Current Pharmaceutical Biotechnology - Volume 13, Issue 12, 2012

Due to the presence of the blood-brain barrier, there is limited drug access into the brain. In order to overcome this challenge, various strategies have been developed to enhance penetration of drugs into the brain. Of these, the most frequently used are pharmacological technologies or comparable methods being developed for brain-targeting drug delivery using receptor- or adsorptive- or transporter-mediated transcytosis and the nose-to-brain route. It goes without saying that exploration of Brain-targeting drug delivery systems has created another potential option for the treatment of central nervous system diseases. In addition to above methods, other technologies for brain-targeting drug delivery (e.g. chemical delivery systems, prodrugs, pharmacological disruption of the BBB and inhibition of drug efflux by P-glycoprotein) are also summaried in this review.

The blood-brain barrier (BBB) is the vessel wall made up of specialized capillary endothelial cells, surrounded by astroglial endfeet and neurons, that govern the exchange of compounds between blood and brain. It protects the brain from harmful compounds potentially present in blood, while it is specifically designed to supply the brain with the required nutrients and to get rid of waste products. The BBB is structurally different from blood capillaries in other tissues. The BBB strictly limits the paracellular exchange of compounds by the so-called tight junctions. Moreover, the capillary endothelial cells contain metabolic enzymes that may convert a compound before entering the brain while transcellular passage across the BBB may be limited or increased by active transport systems. Thus the BBB has an important role in the relationship of the concentration-time profile of compounds in blood and those in the brain. The functionality of the BBB is dynamically regulated, depending on the given conditions. Important examples are changes in BBB functionality that may result in or are brought about by (CNS) disease conditions. All together this indicates the importance of investigations on BBB functionality and resulting transport of compounds for the design and optimization of therapeutic regimens. Thus, BBB investigation is an ever growing and dynamic field studied by pharmacologists, neuroscientists, pathologists, physiologists, and clinical practitioners. This review deals with a general introduction on the physiological characteristics of the BBB, its different transport systems, with particular emphasis on supposed transcytosis mechanisms at the BBB. Specific and detailed information on drug delivery approaches aiming at transcytosis into the brain will be dealt with in other parts of this special issue.

Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.

The blood-brain barrier (BBB), which impedes drug penetration into the central nervous system, is composed of specific structures formed by brain capillary endothelial cells and sheathed by astrocytic end-feet through basement membrane. Many brain drug delivery strategies have focused on adsorptive-mediated transcytosis (AMT), which is triggered by electrostatic interaction between cationic molecules and anionic microdomains on the cytoplasm membrane of the brain capillary endothelial cells. AMT-based drug delivery to the brain can be achieved by using cationic proteins and basic oligopeptides such as cell-penetrating peptides as targetors. Large therapeutic molecules such as neuropeptides and proteins or even drug-encapsulated vectors such as liposomes and nanoparticles can be allowed to access brain parenchyma through AMT when conjugated with these cationic targetors. In this review, I briefly discuss adsorptive-mediated brain delivery systems that may provide physiologic-based strategies for enhanced delivery of therapeutic substances through the BBB.

The endothelial cells of the brain form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain. Traditional attempts to bypass the BBB have been by formulation of drugs with lipophilicity or low molecular weight designed to enable transport via solute nutrient transporters. The identification of many new targets in the brain cells form new ways of thinking drug design as modern therapeutics could be proteins and molecules of genetic origins like siRNA and cDNA that are prevented from entry into the brain unless encapsulated in drug carriers. In many chronic disorders affecting the central nervous system, the BBB is physically intact which further limits the entry of large molecules. The desirable entry of such molecules will be made by formulation of particular drug carriers that will enable their transport into the brain endothelium, or even through the endothelium and into the brain. This review discusses the potential of different principles for drug therapy to the brain with these main emphases on drug transport through the BBB: i) the effects of molecular lipidization, ii) the involvement of solute nutrient carriers, iii) targeted delivery using small peptides with high membrane penetrating properties, iv) treatment with magnetic nanoparticles. These different principles for therapy are also discussed with focus on possibilities of their improvement for targeted delivery to the brain.

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. Intranasal delivery offers a non-invasive and convenient method to bypass the BBB and delivery of therapeutics directly to the brain. The review discusses the potential of intranasal route to deliver drugs to the brain, the mechanisms and pathways of direct nose to brain drug transport, the various factors influencing transnasal drug absorption, the conventional and novel intranasal drug delivery systems, the various intranasal drug delivery techniques and devices, and examples of brain drug transport that have been feasible in treating various brain disorders. Moreover, products on the market, investigational drugs, and the author's perceptions about the prospect of intranasal delivery for treating brain disorders are also been discussed.

Treatment of malignant gliomas remains a challenge irrespective of the recent improvements. Chemotherapeutic agents for malignant gliomas have been particularly inefficient for the existence of blood-tumor barrier (BTB), which hampers the accumulation and uptake in tumor. Moreover, even though blood-brain barrier (BBB) is compromised to some extent under the situation of malignant gliomas, it remains to be the obstacle influencing the therapeutic efficacies via systemic administration. Fortunately, there are many receptors over-expressed on the BTB (glioma cells and/or tumor microvessels) that can mediate ligand modified drug delivery systems targeting to gliomas and enhance tumor uptake. On the other hand, numerous routes have also been explored to circumvent the BBB. In this manuscript, we elucidate the BBB/BTB status under the situation of malignant gliomas and review the receptors over-expressed on BTB and the malignant gliomas targeted drug delivery strategies. We also discuss the perspective of malignant gliomas targeted drug delivery systems with new concepts.

Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Hungtinton's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment.

Despite advances in surgery and drug discovery, brain tumors remain fatal diseases. Early detection and diagnosis of brain tumors is of great importance for improving treatment outcomes. Magnetic resonance imaging (MRI) is a prominent, clinically-relevant imaging modality because of its excellent tissue contrast resolution, direct multiplanar imaging and increased sensitivity to edema. MRI utility is further enhanced with the use of magnetic iron oxide nanoparticles, which can function as both a contrast agent for imaging and as a drug delivery vehicle for treating brain cancer. In this review, the principles of various imaging modalities for brain tumors are discussed with focus on monocrystalline iron oxide nanoparticle (MION)-based MRI contrast agents. A summary is given on the mechanism of contrast effect, magnetophoretic mobility and magnetic retention, and strategies to enhance tumor selectivity, increase spatial resolution and reduce nonspecific uptake of MION.

The blood-brain barrier (BBB) represents a significant obstacle for drug delivery to the brain. Many therapeutics with potential for treating neurological conditions prove incompatible with intravenous delivery simply because of this barrier. Rather than modifying drugs to penetrate the BBB directly, it has proven more efficacious to either physically bypass the barrier or to use specialized delivery vehicles that circumvent BBB regulatory mechanisms. Controlled-release intracranial polymer implants and particle injections are the clinical state of the art with regard to localized delivery, although these approaches can impose significant surgical risks. Focused ultrasound provides a non-invasive alternative that may prove more desirable for acute treatment of brain tumors and other conditions requiring local tissue necrosis. For targeting the brain as a whole, cell-penetrating peptides (CPPs) and molecular trojan horses (MTHs) have demonstrated particular ability as delivery molecules and will likely see increased application. CPPs are not brain specific but offer the potential for efficient traversal of the BBB, and tandem systems with targeting molecules may produce extremely effective brain drug delivery tools. Molecular trojan horses utilize receptor-mediated transcytosis to transport cargo and are thus limited by the quantity of relevant receptors; however, they can be very selective for the BBB endothelium and have shown promise in gene therapy.

Malignant tumors remain virtually untreatable and inevitably lethal despite extensive surgical excision and adjuvant radio- and chemotherapy. Therefore, the development of more effective tumor-selective therapies is necessary. Stem/progenitorcells that self-renew, differentiate and display inherent tumor-tropic properties can be exploited for targeted delivery of therapeutic genes to invasive and metastatic tumors. In this review, we mainly introduce the application in Glioma, Breast cancer, Spinal cord injury, AD and so on. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research.