Brain-specific Drug Delivery Research Articles

Unlocking Dendrimers Future Potential for Brain-Specific Drug Delivery in Cerebroanoreach

The Blood-Brain Barrier (BBB) makes it extremely difficult to get drugs to the brain, yet highly branching macromolecules known as dendrimers show a lot of promise in this regard. This review delves into the current and future prospects of dendrimers in facilitating brain-specific drug delivery within the framework of cerebroanoreach. The unique structural features of dendrimers allow for precise regulation of surface function, size, and shape, which are critical for targeting specific cell types in the brain and increasing blood-brain barrier permeability. Second, they can be conjugated with imaging agents, peptides, or pharmaceuticals thanks to their versatile surface chemistry, which enhances diagnostic capabilities and treatment efficacy. Recent advances in nanoformulations based on dendrimers have demonstrated promising improvements in the solubility, stability, and bioavailability of medications, suggesting their possible use in therapeutic contexts. Various obstacles, such as toxicity profiles and production bottlenecks that require scaling up are also addressed, with a focus on ongoing research projects and potential remedies. One potential solution to the problems with cerebroanoreach is the use of dendrimers for brain-specific drug delivery; this could revolutionize the treatment of neurological diseases and the precision of neurology diagnostics. By synthesizing current knowledge and future directions, this review urges the continuance of interdisciplinary collaboration, which is crucial for fully realizing the potential of dendrimers in neuroscience and therapeutic innovation.

Star-polymer unimolecular micelle nanoparticles to deliver a payload across the blood-brain barrier.

Nanocarrier-mediated therapeutic delivery to brain tissue is impeded by tightly controlled transportation across the blood-brain barrier (BBB). Herein, we report a well-defined core-shell star-shaped unimolecular micelle (star-UMM; a single polymer entity) as an efficient BBB-breaching nanoparticle for brain-specific administration of the fluorescent anticancer drug doxorubicin and in vivo mapping of brain tissues by the near-infrared biomarker IR780 in mice. The star-UMM was engineered by precisely programming the polymer topology having hydrophobic and hydrophilic polycaprolactone blocks and in-built with lysosomal enzyme-biodegradation stimuli to deliver the payloads at intracellular compartments. In vivo imaging in mice revealed prolonged circulation of star-UMM in blood for >72 h, and whole-organ image-quantification substantiated its efficient ability to breach the BBB. Star UMM exhibited excellent stability in blood circulation and reduced cardiotoxicity, was non-hemolytic, had substantial uptake in the cortical neurons of the mouse brain, had lysosomal enzymatic-biodegradation, and exhibited negligible immunogenicity or necrosis. This newly designed star-UMM could have long-term applications in brain-specific drug delivery.

Dual-targeting for brain-specific drug delivery: synthesis and biological evaluation

Ibuprofen is one of the most potent non-steroid anti-inflammatory drugs (NSAIDs) and plays an important role in the treatment of neurodegenerative diseases. However, its poor brain penetration and serious side effects at therapeutic doses, has hindered its further application. Thus, it is of great interest to develop a carrier-mediated transporter (CMT) system that is capable of more efficiently delivering ibuprofen into the brain at smaller doses to treat neurodegenerative diseases. In this study, a dual-mediated ibuprofen prodrug modified by glucose (Glu) and vitamin C (Vc) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to brain. Ibuprofen could be released from the prepared prodrugs when incubated with various buffers, mice plasma and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vitro and in vivo than ibuprofen. Our results suggest that chemical modification of therapeutics with warheads of glucose and Vc represents a promising and efficient strategy for the development of brain-targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads.

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH-dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0−t and Cmax in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter.

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier.

Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included.

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

Despite advances in pharmacotherapy, schizophrenia continues to carry a high societal disease burden related to positive and negative symptoms, and neurocognitive deficits and severe functional impairment. Findings from epigenetics have yet to translate the epigenetics targets to efficacious drug therapy. We review the repertoire of CNS pharmacology of curcumin derived from Curcuma Longa, commonly known as “turmeric”: the well-known curry extract. We highlight the body of evidence in support of the emerging role of curcumin as a panhistone deacetylase (HDAC) inhibitor regulating the expression of genes involved in inflammation and NMDA N-methyl-aspartic acid (NMDA)-glutamate systems, as related to schizophrenia. Based on the findings from translational studies of curcumin extracts, curcumin C-3 complex formulation (Supercurcumin™) and patented liposome-based curcumin (Lipocurc™), we propose that intravenous infusion of Lipocurc™ holds promise as the novel drug lead and preferred targeted brain delivery mode in reprogramming faculty epigenetics network and in remodeling restrictive chromatin configuration in schizophrenia. Phase II/Phase III epigenetics-biomarker-based randomized placebo-controlled trials in treatment resistant schizophrenia are warranted. Our approach of intravenous infusion of Lipocurc™ behaving as pan HDAC inhibitor represents a new paradigm of drug development in combining targeting epigenetics footprints with brain-specific drug delivery system in schizophrenia. Lipocurc™ can open the Pandora box in unexplored therapeutics vistas in modifying the phenotype of treatment resistant schizophrenia.

Phage-displayed peptide-conjugated biodegradable nanoparticles enhanced brain drug delivery

Drug distribution to the brain is one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the presence of the blood-brain barrier (BBB). To enhance brain-specific drug delivery, a cyclic peptide CRTIGPSVC selectively interacting with apo-transferrin (apo-Tf), was modified to the surface of poly (ethyleneglycol)–poly (lactide acid) (PEG-PLA) nanoparticles to yield a novel delivery system (Pep-NP). The in vitro cytotoxicity of the delivery system was low. The cellular uptake of Pep-NP was significantly higher than that of NP. Following intravenous administration, much more notable fluorescence was found in the mice brains with Pep-NP than NP. The results indicated the cyclic peptide modified nanoparticles system had great potential in drug delivery across the BBB, thus providing a safe approach for brain targeting.

The role of autophagy in the neurotoxicity of cationic PAMAM dendrimers

Poly(amidoamine) (PAMAM) dendrimers, are among the most common classes of dendrimers that are intended for a wide range of biomedical applications and extensively investigated for brain-specific drug delivery, imaging and diagnosis. Unfortunately, neurotoxicity of PAMAM dendrimers, the underlying mechanism of which is poorly-elucidated, poses a far-reaching challenge to their practical applications. In this study, we reported that PAMAM dendrimers induced both cytotoxicity and autophagic flux in a panel of human glioma cell lines. Meanwhile, inhibition of autophagy significantly reversed cell death caused by PAMAM dendrimers, indicating the cytotoxic role of autophagy in neurotoxicity caused by PAMAM dendrimers. Akt/mTOR pathway was most likely to participate in initiation of PAMAM dendrimers-induced autophagy. Moreover, autophagy induced by PAMAM dendrimers might be partially mediated by intracellular ROS generation. Collectively, these data elucidated the critical role of autophagy in neurotoxicity associated with exposure to cationic PAMAM dendrimers in vitro, raising concerns about possible neurotoxic reaction caused by future clinical applications of PAMAM dendrimers and providing potential strategies to ameliorate toxic effects of PAMAM dendrimers.

Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease.

ABSTRACTCryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1’s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.

Facilitated brain delivery of poly (ethylene glycol)–poly (lactic acid) nanoparticles by microbubble-enhanced unfocused ultrasound

Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis, but is highly limited by the existence of blood–brain barrier (BBB). In this study, microbubble-enhanced unfocused ultrasound (MEUUS) was developed as an approach to mediate an extensive brain delivery of poly (ethylene glycol) – poly (lactic acid) (PEG–PLA) nanoparticles. Following the MEUUS treatment, the nanoparticles signals were found to penetrate through the vascular walls and distributed deeply into the parenchyma at a significantly higher level (more than 250%) than those of the non-MEUUS treated control. Such effect was reversible and dependent on nanoparticles injection timing, sonication mode and mechanical index. Together with the transmission electron microscopy analysis, the increased brain accumulation of nanoparticles was claimed to be largely mediated by an ultrasound-induced stable cavitation of the microbubble which resulted in mechanical stretching of the vessel wall and consequently induced cellular transcytosis of the nanoparticles. The MEUUS technique was also used to facilitate the brain delivery of PEG–PLA nanoparticles functionalized with amyloid beta-specific antibody 6E10 for enabling the recognition of the hallmarks of Alzheimer's disease that widely distributed in the brain. No erythrocytes extravasation and other visible damages in the brain were detected following the MEUUS treatment. These findings together indicated that unfocused ultrasound with the aid of microbubble could effectively improve the brain delivery of nanoparticles, and this approach might serve as a safe and flexible platform for the potential application of nanoparticles in the diagnosis and therapy of brain diseases.

Development and characterization of glutathione-conjugated albumin nanoparticles for improved brain delivery of hydrophilic fluorescent marker

The glutathione-conjugated bovine serum albumin (BSA) nanoparticles were constructed in the present exploration as a novel biodegradable carrier for brain-specific drug delivery with evaluation of its in vitro and in vivo delivery properties. BSA nanocarriers were activated and conjugated to the distal amine functions of the glutathione via carbodiimide chemistry using EDAC as a mediator. These nanoparticles were characterized for particle shape, average size, SPAN value, drug entrapment and in vitro drug release. Further, presence of glutathione on the surface of BSA nanoparticles was confirmed by Ellman’s assay, which has suggested that approximately 750 units of glutathione were conjugated per BSA nanoparticle. To evaluate the brain delivery properties of the glutathione-conjugated BSA nanoparticles fluorescein sodium was used as a model hydrophilic compound. Permeability and neuronal uptake properties of developed formulations were evaluated against the MDCK-MDR1 endothelial and neuro-glial cells, respectively. The permeability of glutathione-conjugated BSA nanoparticles across the monolayer of MDCK-MDR1 endothelial tight junction was shown significantly higher than that of unconjugated nanoparticles and fluorescein sodium solution. Similarly, glutathione-conjugated nanoparticles exhibited considerably higher uptake by neuro-glial cells which was inferred by high fluorescence intensity under microscope in comparison to unconjugated nanoparticles and fluorescein sodium solution. Following an intravenous administration, nearly three folds higher fluorescein sodium was carried to the rat brain by glutathione-conjugated nanoparticles as compared to unconjugated nanoparticles. The significant in vitro and in vivo results suggest that glutathione-conjugated BSA nanoparticles is a promising brain drug delivery system with low toxicity.

Targeting the brain with PEG–PLGA nanoparticles modified with phage-displayed peptides

The relative impermeability of the blood-brain barrier (BBB) results from tight junctions and efflux transport systems limits drug delivery to the central nervous system (CNS), and thus severely restricts the therapy of many central nervous system diseases. In order to enhance the brain-specific drug delivery, we employed a 12-mer phage display peptide library to isolate peptides that could target the drug delivery system to the brain. A 12-amino-acid-peptide (denoted as Pep TGN) which was displayed by bacteriophage Clone 12-2 was finally selected by rounds of in vivo screening. Pep TGN was covalently conjugated onto the surface of poly (ethyleneglycol)-poly (lactic-co-glycolic acid) (PEG–PLGA) based nanoparticles (NPs). The cellular uptake of Pep TGN decorated nanoparticles was significantly higher than that of unmodified nanoparticles when incubated with bEnd.3 cells. Enhanced brain accumulation efficiency together with lower accumulation in liver and spleen was observed in the nude mice intravenously injected with Pep TGN conjugated nanoparticles compared with those injected with plain nanoparticles, showing powerful brain selectivity of Pep TGN. Coumarin 6 was used as a fluorescent probe for the evaluation of brain delivery properties. The brain Drug Targeting Index (DTI) of coumarin 6 incorporated in targeted nanoparticles was significantly higher than that of coumarin 6 incorporated in plain nanoparticles. In conclusion, the Pep TGN is a motif never been reported before and Pep TGN modified nanoparticles showed great potential in targeted drug delivery across the blood brain barrier.

Nanoparticle-Mediated Brain-Specific Drug Delivery, Imaging, and Diagnosis

Central nervous system (CNS) diseases represent the largest and fastest-growing area of unmet medical need. Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis. With the aid of nanoparticles of high specificity and multifunctionality, such as dendrimers and quantum dots, therapeutics, imaging agents, and diagnostic molecules can be delivered to the brain across the blood-brain barrier (BBB), enabling considerable progress in the understanding, diagnosis, and treatment of CNS diseases. Nanoparticles used in the CNS for drug delivery, imaging, and diagnosis are reviewed, as well as their administration routes, toxicity, and routes to cross the BBB. Future directions and major challenges are outlined.

ダイナミックインターフェースとしての血液脳関門機能と薬物脳移行相関

Lipophilicity and molecular weight have long been believed to be determinants of the transfer of drugs into the central nervous system(CNS) across the blood-brain barrier(BBB), which is formed by the brain capillary endothelial cells (BCECs). However, recent advances in studies on the BBB transport of xenobiotics, as well as nutrients and neuroactive agents, have led to a change in our concept of the BBB. It is no longer regarded as a static lipoidal membrane harrier of endothelial cells which have tight junctions without fenestrations, but rather is censidered to be a dynamic interface which has physiological functions for the specific and selective membrane transport of many compounds, as well as degradative enzyme activities. It has carrier-mediated transport systems for relatively small molecules, an absorptive-mediated endocytosis system for positively charged peptides and a receptor-mediated endocytosis system specific to certain other peptides. The recent discovery of P-glycoprotein as a specific efflux pump in addition to the above influx systems confirmed the idea that the BCECs form a well organized barrier that by actively and selectively controls the influx and efflux of compounds. From the viewpoint of drug delivery, although an increase in the lipophilicity of compounds is useful to enhance the permeation across the BBB, such a strategy would also increase the permeation into tissues other than brain. Accordingly, for the development of brain-specific drug delivery systems for neuroactive compounds, it is important to understand and utilize the specific transport mechanisms of the BCECs. Here I describe the physiological and molecular characterization of the transport mechanisms of the BBB for natural compounds, as well as bioactive xenobiotics.

Drug delivery to the brain utilizing blood-brain barrier transport systems

The importance of the blood-brain barrier (BBB) transport system in drug delivery to the brain has been discussed. Carrier-mediated transport systems of monocarboxylic acid, amine and neutral amino acid at the BBB could be utilized as pathways for acidic, basic and amphoteric drug delivery, respectively. For peptide drug delivery, the transcytosis system would be a useful pathway. Especially by introducing the basic amino acids, arginine and lysine, to the peptide molecule, the possibilities of electrostatic interaction between the positively charged moiety of the peptide and the negatively charged region of the surface of the brain capillaries would be increased, resulting in the facilitation of an absorptive-mediated transcytosis. Further understanding of the various transport systems of nutrients and drugs among the BBB and peripheral organs would help provide more rational strategies for the brain-specific drug delivery design.

Correlation between hydride transfer and one-electron oxidation of dihydropyridines and heterocycles

The 1,4-dihydrotrigonelline amides and esters are extensively used for brain-specific drug delivery. Oxidation of the dihydropyridine to a quaternary salt is the key step in this process. Water addition across the 5,6-double bond in these dihydropyridines is an unwanted, irreversible reaction. All these processes were studied theoretically, using MNDO/2. It was found that the oxidation process is very sensitive to substituents, like 6-methyl. An excellent correlation between the hydride removal vs. one-electron oxidation (both adiabatic and vertical I p- s) was found. The water addition is not affected sterically by the 6-substituent, as the protonation of the enamine system on C 5 is the rate determining step. The calculations were extended to pyridazines and 1-benzyldihydroisonicotinamide. All results are in very good agreement with experimental evidence and suggest that calculations of this kind can effectively predict the various rate processes involved in this chemical drug delivery system.

A MINDO/3 study of a substituted benzo[b] isoquinolizinium salt ⇆ benzo[b] quinolizine system

Dihydropyridine ⇆ pyridinium salt redox systems of biologically important molecules were studied using a MINDO/3 technique. The systems investigated broadly resembled many pharmacologically-active agents which are applicable to brain specific drug delivery. In particular a model for the protoberbine anticancer alkaloid berberine was considered. Optimized geometries, charge densities and other molecular properties were generated for the model and this information was compared to a simple pyridinium salt ⇆ dihydropyridine system. These values were found to correlate well with experimental chemical and biological data.