Issue: Vol. 2 No. 5 July/August 2002, Posted Date: 3/27/2008

Bypassing the Blood-Brain Barrier to Deliver Therapeutic Agents to the Brain and Spinal Cord

 

ABSTRACT

Intranasal delivery provides a practical, noninvasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the blood-brain barrier to be rapidly delivered to the central nervous system (CNS). It also directly targets drugs that do cross the blood-brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. This method works because of the unique connection that the olfactory and trigeminal nerves, involved in sensing odors and chemicals, provide between the brain and external environment. Intranasal delivery does not require any modification of therapeutic agents and does not require that drugs be coupled to any carrier. A wide variety of therapeutic agents, including both small molecules and macromolecules can be rapidly delivered to the CNS using this intranasal method.

INTRODUCTION

For decades, the blood-brain barrier has prevented the use of many therapeutic agents for treating Alzheimer's disease, stroke, Parkinson's, head injury, spinal cord injury, depression, anxiety, and other CNS disorders. The blood-brain barrier impedes the use, for example, of many of the newer genetically engineered drugs, such as human recombinant neurotrophic factors and other therapeutic agents that can protect brain cells from damage and promote nerve repair. Often after drug designers, medicinal chemists, pharmacologists, and toxicologists have identified the most potent, specific, and safest analog of a particular drug, they have to abandon it in favor of a lesser drug simply because it does not cross the blood-brain barrier. This problem may be solved in part by the use of intranasal delivery, which provides a simple, practical, and rapid route of delivery into the CNS because of the unique connection between the nose and the brain that has evolved to sense odors and other chemical stimuli.

OLFACTORY & TRIGEMINAL PATHWAYS TO THE CNS

The neural connections between the nasal mucosa and the brain provide a unique pathway for noninvasive delivery of therapeutic agents to the CNS.1-3 It has been known for many years that pathogens and toxic metals could be transported from the nasal mucosa to the CNS along neural pathways.2, 3 However, it has only recently been appreciated that these same pathways can be used to deliver therapeutic agents to the CNS1-28 (Figure 1, Image courtesy of Robert Thorne, PhD, Alzheimer's Research Center, Regions Hospital, St. Paul, MN.)

The olfactory neural pathway provides both intraneuronal and extraneuronal pathways into the brain.1,4,29-32 The intraneuronal pathway involves axonal transport and requires hours to days for drugs to reach different brain regions.1, 4, 29-32 The extraneuronal pathway probably relies on bulk flow transport through perineural channels, which deliver drug directly to the brain parenchymal tissue, to the cerebrospinal fluid (CSF), or to both.1 This extraneuronal pathway allows therapeutic agents to reach the CNS within minutes.1, 4-8 Intranasal delivery of agents to the CSF is not surprising as CSF normally drains along the olfactory axon bundles as they traverse the cribriform plate of the skull and approach the olfactory submucosa in the roof of the nasal cavity where the CSF is then diverted into the nasal lymphatics.33-35 (See review by R.G. Thorne & W.H. Frey, II in Clinical Pharmacokinetics. 2001; 40(12):907-946). Thorne et al.8 have presented preliminary evidence that the trigeminal neural pathway also may be involved in rapidly delivering protein therapeutic agents, such as insulin-like growth factor-I to the brain and spinal cord following intranasal administration. The trigeminal nerves innervating areas of the nasal cavity are responsible for most chemoperception other than olfaction and sense diverse stimuli, including hot spices, formaldehyde, and other chemicals.36

INTRANASAL DELIVERY OF PROTEIN THERAPEUTIC AGENTS TO THE CNS

A number of protein therapeutic agents have been successfully delivered to the CNS using intranasal delivery in a variety of species. Neurotrophic factors, such as NGF,5-7 IGF-I,8 FGF13 (aFGF and bFGF), and ADNF12 (including ADNF-9 and NAP) have been intranasally delivered to the CNS in rodents as has a VIP analog.11 CNS concentrations of intranasally delivered NGF (26,500 daltons) varied from about 0.1 to 4.0 nM.5-7 Studies in humans with proteins, such as AVP,19 a CCK analog,20 MSH/ACTH,21,22 and insulin16 have concluded that they are also delivered directly to the brain from the nasal cavity along the olfactory neural pathway. Thorne and Frey have recently reviewed intranasal delivery of neurotrophic factors and other proteins to the CNS.1

Delivery of protein therapeutic agents to the CNS clearly involves extraneuronal transport as it occurs within minutes rather than hours.1, 4-8 While a number of protein therapeutic agents have been found in CNS tissues following intranasal administration, significant amounts of proteins with molecular weights above about 10 kDa have not been reported as yet in the CSF.1,8 Thus, there may be a size barrier to CSF entry following intranasal administration.

Studies in rodents have examined the effects of intranasally administered CNS therapeutic agents. The therapeutic benefit of intranasal delivery of proteins has been demonstrated by Liu et al. in stroke studies. Liu et al.9, 10 have shown that intranasal IGF-I reduces infarct volume and improves neurologic function in rats with middle cerebral artery occlusion (MCAO). A preliminary report indicates that intranasal treatment is effective even when delayed for 4 hours after the onset of MCAO.37 Kucheryanu et al.13 have demonstrated that intranasal bFGF in an MPTP-induced mouse model of Parkinson's disease suppressed rigidity and increased motor activity. They also reported that intranasal aFGF reduced tremors and increased striatal dopamine, DOPAC, and HVA in the animals.13 Gozes et al.11 have shown that intranasal administration of a VIP analog (28 amino acids) prevented learning and memory impairments resulting from cholinergic blockade in rats treated with aziridium. Gozes et al.12 also demonstrated that a nine amino acid fragment of ADNF (ADNF-9) and an ANDF-like peptide (NAP) also protected against short-term memory loss in this same animal model.

Research in humans has also provided evidence for direct delivery of therapeutic agents to the CNS from the nasal cavity. Studies in humans by Pietrowski and colleagues have demonstrated much greater brain evoked potential changes with intranasal than with intravenous AVP19 or the cholecystokinin analog CCK-8.20 Kern et al.16 have demonstrated CNS effects of intranasal insulin in humans without altering plasma glucose or insulin levels and of intranasal corticotropin-releasing hormone (CRH) without altering plasma cortisol or CRH levels.17 Perras et al.18 have reported that intranasal growth hormone-releasing hormone (GHRH) not only increased rapid eye movement sleep and slow wave sleep in humans, but also decreased growth hormone, which is likely due to a CNS effect of the GHRH following direct delivery to the brain. Finally, Smolnik et al.21 concluded that the action of intranasal ACTH4-10 on human event-related brain potential and attention was due to direct delivery of the peptide from the nose to the brain and did not require prior resorption into the blood. Fehm et al.22 reported that following intranasal administration of MSH/ACTH4-10 to humans, MSH/ACTH4-10 increased significantly in the CSF but not in the blood, and concluded that the peptide directly entered the CNS from the nasal cavity. They also found that intranasal MSH/ACTH4-10 significantly reduced body fat and body weight presumably by acting on the hypothalamic melanocortin system.

INTRANASAL DELIVERY OF DNA PLASMIDS TO THE CNS

Yu-Kyoung Oh et al.27 have reported that 24 hours after intranasal administration of DNA plasmids, the level of plasmid in brain was 3.9- to 4.8-fold greater than the plasmid concentration in the lungs and spleen. They also found that the plasmid DNA reached the brain within 15 minutes following intranasal administration. The authors conclude, "The higher distribution of plasmids to the brain after intranasal administration indicates that nasal administration might be a potential route for the delivery of therapeutic genes to the brain with reduced side effects to other organs." The plasmid administered in this study (7.2 kb, about 2.2 x 106 daltons) was very large, as was the plasmid detected in the brain, when compared to protein therapeutic agents that have been intranasally delivered to the brain.27 The authors also demonstrate excellent delivery of the vaccine to the draining cervical lymph nodes and suggest that an intranasal route providing for substantial absorption of DNA might have potential as a promising non-invasive delivery route for DNA vaccines.

INTRANASAL DELIVERY OF SMALL MOLECULES TO THE CNS

In addition to the small peptides [AVP, CCK-8, VIP analog, MSH/ACTH4-10, ADNF-9, and NAP] previously described, many other small molecules have been shown to transport directly to the brain and/or CSF from the nasal cavity. These have been reviewed by Illum2 and Mathison et al.3 They include the demonstration in non-human primates of intranasal delivery of estrogen40 and progesterone40, 41 to the CSF. Studies have also suggested that intranasally administered L-NAME28 and cocaine2, 42 may transport directly to the CNS of humans and animals from the nasal cavity.

Sakane et al.23 demonstrated that following intranasal administration of the antibiotic cephalexin to rats that CSF concentrations reached 4.49 ± 2.48 µG/mL (13 µM) at 15 minutes but declined to approximately half that concentration at 30 minutes. Because cephalexin does not cross the BBB well and because CSF concentrations were 166-fold higher after intranasal than systemic administration in spite of similar blood levels, the authors concluded that cephalexin entered the CSF directly from the nasal cavity.

The properties of small molecules, including size and lipophilicity, have been reported to affect delivery to the CNS following intranasal administration.24-26 Using a series of fluorescein isothiocyanate-labeled dextrans (FITC-dextrans) with increasing molecular weights, Sakane et al.26 found that dextrans with molecular weights of up to 20,000 daltons can be transported directly from the nasal cavity of rats into the CSF.26 The concentration of the FITC-dextrans in the CSF increased with decreasing molecular weight. These FITC-dextrans are not found in the CSF after intravenous administration. Similarly, a comparison of the brain olfactory bulb concentrations achieved 30 minutes after intranasal administration of 7.4 n mol dopamine (153 daltons)38 with those obtained after intranasal administration of 7.4 n mol NGF (26,500 daltons)6,7 to rats reveals a five-fold higher delivery of the lower molecular weight dopamine. Comparing the percentage of the original dose remaining in the brain 30 to 45 minutes after intranasal administration for dopamine (0.12%)14 and NGF (0.023%)7 in rodents reveals a similar difference.1 In addition, with most small molecules, a significantly higher molar dose can be delivered intranasally than with larger protein or DNA therapeutic agents. Thus, considerably higher concentrations of small molecules are achievable in the CNS with intranasal delivery.

Intranasally administering a series of sulfonamides of varying lipophilicity to rats, Sakane et al.25 have shown that increasing lipophilicity enhances the direct uptake of sulfonamides from the nasal cavity into the CSF. Even with the much higher plasma levels achieved with intravenous administration, CSF levels of the sulfonamides were much lower than with intranasal delivery.25 Studies reviewed by Illum2 and Mathison3 demonstrate that other small molecules, including metals and dyes, are also delivered to the CNS following intranasal administration. Most recently, Liu et al.39 have presented preliminary data demonstrating decreased infarct volume and improved neurologic function in rats with stroke (MCAO) who were treated intranasally with the flavonoid antioxidant myricetin (0.15 mg). These benefits were not observed with subcutaneous treatment using an even larger dose of myricetin (5 mg).39

ADVANTAGES & LIMITATIONS OF INTRANASAL DELIVERY

There are limitations on the use of intranasal delivery as a means to bypass the BBB, including limitation on the concentrations achievable in different regions of the brain and spinal cord, which will vary with each agent. As previously noted in this paper, delivery is expected to decrease with increasing molecular weight of the drug. Additionally, some therapeutic agents may be susceptible to partial degradation in the nasal mucosa or may cause irritation to the mucosa. Finally, nasal congestion from colds or allergies may interfere with this method of delivery.

In summary, the advantages of intranasal delivery are considerable. It is both rapid and noninvasive. It bypasses the BBB and targets the brain and spinal cord, reducing systemic exposure and thus systemic side effects. Even for drugs that can cross the BBB, it can reduce systemic side effects by reducing the need for the drug to enter the systemic circulation. It does not require any modification of the therapeutic agent being delivered and should work for a wide range of drugs. Intranasal delivery may facilitate the treatment and prevention of many different neurologic and psychiatric disorders.

NOTE: As this paper went to press, J. Born et al. published work demonstrating intranasal delivery of neuropeptides to the CSF of humans in Nature Neuroscience. 2002:5(6):514-516.

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BIOGRAPHY

Dr. William H. Frey II, currently serves as Director of the Alzheimer's Research Center at Regions Hospital in St. Paul, Professor of Pharmaceutics at the University of Minnesota, and consultant to the pharmaceutical and biotechnology industries. His patents, owned by Chiron Corporation and the HealthPartners Research Foundation, target non-invasive delivery of therapeutic and diagnostic agents to the brain and spinal cord for treating neurologic and psychiatric disorders and the use of antioxidants to treat and prevent disease. Dr. Frey has been interviewed on Walter Cronkite's Universe, the Today Show, Good Morning America, 20/20, All Things Considered, and on many other programs in the Unites States and abroad. Articles examining Dr. Frey's research have appeared in the Wall Street Journal, The New York Times, Forbes, U.S. News and World Report, the New Scientist, and numerous other journals and newspapers. Dr. Frey earned his BA in Chemistry at Washington University and his PhD in Biochemistry from Case Western Reserve University.

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