The Brain as a Drug Target

The central nervous system (CNS) is a sanctuary site and is protected by various barriers. These regulate brain homeostasis and the transport of endogenous and exogenous compounds by controlling their selective and specific uptake, efflux, and metabolism in the brain. Unfortunately, potential drugs for the treatment of most brain diseases are therefore often not able to cross these barriers. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. Here we discuss briefly the biology and physiology of the blood-brain barrier (BBB) and the blood-cerebro-spinal-fluid barrier (BCSFB), and, in more detail, the possibilities for delivering large-molecular-weight drugs by local and global delivery and by viral and receptor-mediated nonviral drug delivery to the (human) brain.

"In vitro" evaluation of blood-brain barrier transport

The major challenge for the treatment of neuronal diseases is the inability of therapeutic moieties to cross the blood–brain barrier (BBB) and nasal mucosal barrier. The therapeutic moieties for the treatment of brain diseases lack targeting due to its non-specificity toward receptors located at BBB and Pgp efflux mechanism. This results in impeding its ability to reach to maximum effective concentration. Many of these therapeutic moieties possess dose-limiting systemic side effects which along with complex dosage regimens hinder patient compliance and result in discontinuation of treatment. A number of drug delivery and drug-targeting systems have been investigated to increase drug bioavailability and the fraction of the drug accumulated in the targeted area, in order to minimize drug degradation and loss, as well as to reduce harmful side effects. Among all, PLGA NPs have been achieved fascinating properties as a carrier system owing to its biodegradable, biocompatible, and easy functionalization properties. Most importantly PLGA is available in various ratios which can be helpful for tuning the entrapment/loading of therapeutic moieties in NPs. Intranasal delivery has come to the forefront as a method that can bypass the BBB and target drugs directly to the brain as an alternative to invasive methods. The objective of this chapter is to provide a broad overview on current strategies for brain drug delivery and its applications. It is hoped that this chapter could inspire readers to discover possible approaches to deliver drugs into the brain. After an initial overview of the BBB and intranasal route in both healthy and pathological conditions, this chapter revisits, according to recent publications, some questions that are controversial, such as whether nanoparticles by themselves could cross the BBB and whether drugs are specifically transferred to the brain by actively targeted nanoparticles. Furthermore, in this chapter, various conjugation strategies for attaching targeting moieties to the surface of nanocarrier have been included. Current non-nanoparticle strategies are also reviewed, such as delivery of drugs through the permeable BBB under pathological conditions and using noninvasive techniques to enhance brain drug uptake.

It was just over a hundred years ago that the famous Paul Ehrlich put forward his theory of “the magic bullet”, as an approach to overcome and tame different disease states. Among these, targeting to the cancer cells in varying bodily locations (organs) is of prime interest. Scientists have ever since worked on the principle of drug targeting, based on this idea of specifically delivering various drugs to diseased cells. Of particular interest are anticancer, biotherapeutic, genetically engineered and protein/ peptide based drugs. Progress in the field of drug targeting has been slow till thirty five years ago. With the advent of the monoclonal antibody technology in the mid seventies of the last century as well as the development of liposomal and polymeric nanoparticle carriers, the drug targeting field enjoyed a welcoming expansion and the clinical applications of these novel drug delivery systems became a feasible aim. Monoclonal antibodies, liposomes, polymers, proteins and many other entities have ever since seen the light as carrier molecules, and as with most technological developments, have all encountered a vast array of difficulties. They range from problems in the synthesis of the carriers and drug conjugates to unfavorable pharmacokinetics and toxicity. Furthermore, lack of knowledge on the anatomical and physiological barriers in the body have hampered their clinical application. However, many problems have been solved, not in the least due to the advent of recombinant DNA technology to construct better defined carriers that can be produced in large amounts, and advanced pharmaceutical formulation technology. Similarly, the rapid developments in molecular biology, cell biology and immunology led to a better understanding of the processes taking place in vivo upon administration of carriers and conjugates. Only a few polymer or protein based drug targeting strategies have successfully reached the clinic and an important question in the coming years will be whether these strategies eventually will reach the international drug market. All will depend on their effectiveness and improved toxicity profiles as compared to free drug only and the ease of their production at large scale. Furthermore, it should be pointed out that the most promising drug carrier devices have been liposomes and biodegradable polymeric nanoparticles, being targeted to various bodily parts, mainly using the active drug targeting strategy via antibodies. An important and novel area to be considered in drug targeting is conditional gene expression, which could be regarded as the control of protein delivery from within cells. The key to this strategy in the future will be to regulate gene expression engineered promoters. Regulatory systems could be designed, from individual regulatory elements, to promote expression in the presence of specific transcription factors which are over-expressed in tumors. This requires detailed knowledge of the control of gene expression in different tumor types. The design of specific promoters from scratch is not a realistic prospect at present. There is not enough knowledge on how different regulatory elements combine and how they need to be structured to achieve specificity. At present interest is focused on promoters of genes which are known to be over-expressed in tumors. The literature on this subject is expanding rapidly, and offers a better approach to cancer gene therapy than the use of viral promoters. When viral vectors are used for cancer gene therapy, the control of viral replication within tumors could offer a complementary level of specificity, provided targeted replication can be achieved safely. The Copyright © 2007 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services Iranian Journal of Pharmaceutical Research (2007), 6 (3): 149-150

Delivery of drugs into the brain is one of the most interesting and challenging areas of research. The blood-brain barrier (BBB) is a highly selective semipermeable membrane that separates blood from the brain in the central nervous system. It acts as a barrier to protect the brain from microbes, neurotoxins and other chemical substances and also blocks the entry of many drugs into the brain. An estimated 6.8 billion people die every year from CNS diseases like Parkinson’s disease, Alzheimer’s disease, sclerosis, brain stroke, dementia and others. According to WHO, one billion people are affected worldwide, about 50 million suffer from epilepsy and 24 million suffer from Alzheimer and other dementias. This indicates the importance of the delivery of drugs into the brain for treating various neurological diseases and psychological disorders. In drug targeting, a concept was introduced by Dr. Paul Ehrlich as a ‘magic bullet’ that gave tremendous hope for the researches to deliver drugs into the brain. This review discuses about various drug targeting strategies and applications of nanotechnology in designing drug delivery systems with the ability to cross through the BBB for treating neurological diseases.

Drug targeting to the kidney with low-molecular-weight proteins

Nanoparticle design characterized by In Silico preparation parameter prediction using ensemble models

Breast cancer accounts for approximately 25% of cancer cases and 16.5% of cancer deaths in women, and the World Health Organization predicts that the number of new cases will increase by almost 70% over the next two decades, mainly due to an ageing population. Effective diagnostic and treatment strategies are, therefore, urgently required for improving cure rates among patients since current therapeutic modalities have many limitations and side effects. Nanomedicine is evolving as a promising approach for cancer management, including breast cancer, and various types of organic and inorganic nanomaterials have been investigated for their role in breast cancer diagnosis and treatment. Following an overview on breast cancer characteristics and pathogenesis and challenges of the current treatment strategies, the therapeutic potential of biocompatible organic-based nanoparticles such as liposomes and polymeric micelles that have been tested in breast cancer models are reviewed. The efficacies of different drug delivery and targeting strategies are documented, ranging from synthetic to cell-derived nanoformulations together with a summary of the interaction of nanoparticles with externally applied energy such as radiotherapy. The clinical translation of nanoformulations for breast cancer treatment is summarized including those undergoing clinical trials.

Brain distribution spaces of mannitol-3H, inulin-14C, and dextran-14C in the rat.

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer include chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from the treatment and improve the quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allow passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer.

The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle- and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB. This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle- and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy.

Neuroinflammation is one of the major pathogeneses in Alzheimer's disease (AD) and mainly involves abnormal inflammatory activation of microglia by multiple pathological stimuli. The treatment of AD remains a major challenge due to the multifactorial characterization of AD and the inefficient ability of therapeutic drugs to permeate through the blood‒brain barrier (BBB). Accordingly, drug combination treatment and drug carrier delivery have become important therapeutic tools for the treatment of multifactorial diseases, especially AD. Inflammatory cytokine levels in microglia, including NO, TNF-α, IL-1β, IL-4, and IL-10, were detected. The Morris water maze and object location task were used to investigate the learning and memory functions of APP/PS1 mice in different treatment groups. The number of neurons and plasticity of synapses were evaluated by immunofluorescence double labelling. Additionally, the ratio of β-amyloid plaques and the number of activated microglia were evaluated by immunofluorescence staining. The concentrations of β-amyloid plaques and inflammatory factors in the hippocampus were determined by ELISA. Microglia-derived exosomes (Exos) were extracted and purified by size exclusion chromatography. The distribution of exosomes and drugs was investigated in vitro and in vivo. Compared to single drug interventions, the combination of Ber and Pal (Ber/Pal) modulated microglial inflammatory cytokine levels. Ber/Pal promoted the recovery of learning and memory impairment in APP/PS1 mice. Immunofluorescence staining indicated that Ber/Pal restored neurons, inhibited Aβ plaque formation and microglial activation, and regulated the secretion of inflammatory factors. Exos promoted the accumulation of drugs in cells and tissues and improved the targeting of drugs across the BBB. Ber/Pal could offer a synergistic and more comprehensive therapeutic effect in AD. Additionally, the microglia-derived Exos-Ber/Pal delivery system promoted the targeting and permeation of drugs into the brain, suggesting a creative strategy for targeting AD therapy by regulating neuroinflammation in microglial cells.

Determinants of drug delivery and transport to solid tumors

Engineered nanoparticles that can facilitate drug formulation and passively target tumours have been under extensive research in recent years. These successes have driven a new wave of significant innovation in the generation of advanced particles. The fate and transport of diagnostic nanoparticles would significantly depend on nonselective drug delivery, and hence the use of high drug dosage is implemented. In this perspective, nanocarrier-based drug targeting strategies can be used which improve the selective delivery of drugs to the site of action, i.e. drug targeting. Pharmaceutical industries majorly focus on reducing the toxicity and side effects of drugs but only recently it has been realised that carrier systems themselves may pose risks to the patient. Proteins are compatible with biological systems and they are biodegradable. They offer a multitude of moieties for modifications to tailor drug binding, imaging or targeting entities. Thus, protein nanoparticles provide outstanding contributions as a carrier for drug delivery systems. This review summarises recent progress in particle-based therapeutic delivery and discusses important concepts in particle design and biological barriers for developing the next generation of particles drug delivery systems.

Entry of blood circulating agents into the brain is highly selectively con-trolled by specific transport machineries at the blood brain barrier (BBB), whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Brain capillary endothelial cells (BCECs) form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics). The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.