Brain targeting PBCA nanoparticles and the blood–brain barrier

Abstract

NanomedicineVol. 4, No. 5 EditorialFree AccessBrain targeting PBCA nanoparticles and the blood–brain barrierB WilsonB WilsonDepartment of Pharmaceutics, Dayananda Sagar College of Pharmacy, Kumaraswamy layout, Bangalore 560078, India. Search for more papers by this authorEmail the corresponding author at b_wilson@rediffmail.comPublished Online:3 Jul 2009https://doi.org/10.2217/nnm.09.29AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The brain is quite unique from other organs of the body. Despite enormous advances in brain research, CNS brain disorders still remain accountable for a high number of hospitalizations requiring prolonged care. It is estimated that approximately 1.5 billion people worldwide are suffering from various CNS disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-dementia and stroke, among others. In recent years, the explosion of interest in the biological aspects of CNS disorders as well as the brain has led to an improvement in the understanding and the treatment of these diseases; however, they still remain chronic and debilitating disorders for many patients. As demographic trends show an increase in the percentage of elderly people in the population, diseases of the brain are becoming a major health problem. It is expected that the number of cases of CNS diseases will be around 1.9 billion by 2020 [1]. Despite these challenges, brain drug targeting plays a vital role and gives tremendous hope for the treatment of these disorders. This area of study is fascinating as well as challenging to the scientists who are in this domain.Brain drug targetingDrug targeting is the delivery of drugs to receptors, organs or any other specific part of the body to which one wishes to deliver the drug exclusively. The concept of drug targeting was first perceived by Paul Ehrlich, who proposed drug delivery to be like a ‘magic bullet’, where a drug–carrier complex/conjugate delivers drug(s) exclusively to the preselected target cells in a specific manner. The blood–brain barrier (BBB) has always presented a challenge to scientists for brain drug targeting. The BBB has evolved in such a way that it protects the brain from various foreign substances such as neurotoxins. This mechanism makes the BBB an insurmountable barrier for numerous highly essential drugs, including antibiotics, cytostatics and other CNS-active drugs.The BBB as a barrier for brain targetingThe BBB, a mechanical membrane that separates blood from the brain, was first proposed at the beginning of the 20th century by Lewandowsky [2] and this view was later confirmed. The BBB consists of endothelial cells connected by complex tight junctions, and a pool of enzymes, receptors, transporters and efflux pumps of multidrug resistance pathways. Endothelial cells of brain capillaries have fewer pinocytotic vesicles and more mitochondria than those of capillaries elsewhere in the body. They lack fenestrations and inter-endothelial passages. Microvessels make up an estimated 95% of the total surface area of the BBB, and represent the principal route by which substances enter the brain. Vessels in the brain were found to have smaller diameters and thinner walls than vessels in other organs. As a result, most CNS-active drugs are unable to reach the brain in therapeutically active concentrations.PBCA nanoparticles for brain targetingMany strategies have been developed to overcome the hurdles caused by the BBB. They include both invasive and noninvasive approaches. The invasive approaches include the temporary disruption of the BBB, which allows the entry of drugs to the brain, and direct drug delivery to the brain by means of intraventricular or intracerebral injections, and intracerebral polymeric implants. The noninvasive approaches use colloidal drug carriers. Among the noninvasive approaches, polymeric nanoparticles, especially poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80, have recently received much attention from neuroscientists as an attractive and innovative carrier for brain targeting. These nanoparticles may be defined as ‘a submicron drug-carrier system, which are generally polymeric in nature’. Since nanoparticles are small in size, they easily penetrate into small capillaries and can be taken up within cells, allowing efficient drug accumulation at targeted sites in the body. The first reported nanoparticles were based on nonbiodegradable polymeric systems. Their use for systemic administration, however, could not be considered because of the possibility of chronic toxicity due to the tissue and immunological response towards the nondegradable polymer. Hence, nanoparticles prepared with biodegradable polymers such as poly(cyanoacrylate) were exclusively studied. The use of biodegradable materials for nanoparticle preparation allows sustained drug release at the targeted site over a period of days or even weeks after injection.Poly(cyanoacrylate) nanoparticles were first prepared by Couvreur et al. in 1979 [3]. PBCA nanoparticles are considered to have relatively low toxicity, and, moreover, PBCA is among the most rapidly biodegrading synthetic polymers. PBCA nanoparticles undergo in vivo degradation by enzymatic ester hydrolysis, producing a primary alcohol, butanol and water-soluble poly(2-cyanoacrylic acid). As a result of this rapid degradation, as well as the low molecular weight of the polymer in the nanoparticle, the polymer material is rapidly eliminated from the body. The main advantages of using nanoparticles for brain drug targeting include their ability to deliver drugs to the brain without changing the drug’s original characteristics, as well as to decrease drug escape in the brain and reduce peripheral toxicity.Although Speiser had the idea of using nanoparticles for brain targeting in 1980 [4], the use of polysorbate 80-coated nanoparticles for drug delivery into the brain was initiated from the findings of Tröster et al. in 1990 [5]. It was observed that coating of 14C-labeled poly(methylmethacrylate) nanoparticles with various surfactants, including polysorbate 80, significantly increased the concentration of nanoparticles in the brain after intravenous injection in rats. Later, the role of polysorbate 80 was confirmed by in vitro bovine microvessel endothelial cell culture studies and polysorbate 80 was considered as a potential substance for brain targeting. Since then, many drugs have been delivered into the brain using PBCA nanoparticles coated with polysorbate 80. The first drug transported across the BBB using nanoparticles was a hexapeptide, dalargin. Intravenous injection of dalargin bound to polysorbate 80-coated nanoparticles led to dose-and time-dependent antinociceptive effects [6]. Other drugs that have been transported across the BBB using polysorbate 80-coated PBCA nanoparticles include the dipeptide kytorphin, loperamide, tubocurarine, MRZ 2/576 (NMDA-receptor antagonist), doxorubicin, tacrine and rivastigmine, among others. Recently, studies led by Steiniger et al.[7] clearly demonstrated the effectiveness of nanoparticles for drug delivery to the brain. Their results showed that doxorubicin bound to polysorbate 80-coated PBCA nanoparticles produced a high antitumor effect against an intracranial glioblastoma in rats.Mechanism of PBCA nanoparticle-mediated drug delivery into the brainAlthough the exact mechanism behind the delivery of drugs into the brain using polysorbate 80-coated PBCA nanoparticles is not fully understood, several mechanisms have been proposed for the transport of these nanoparticles across the BBB. The need for polysorbate 80 coating for delivery has been explained by the fact that drugs bound with PBCA nanoparticles without polysorbate 80 coating showed no pharmacological effects. Kreuter has given a number of possible mechanisms that could explain the mechanism of drug delivery across the BBB [8]. The mechanism of endocytosis was supported by many studies. This mechanism suggests that PBCA nanoparticles coated with polysorbate 80 adsorb ApoE and/or B from the blood after injection. ApoE plays a vital role in the transport of low-density lipoprotein into the brain. Polysorbate 80 acts mainly as an anchor for the apolipoprotein-coated nanoparticles. Therefore, the nanoparticles mimic low-density lipoproteins and interact with the brain capillary endothelial cells, finally transferring the drug into the brain via receptor-mediated endocytosis. Alternatively, Olivier et al. suggested that the targeting efficiency of the particles is related to the disruption or opening of the BBB, which is probably caused by the toxic effects of the PBCA nanoparticle degradation products on the BBB [9]. However, this concept of the opening of the BBB due to the toxicity of the degraded products of polysorbate 80-coated PBCA nanoparticles was later disproved through in vitro and in vivo studies. Further studies were carried out by attaching ApoE to human serum albumin nanoparticles via an avidin/biotin linker. This system, when loaded with loperamide, produced a dose-dependent analgesic effect, which explains the role of ApoE in brain drug transport [10]. A recent study examined the effectiveness of other apolipoproteins such as ApoE3, B-100 and A-I in brain targeting. The apolipoproteins were coupled to the human serum albumin nanoparticles by direct covalent coupling and that could achieved comparable pharmacological effects [11]. This shows the existence of more than one nanoparticle–brain endothelium interaction mechanism. But the fact is that none of the aforementioned mechanisms are either fully accepted or rejected. Hence, further studies are required to come to a final conclusion regarding the mechanism of drug transport to the brain using PBCA nanoparticles.Issues related to brain drug targetingThe major issue for brain drug targeting is the BBB. In the case of CNS drug development, the BBB has been called “the problem behind the problem” [12]. In consequence of the BBB, the pharmacological activities of more than 98% of potentially active therapeutic agents used to treat CNS disorders are diminished [13]. Drug delivery to the brain requires advances in both drug discovery and brain drug targeting. The recent remarkable market growth of CNS drugs has created many research programs to develop new drugs for brain diseases. But the irony is that most of the CNS research is focused on drug discovery rather than drug-delivery technologies and approximately 1% of pharmaceutical companies worldwide have a BBB drug targeting program [14]. Currently, the global market for CNS treatments is steadily increasing and is expected to reach beyond US$75.3 billion in 2010 and $102 billion in 2015 [15]. As the global market for pharmaceuticals to treat CNS disorders is one of the largest pharmaceutical therapeutic areas, it is the right time for pharmaceutical companies to take steps to initiate BBB drug targeting programs. Even though PBCA nanoparticles are considered to be less toxic, it appears that the toxicity of degraded products, especially in the brain environment, has not been fully elucidated. Other major issues are: ▪ The feasability of large-scale industrial production, as well as further coating with polysorbate 80▪ The chance of drug leakage in the medium during the process of coating▪ Sterilization▪ Cost–effectivenessThe ability of PBCA nanoparticles to sustain drug release is also important. It is indicated that PBCA nanoparticles release most of their content within 24 h. As brain-related diseases require longer time periods to cure, repeated intravenous injections may lead to poor compliance. The possibility of brain drug targeting using polysorbate 80-coated PBCA nanoparticles by an oral route has been studied by a few authors. Preliminary studies indicate some promising results [16], but this area has not been fully explored. If oral brain drug targeting becomes a reality it will be a major scientific achievement as it will enable higher patient compliance.ConclusionThere is no doubt that the BBB currently represents an insurmountable barrier for brain drug targeting. Recent lifestyle changes pave the way for an increase in neurodegenerative disorders. This highlights the paramount importance of studies into brain drug targeting. In summary, the application of nanoparticles, especially polysorbate 80-coated PBCA nanoparticles, to target drugs in the brain is extremely promising. If drug delivery to the brain is achieved by nanoparticles, then it will be possible to reformulate and deliver promising CNS-active drugs that are currently unable to cross the BBB into the brain. Although this still remains a challenge, we can now see the light at the end of the tunnel.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Pardridge WM: Brain Drug Targeting: The Future of Brain Drug Development. Cambridge University Press, Cambridge, UK (2001).Google Scholar2 Lewandowsky M: Zur lehre der cerebrospinalflussigkeit. Z. Klin. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download