a rat brait taken 20 hours after the injection of ['25l] brain-derived neurotrophic factor into the lateral ventricle (LV) of a rat (Yan et al., 1994). The neurotrophin is distributed only to the ipsilateral ependymal surface of the brain, which is consistent with the unidirectional flow of CSF within the brain. There is minimal penetration of the drug to the ipsilateral brain parenchyma, and no distribution to the contralateral side An alternative drug delivery strategy is implantation within the brain of either genetically engineered cells secreting a neurotrophin, or polymeric matrix containing the neurotrophin. The coronal section autoradiogram was obtained 48 hours after the intracerebral implan tation of a 2-mm diameter polymeric disc comprised of poly (ethylene-covinyl acetate) and 5 mg of ['2°l]-nerve growth factor (NGF (Krewson et al., 1995). The NGF concentration immediately surrounding the polymeric implant is extremely high, but is decreased 10-fol within a diffusion distance of 500 um from the polymer/tissue interface; the majority of the brain space containing NGF is occupied by the 2-mm polymeric disc. If the invasive strategies are unsuccessful, then it is usually advocated that small molecules provide a strategy fo dealing with the brain drug delivery problem. However, even if a neurotrophin-mimetic small molecule was discovered, this drug woul need a BBB drug delivery strategy if the small molecule mimetic lacks the dual criteria of lipid solubility and molecular weight less tha a 400 to 600 d threshold (Fig. 2). Thus, in the absence of practical BBB drug delivery strategies, present day CNS drug discover programs have a high likelihood of ending in program termination. tributes drug to blood, but not to brain, has been shown repeatedly. The intraventricular infusion of B-interferon in primates results in the presence of the cytokine in blood, but not in brain (Billiau et al., 1981). Similar results are found after the intraventricular injection of a-interferon in rats (Grieg et al., 1988), or 6-mercapto- purine, a small molecule, in primates (Covell et al., 1985). When a small molecule, atenolol, is administered in the left ventricle of rats, no drug is found in the dial- ysate of a fiber placed into the adjacent cerebral cortex (deLange et al., 1994). After the ICV infusion of acet- aminophen, the drug is distributed to the peripheral cir- culation, is transported across the BBB, and the drug then diffuses into the dialysate of a fiber contained in the adjacent cerebral cortex (deLange et al., 1994). These results confirm earlier observations by Aird (1984) that the dose of barbiturate that induces pharmacologic ef- fects in animals after intraventricular or intravenous in- jection is identical. That is, drug infused into the ven- tricular compartment distributes to the peripheral blood- The fact that intraventricular drug administration only results in drug distribution to the ependymal surface is

FIG. 6. The pharmacokinetic rule for brain drug delivery states that the brain uptake, measured as percent of injected dose (ID) of drug delivered per gram of brain is a dual function of the BBB permeability-surface area product, and the plasma area under the concentration curve (AUC). The permeability-surface area product is a function of the BBB transport vector, and the plasma AUC is a function of the systemic pharmacokinetics of the drug, which is in turn a function of the intrinsic chemical properties of the drug. When small molecules are attached to lipid carriers, the BBB permeability-surface area product may increase several-fold. However, the organ clearance of the drug by peripheral tissues is also increased, which results in a proportional decrease in the plasma AUC. Thus, the increased perme- ability-surface area product and the decreased plasma AUC tend to have offsetting effects with minimal increases in percent ID/g being achieved with strategies that aim to increase the lipid solubility of the drug. to both the BBB permeability-surface area product and the plasma area under the concentration curve (AUC). When the lipid solubility of a drug is increased, the BBB permeability-surface area product may be increased, but the plasma AUC is decreased, generally in proportion to the increase in BBB permeability-surface area product. The decreased plasma AUC occurs because the enhanced lipid solubility of the compound results in an increased distribution of the drug into virtually all peripheral tis- sues with concomitant rapid removal from the blood- stream. Thus, the increased permeability-surface area product caused by the lipid carrier is offset by the de- creased plasma AUC. For example, when azidothymi- dine is coupled to an adamantane carrier, the azidothy- midine is removed from plasma 10 times faster relative to the unconjugated azidothymidine (Tsuzuki et al., 1994). Penetration of the drug into the CSF is actually decreased by attachment to the carrier because of the profound effect of the lipid carrier on the plasma AUC of the drug. The concentration of azidothymidine in brain tissue is unchanged after peripheral administration of free azidothymidine or azidothymidine in the form of the ipid carrier. This constancy of the percent injected dose per gram is caused by the offsetting effects of the in- creased permeability-surface area product and the de- creased AUC caused by use of the lipid carrier. Apart from these pharmacokinetic considerations, the use of a ipid carrier may require that the drug still react with the target receptor in brain while the drug is conjugated to the lipid carrier. If the drug must be released in brain from the lipid carrier to interact effectively with the tar- get receptor, then the covalent bond joining the drug and The principal problem with using lipid carriers is pre- dicted by the pharmacokinetic rule (Fig. 6). The uptake of a drug in the brain, quantified as percent of injected dose delivered per gram of brain, is directly proportional

BLOOD-BRAIN BARRIER PEPTIDE RECEPTOR SYSTEMS FIG. 7. Blood-brair\ barrier peptide receptor systems include those for insulin, insulin-like growth factor (IGF)-I, IGF-II, transferrin, and leptin (Golden et al., 1997). The insulin, IGF, transferrin, and leptin receptor systems are believed to mediate the transcytosis of these circulating ligands through the brain capillary endothelium and into the brain interstitial fluid. The scavenger receptor binds modified proteins such as acetylated low density lipoprotein and mediates only the endocytosis of acetylated low-density lipoprotein (LDL) into the brain capillary endothelium, not transcytosis (Triguero et al., 1990). Lectins, such as wheat germ agglutinin, bind to brain endothelial carbohydrate sites (Broadwell et al., 1988), and cationic proteins, which bind to brain endothelial anionic sites, undergo absorptive- mediated transcytosis through the BBB (Triguero et al., 1990).

FIG. 8. Drug targeting to primate or human brain via a monoclonal antibody (MAb) to the human insulin receptor. (A) The insulin receptor is a tetrameric structure comprised of two a chains, that contain the insulin receptor binding site, and two 8 chains that contain the tyrosine kinase activity and project into the intracellular compartment. The 83-14 MAb binds to an epitope contained within amino acids (AA) 469 to 592 of the a chain, which projects into the extracellular (plasma) compartment of brain capillaries. (B) The 83-14 MAb causes continuous immunostaining of brain capillary endothelium in frozen sections of rhesus monkey brain, indicating the microvascular origin of the immunoreactive insulin receptor in brain is at the endothelium (Pardridge et al., 1995). (C) There is rapid transport of ['75l]-labeled 83-14 MAb into the brain of anesthetized rhesus monkeys in vivo and the brain volume distribution is greater than 1 mL/g, which is a volume that exceeds the glucose volume distribution in brain. In contrast, a mouse IgG2a isotype control antibody is confined to the plasma compartment in primate brain in vivo. (D) The methods for preparing thiol-ether conjugates of the 83-14 MAb and streptavidin (SA) are outlined. These methods allow for retention of the bifunctionality of the 83-14/SA conjugate. (E) Human brain capillaries are used in radioreceptor assays and an in vitro model system of blood-brain barrier transport to assess the bifunctionality of the 83-14/SA conjugate. The specific brain capillary uptake of [SH]-biotin bound to the 83-14/SA conjugate is blocked by high concentrations of unconjugated 83-14 MAb, indicating the uptake of the [°H]-biotin by the human brain capillaries is mediated via the human blood-brain barrier insulin receptor (Wu et al., 1997).

FIG. 9. (A) The amyloid imaging agent is comprised of three domains: radiolabeled AB‘~*° that binds to the amyloid of a brain wit Alzheimer’s Disease (AD); the linker domain which is comprised of a 14-atom spacer attached to a biotin moiety that is bound to an avidii analog such as streptavidin; a BBB transport domain comprised of an anti-receptor MAb such as the 83-14 MAb to the human BBB insuli receptor for studies in Old World primates or humans, or the OX26 MAb to the rat transferrin receptor for studies in rats (Saito et al., 1995) (B) Film autoradiogram of a section of human brain with AD cortex that had been labeled with the ['25I,biotinyl]JAB'~° that is conjugate to the OX26/SA BBB delivery system. The study shows the ['2°l,biotinylJAB’~“° amyloid imaging agent still binds the amyloid plaques c AD brain despite conjugation to the OX26/SA BBB delivery system; there is heavy amyloid binding in the gray matter with general sparin of the internal white matter tracks. This signal is completely blocked by the inclusion of 10 uM unlabeled AgB'~®, indicating the amyloi imaging agent is binding specifically to the amyloid of the brain with AD (Saito et al., 1995). (C) The ['2°l,biotiny|]AB*~*° was injecte intravenously into anesthetized young rhesus monkeys, the animals were killed 3 hours later, and 20 um frozen sections were prepare for film quantitative autoradiography (QAR). The QAR for either the left or right hemisphere is shown in the left hand panel and indicate there is no measurable brain uptake of the AB'~*°, because of the failure of this neuropeptide to undergo significant transport through th primate BBB in vivo. However, when the ['25I,biotinylJAB'~*° is conjugated to the 83-14/SA BBB delivery vector, there is robust brai uptake of the neuropeptide at 3 hours after intravenous injection in the rhesus monkey (right panel). Indeed, the QAR pattern i comparable to a “2-deoxyglucose” scan, and clearly shows the areas of demarcation between gray matter and white matter tracks i primate brain cortex. The brain radioactivity is decreased greater than 90% by 48 hours after injection in control animals that lack CN: AB amyloid (Wu et al., 1997). 40 amino acids of this peptide, designated AB'~*°, is soluble in aqueous solution and may be iodinated. The ['*51]-AB!~° deposits at pre-existing amyloid in sections of brains with Alzheimer’s Disease (Maggio et al., 1992), and is a more sensitive marker of tissue amyloid than is a antibody directed against an amyloidotic com- ponent. However ['*°I]-AB'~*° undergoes negligible transport through the BBB (Saito et al., 1995), because there is no specific receptor for this neuropeptide at the BBB. AB’? has been iodinated and biotinylated and conjugated to the OX26/SA delivery system. As shown is Fig. 9A, this amyloid imaging agent is comprised of three domains: an amyloid binding domain consisting of the radiolabeled AB'~“°; a linker domain consisting of a 14-atom spacer attached to biotin and streptavidin; and a BBB transport domain consisting of the anti-receptor In addition to peptide-based therapeutics, it is also possible to deliver peptide radiopharmaceuticals through the BBB for the purposes of diagnosing brain disorders. For example, brain tumors that selectively express the epidermal growth factor receptor could be detected by the BBB delivery of a radiolabeled epidermal growth factor peptide radiopharmaceutical. The amyloid burden in the brain of patients with Alzheimier’s Disease may be semi-quantitated by delivering across the BBB an amy- loid imaging agent. The amyloid in the brain of the pa- tient with Alzheimer’s Disease is caused by the deposi- tion of a 43 amino acid AB amyloidotic peptide. The first

£ FIG. 10. (A) Strategy for conjugating a receptor-specific MAb to a liposome via tethering of the MAb via a stable thiol-ether (S) linkage at the tip of a polyethyleneglycol (PEG) tail that is in turn linked to a phospholipid within the surface of the liposome (Huwyler et al., 1996). (B) When [SH]-daunomycin is entrapped within a pegylated OX26 immunoliposome and injected intravenously into anesthetized rats, the brain volume of distribution (Vp) increases with time and exceeds 200 uL/g at 24 hours after injection. (C) The plasma pharmacokinetics of [H]-daunomycin injected intravenously into rats is shown for four different forms of the drug: free drugs; drug entrapped in a conventional liposome (LIPO) that contains no PEG and no attached receptor-specific MAb; daunomycin entrapped in a pegylated OX26 immunoliposome (LIPO-PEG-MAb); and daunomycin entrapped in a pegylated liposome (LIPO-PEG) that contains no MAb. Data are mean + SE (n = 3). The data show that there is unfavorable pharmacokinetics for either free daunomycin or daunomycin entrapped in conventional liposomes. However, the plasma AUC of the daunomycin entrapped in liposomes is greatly increased with pegylation technology (see LIPO-PEG curve). The plasma AUC is partially reduced by conjugation of the OX26 MAb to the tip of the pegylated liposome because there is vector-mediated uptake of the pegylated immunoliposome into tissues in the rat that express the transferrin receptor (Huwyler et al., 1996). (D) Confocal fluorescent microscopy of isolated rat brain capillaries reacted with OX26 pegylated immunoliposomes. These liposomes contained rhodamine conjugated to the surface of the phospholipid that allowed for visualization by confocal microscopy. The study shows binding of the OX26 pegylated immunoliposome to both the luminal and abluminal membranes of rat brain capillaries. When pegylated immunoliposomes were prepared with the mouse IgG2a isotype control instead of the OX26 MAb, there was no specific uptake of the pegylated immunoliposome by rat brain capillaries. (E) Confocal fluorescent microscopy using rhodamine labeled pegylated OX26 immunoliposomes shows receptor-mediated endocytosis of the complex into rat glioma (RG)-2 cells that contain rat transferrin receptor on the surface of the cell. These studies indicate the OX26 MAb is able to trigger receptor-mediated endocytosis of the 85 nm pegylated immunoliposome into cells expressing transferrin receptor (Huwyler et al., 1997).

FIG. 11. Antisense therapeutics include phosphodiester (PO) oli- godeoxynucleotides (ODN), phosphorothioate (PS) ODN, and peptide nucleic acids (PNA). The PO-ODN and PS-ODN are polyanionic, but the PNA have an electrically neutral peptide backbone. The PNA lack the nuclease susceptibility of the PO- ODN, and the CNS toxicity or plasma protein binding problems of the PS-ODN. Antisense oligodeoxynucleotides (ODN) are poten- tially powerful CNS therapeutics that may inactivate translation of specific transcripts or facilitate premature degradation of specific transcripts via RNase H activity (Stein and Cheng, 1993). Phosphodiester (PO)-ODN are too labile in either blood or brain to be effective phar- maceuticals because of the rapid inactivation of PO- ODN by 3’-exonucleases (Fig. 11). Phosphorothioate (PS)-ODN are metabolically stable and resistant to 3’- exonucleases. However, PS-ODN bind nonspecifically to a variety of cellular proteins, and this causes nonse- quence-related pharmacologic effects. For example, PS- ODN inhibit HIV uptake in lymphocytes by nonspecif- ically binding to CD4 and interfering with viral transport across the cell membrane, and this effect is unrelated to the specific nucleotide sequence of the antisense agent (Yakubov et al‘, 1993). Although PS-ODN are nonspe- cifically taken up by cells in culture, there is no measur- able brain uptake of PS-ODN after systemic administra- tion (Wu et al., 1996). Accordingly, PS-ODN have been delivered to the brain by intraventricular infusion. How- ever, if the infusion dose generates an intrathecal con- centration greater than 1 ~M PS-ODN, then severe neu- rotoxicity ensues (Fig. 11), and can include cord necro- sis, paralysis, and death (Whitesell et al., 1993; Wojcik et al., 1996).

Valentino Laquintana

Current Topics in Medicinal Chemistry, 2009

This paper provides a mini-review of some recent approaches for the treatment of brain pathologies examining both medicinal chemistry and pharmaceutical technology contributions. Medicinal chemistry-based strategies are essentially aimed at the chemical modification of low molecular weight drugs in order to increase their lipophilicity or the design of appropriate prodrugs, although this review will focus primarily on the use of prodrugs and not analog development. Recently, interest has been focused on the design and evaluation of prodrugs that are capable of exploiting one or more of the various endogenous transport systems at the level of the blood brain barrier (BBB). The technological strategies are essentially non-invasive methods of drug delivery to malignancies of the central nervous system (CNS) and are based on the use of nanosystems (colloidal carriers) such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, polymeric micelles and dendrimers. The biodistribution of these nanocarriers can be manipulated by modifying their surface physico-chemical properties or by coating them with surfactants and polyethylene-glycols (PEGs). Liposomes, surfactant coated polymeric nanoparticles, and solid lipid nanoparticles are promising systems for delivery of drugs to tumors of the CNS. This mini-review discusses issues concerning the scope and limitations of both the medicinal chemistry and technological approaches. Based on the current findings, it can be concluded that crossing of the BBB and drug delivery to CNS is extremely complex and requires a multidisciplinary approach such as a close collaboration and common efforts among researchers of several scientific areas, particularly medicinal chemists, biologists and pharmaceutical technologists.

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