Intranasal delivery of biologics to the central nervous system☆
Graphical abstract
Introduction
The blood–brain barrier (BBB) is located at the level of the cerebral microvasculature and is critical for maintaining central nervous system (CNS) homeostasis. Although the BBB restricts the entry of potentially neurotoxic substances into the brain, it also presents a major obstacle to the delivery of therapeutics into the CNS for disease treatment. The BBB exhibits a low rate of pinocytosis and possesses tight junctions (TJ) which form a seal between opposing endothelial membranes [1]. The presence of TJ at the BBB creates a high transendothelial electrical resistance of 1500–2000 Ω∙cm2 compared to 3–30 Ω∙cm2 across most peripheral microvessels [2], [3]. This high resistance is associated with very low permeability, i.e. the BBB greatly restricts paracellular diffusion of solutes from the blood into the brain. Typically, only small, lipophilic molecules appreciably cross the normal, healthy BBB via transcellular passive diffusion, although some limited transport of certain peptides and peptide analogs has been reported [4]. Essential nutrients such as glucose or iron gain entry into the CNS through specific transporters such as the glucose transporter 1 or receptors such as the transferrin receptor [5], [6]. Receptors and transporters for gastrointestinal hormones involved in regulating metabolism are expressed at the BBB in order to convey information between the CNS and periphery [7]. In addition to its low paracellular permeability and low rate of pinocytosis, the BBB also expresses a high number of drug transporters (e.g. P-glycoprotein) which further restrict brain entry of many endogenous and exogenous substances that would otherwise be predicted to cross the BBB based on molecular weight (MW) and lipophilicity considerations [8], [9].
Although there are many examples of small MW drugs which cross the BBB, nearly all large MW substances are severely restricted from crossing the BBB under normal conditions; indeed, the only examples of large MW drugs approved for clinical use in treating a neurological illness are those that act via peripheral mechanisms (e.g. type I interferons for treating multiple sclerosis). Many large MW substances have shown substantial promise in treating aspects of CNS diseases based on studies utilizing in vitro systems and animal models. However, it will likely be necessary to implement drug delivery strategies that overcome the formidable obstacles presented by the various barriers of the CNS (the BBB and blood–cerebrospinal fluid (CSF) barriers) for these studies to ultimately be translated to the clinic [10]. Intraparenchymal, intracerebroventricular, and intrathecal injections/infusions are capable of delivering therapeutics directly to the CNS, but these routes of administration are invasive and likely not practical for drugs which need to be given chronically. The intranasal (IN) route of administration provides a non-invasive method of bypassing the BBB to potentially deliver biologics such as peptides, proteins, oligonucleotides, viral vectors, and even stem cells to the CNS. The IN route has long been associated with a number of advantages (Table 1), e.g. rapid onset of effects using non-injectable administration methods and a growing record of experience with approved formulations (e.g. nasal spray of the 3.5 kDa polypeptide hormone calcitonin has been used for many years to treat postmenopausal osteoporosis); the major disadvantage of the route (Table 1), aside from the challenge of reproducibility, is that limited absorption across the nasal epithelium has restricted its application to particularly potent substances, although this can be overcome by use of permeation enhancers in some cases [11]. While nasal delivery has probably been the most successful of the alternative transmucosal routes as a portal of entry into the systemic circulation for substances that cannot be given orally [12], with a large number of intranasally applied drugs in clinical use [11], research into whether the IN route might deliver potentially therapeutic amounts of larger biologics such as proteins to the CNS was first described only a little over a decade ago [13], [14]. Delivery of biologics and a variety of other substances from the nasal passages to the brain has now been documented in numerous animal and clinical studies [15], [16], [17]. Here we will provide an overview of relevant nasal anatomy and physiology and discuss the pathways and transport mechanisms that may be involved in the distribution of biologics from the nasal cavity to the CNS. We will also summarize the findings of key studies that convincingly show entry and/or efficacy of biologic drugs introduced to the CNS using the intranasal route of administration.
Section snippets
General considerations
The nasal cavity extends from the nostrils (nares) to the nasopharynx and is divided longitudinally by the nasal septum [18]. The human nasal cavity only extends approximately 12–14 cm in length yet has a large absorptive surface area of ~ 160 cm2 due to three bony structures called turbinates or conchae (inferior, middle and superior) which also aid in filtering, humidifying and warming inspired air [18]. Table 2, Table 3 summarize important comparative aspects of nasal anatomy with respect to
Pathways from the nasal passages to the central nervous system
The precise pathways and mechanisms by which a drug travels from the nasal epithelium to various regions of the CNS have not been fully elucidated. The central distribution of [125I]-labeled proteins following IN administration in rats and monkeys has suggested that delivery occurs along olfactory and trigeminal nerve components in the nasal epithelium to the olfactory bulb and brainstem, respectively, with further dispersion to other CNS areas from these initial points of brain entry [36], [37]
Animal data
Numerous studies have demonstrated IN drug delivery to effectively treat animal models of CNS diseases. Most of these studies did not show pharmacokinetic data which clearly demonstrated brain uptake of the nasally administered compound but rather presented pharmacodynamic data showing a positive effect following IN delivery of a substance in an animal model. This makes it difficult to ascertain whether the drug bypassed the BBB via direct nose-to-brain pathways to enter the CNS, crossed the
Conclusions
CNS drug delivery is difficult due to limitations presented by the BBB. IN delivery of drugs is a potential strategy to overcome the obstacles imposed by the BBB and is an attractive option due to its non-invasiveness. A number of animal studies have shown biologics to directly reach the brain following IN administration. Studies in humans corroborate these findings and show that IN delivery of biologics to the CNS is not unique to rodents with much smaller brains. The majority of reports have
Acknowledgments
This work was supported by the University of Wisconsin—Madison School of Pharmacy and the Graduate School at the University of Wisconsin. The authors thank Daniel Wolak and Mohan Gautam (University of Wisconsin—Madison) for reviewing the manuscript. RGT acknowledges (i) periodically receiving honoraria for speaking to organizations within academia, foundations, and the biotechnology and pharmaceutical industry and (ii) occasional service as a consultant on CNS drug delivery to industry.
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This review is part of the Advanced Drug Delivery Reviews theme issue on "Delivery of Therapeutics to the Central Nervous System".