Nanotherapeutic Strategies and New Pharmaceuticals: Part II E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2006
Advances in technology have enabled medicinal chemists to discover and formulate several highly specific, biocompatible, and non-toxic therapeutic agents for clinical applications. Nanotechnology has achieved significant progress in the last few decades and is crucial in every field of science and technology. Nanotechnology-based pharmaceuticals offer multifaceted and alternative methodologies in comparison to the limitations of many conventional clinical therapies. Expertise in designing and developing nanoformulations has helped in targeted drug delivery. Recently, the use of innovative therapeutic agents, particularly in nanomedicine, has accounted for a significant portion of the global pharmaceutical market and is predicted to continue to grow rapidly in the near future. Nanotherapeutic Strategies and New Pharmaceuticals is an accessible multi-part reference which informs the reader about several new techniques based on nanotechnology. The chapters explain relevant topics in detail. The book is designed to encourage and help undergraduate, graduate and post-graduate students in the field of nanotherapeutics, pharmaceuticals and bio-organic chemistry through the use of didactic language and simple illustrations. Part 2 of this book covers the potential of nanotherapeutics and natural therapies for treating neurological diseases, targeting ion channels, signal transduction therapy, gene therapy of single gene mutation diseases and for nanoformulations for special purposes such as wound healing and stimuli-responsive drug delivery. The book also features a chapter that summarizes the types of nanoparticles tailored for specific molecular targets that mediate different diseases. The book set serves as a textbook for students in pharmacology and medical biochemistry, as well as a quick reference for researchers on bio-organic chemistry, as well as general readers interested in nanomedicine.
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PREFACE
Dr. Shahid Ali KhanThe field of nanotechnology evolved as a discipline and is not a mere specialization. It requires multiple fields such as engineering, physics, chemistry, mathematics, medicine, and pharmacy to be integrated. This book provides a quick review of the practical aspects of these diverse arenas. Advances in nanotechnology have increased the feasibility to tailor the functional modalities that assist in targeting selective biological barriers for drug delivery and other biomedical applications. This book provides knowledge to the students interested in nanotechnology research. This book paves a path between pharmacy and nanoscience while striking an equilibrium between approachability and depth.
All the editors of this book have research collaborations with various local and international universities in the field of nanoscience. They had supervised M. Phil and Ph.D. students in the field of nanoscience and pharmaceutical technology. They had published manuscripts on nanotechnology in Advanced Drug Delivery Reviews and other prestigious journals.
Phoebe’s chapter discusses the role of the blood-brain barrier comprising of a highly selective semipermeable border of epithelial cells that shield the brain from substances that impede the transportation of drug delivery used to treat various neurological disorders. Bello et al. reported the molecular mechanisms underlying silver, gold, Iron Oxide, Titanium Dioxide, Cerium Oxide, Zinc Oxide, Nitric oxide-releasing nanoparticles’ therapeutic action in cancer, diabetes, bacterial, fungal, viral and inflammatory diseases. The mechanisms of anticancer activity of the nanoparticles ranging from ultra-structure disruption, generation of reactive oxygen species (ROS), induction of DNA damage, inactivation of proteins that regulate signaling pathways, inhibition of migration and angiogenesis as well as induction of apoptosis are debated. Fahad et al. described the delivery of plant-derived nanoparticles comprised of nano-hydrogels, emulsions, and liposomes to targeted sites for disorders of voltage-gated channels. Zubair et al. explained the synthesis techniques pertaining to polymeric injectable hydrogels to reach safely to the targeted site. Abid et al. elucidated the antimicrobial drug-loaded polymeric nanofibers for wound dressing. The technology such as electrospinning and characterization of nanofibers for the drug release, shape, surface quality, ability to endure mechanical shocks, antimicrobial activity, and in vivo wound healing effectiveness are also discussed. Fazle et al. discussed the techniques regarding the synthesis, characterization, and biosafety of flavonoid-loaded polymeric nanoparticles, liposomes, matrix systems, and micro-emulsions by ameliorating their pharmacological activity and reducing the side effects. Jawaria and Fahad et al., in the subsequent two chapters, had described the molecular mechanisms underlying the channelopathies caused by various genetic or acquired factors. Different neurological diseases such as migraine, epilepsy, small fiber neuropathy, paroxysmal pain disorder, dravet syndrome, and congenital insensitivity to pain are explained, and their gene therapy and editing are discussed.
The chapters of this book are written by scientists and researchers of specialized fields and overtly different scientific backgrounds, but everything boiled down to one common goal – Nanoscience. The tremendous consequence of the combined effort led to this book, “Nanotherapeutic strategies and new pharmaceuticals Part 2.”
About the Editors
Shahid Ali KhanShahid Ali Khan (Editor)
Shahid Ali Khan did his master of science (MSC) in 2010 in organic chemistry from Kohat University of Science and Technology, and Master of Philosophy (MPhil) in Natural Product and Medicinal Chemistry in 2014 from ICCBS Karachi and PhD in Nanocatalysis in 2017 from King Abdulaziz University, Saudi Arabia. Dr. Khan got the best PhD thesis award in natural sciences, awarded by King Abdulaziz University. Dr. Khan joined the University of Swabi as Assistant Professor in Feb. 2018 and still working in the same University. During his stay at the University of Swabi, Dr. Khan has supervised many MPhil, MSC and BS students. Currently, many students of Dr. Khan's research group are involved in the synthesis and designing of nanocatalyst and hydrogels for various technological applications. . Moreover, Dr. Khan is working on multi-dimensional projects including Natural product chemistry, medicinal chemistry, Nanocatalysis and self-assembled hydrogels for diverse applications. Dr. Khan is also involved in the designing and synthesis of thin films as solid support for the stabilization of zero-valent metal nanoparticles. Dr. Khan is teaching various courses in Organic Chemistry, Physical chemistry, and spectroscopy to BS, MS and PhD students.
In brief, Dr. Khan has published 62 publications with a cumulative impact factor of 260 and published 5 book chapters in various international journals of high repute.
Dr. Khan edited the book entitled “Nanotherapeutics strategies and new pharmaceuticals Part 1.
Saad Salman (Co-Editor)
Saad Salman is a Lecturer at the Department of Pharmacy, The University of Lahore (Islamabad Campus), teaching Undergraduate and Postgraduate students. He is a Certified Health Researcher from NIH, USA. He has over twenty-one International publications, two International books, two book chapters, and thirty abstracts published. He is the founder and CEO of Research and Publication Inc. provides solutions to research students. He had received numerous awards at various conferences. He is an active member of the American Society of Pharmacology and Experimental Therapeutics (ASPET), the American Pharmacist Association, and American Society of Consultant Pharmacists.
Youssef O. Al-Ghamdi (Co-Editor)
Youssef O. Al-Ghamdi received a bachelor’s degree in Chemistry from Umm AL-Qura University, Makkah, Saudi Arabia, in 2008. Dr. Alghamdi received his master’s degree in Organic Chemistry from King Khalid University, Abha, Saudi Arabia, in 2012, and the Ph.D. degree in Organic Chemistry, Polymers King Abdualaziz University, Jeddah, Saudi Arabia in 2018. He joined the College of Science at Al-Zulfi branch, Majmaah University, as the head of the chemistry department. Dr. Alghamdi heading several units such as Planning and Development, and Unit of Scientific Affairs. He is a member of the College Council, College of Science, Al-Zulfi, Majmaah University and a member of Labs and Facilities. Dr. Youssef O. Al-Ghamdi is involved in teaching various courses in Organic Chemistry, to BS and he has published 20 publications.
List of Contributors
Nanotherapeutics for Treatment of Neurological Disorders
Phoebe Wilson1,*Abstract
Our brains are undisputedly regarded as one of the most complex biological structures, therefore it is not surprising that there are challenges associated with the transportation of therapeutic agents across this organ. This may be attributed in large part to the blood-brain barrier (BBB), which maintains a very stable environment in order to sustain normal brain function. The blood-brain barrier is comprised of a highly selective semipermeable border of epithelial cells that shield the brain from unwelcome and invasive substances. It is so effective, however, that it impedes the transportation of drug delivery used to treat various neurological and cerebrovascular disorders, such as Parkinson’s Disease (PD), Alzheimer’s Disease (AD), stroke, and gliomas (tumors in the brain and spinal cord). Consequently, many central nervous system disorders are undertreated. Significant advances in nanotechnology have increased the feasibility for biomedical applications to the brain, as nanopharmaceuticals may be tailored with functional modalities that assist to target selective brain tissue.
1. INTRODUCTION
There is ample evidence to suggest that neurological disorders exist as one of the greatest threats to public health, with recent studies crediting them as the second leading cause of deaths [1]. The increase in patients diagnosed with disorders is contested by the growing demand for effective treatments, which are met with their own obstacles. One of the largest challenges for delivering therapeutic molecules is their inability to breach the blood-brain barrier (BBB). The BBB is formed as astrocytes wrap their “feet” around capillaries in the brain. The tight junctions situated between epithelial cells in the capillary wall, accompanied by the covering comprised of foot-like extensions of the astrocytes, form a barrier
that regulates the passage of most ions and molecules between the blood and the brain tissue.
If they were to traverse the brain freely, ions such as sodium (Na+) and potassium (K+) could hinder the transmission of nerve impulses. Water, glucose, oxygen, carbon dioxide and small, lipid-soluble molecules are able to diffuse across the barrier with ease. Delivery drugs need to be constructed with optimal lipid solubility in mind, however, this is not a simple feat. By increasing the lipophilicity of the drug through chemical modification, there is a potential risk for decreased systematic solubility, and so the desired pharmacokinetic result may not be obtained.
The introduction of nanotechnology and nanoscience has served as the driving force for developing new strategies to treat neurological conditions. Their ability to penetrate the blood-brain barrier is in large part due to their malleable nature, as they can be modelled into different morphological structures in order to reach their constituent targets. The size of these NPs often resembles biomolecules, which plays a key role in drug targeting. The basis for nanotechnological drug delivery calls for the use of a nanoscopic scale (or nanoscale) and a therapeutic agent, which serve to function as the nanocarrier and the ‘consignment’, respectively [2]. Both systems’ properties are contingent upon whether the drug absorbs into or conjugates to the external surface of the nanoparticle, or instead is enclosed within [2]. These modifications help to supplement blood-brain barrier entry and disease-targeting efficiency [3].
2. TRANSPORTATION MECHANISM
Although the blood-brain barrier provides an impermeable border to particular solutes, brain capillary endothelial cells are able to assist the transcapillary exchange of others. Vital substances such as glucose are able to pass through the barrier in order to facilitate the generation of adenosine triphosphate (ATP) and neurotransmitters. Molecules are able to enter the brain tissue in a paracellular manner, by means of passive diffusion or via solute carriers and vesicular transport, as exhibited in Fig. (1) [4].
2.1. Paracellular Transportation
Paracellular transport is characterized by the transfer of substances between adjacent epithelial cells [5]. Smaller, hydrophilic materials can passively penetrate the blood-brain barrier through paracellular pathways, while large molecules are restricted due to the tight junctions that are present [6]. For that reason, the majority of peptides, proteins, and other macromolecules are inhibited from traversing through. Consequently, many problems have arisen from synthesizing these molecules for oral absorption and delivery [5, 6].
2.2. Transcellular Passive Diffusion
Transcellular passive enables the interaction between small, hydrophobic molecules and the endothelium of the blood-brain barrier [4, 7]. Drug molecules are able to passively diffuse into the cellular membrane via transcellular diffusion. Unfortunately, not all small-scale and hydrophobic molecules are able to diffuse across the endothelial layer, thus prompting further research [8].
2.2.1. Transporters
Transporters are able to assist drug molecules throughout the course of receptor-mediated transcellular crossing [6], as they would otherwise be unable to progress through the blood-brain barrier [4]. In recent years, transporters have aided the bioavailability of nanotherapeutics (NTs) via both oral and non-oral distribution and together with NPs, can vastly improve the overall efficacy of drug delivery [9].
2.2.2. Transcytosis
Transcytosis is most commonly observed in epithelial cells and involves the transportation of macromolecules across the interior of the cell. Unlike other transport mechanisms, transcytosis facilitates larger molecules that ordinarily struggle to cross the blood-brain barrier [4]. The system is broken down into multiple steps: endocytosis, vesicular transferral, and exocytosis, and is able to operate in an adsorptive-mediated or receptor-mediated manner 10. Adsorptive-mediated transcytosis is present for positively-charged ions and macromolecules located on the endothelial cells’ periphery, whereas receptor-mediated transcytosis relies on one frequent pathway for transportation 4. Both methods have been utilised as a means for the successful delivery of NPs across the blood-brain barrier [4, 6].
3. NPs TYPES
There are several variations of NPs types, each of which boast their own unique pharmacodynamic characteristics. General guidelines recommend that NPs be non-toxic and biocompatible, while maintaining a diameter less than 100 nanometers (unless it is involved in cell-mediated transport) [11]. Any larger size may compromise the efficacy of the NPs due to the restricted nature of the extracellular space [4, 10]. Additionally, NTs should maintain limited aggregation or dissociation and prompt minimal drug alterations such as biochemical degradation. This section provides an overview of contrasting NPs types (Fig. 2-B), and inorganic NPs (Fig. 2-C).
Fig. (2)) Schematic illustration of various polymeric nanoparticles, inorganic nanoparticles, and lipid-based nanoparticles.3.1. Lipid-Based NPs
Lipid-based NPs are incredibly stable drug carriers that possess minimal toxicity when administered in vivo [12]. For that reason, they are regarded as one of the most promising candidates for successful drug delivery. Two of the most common types are solid lipid NPs (SLNs) and liposomes. Solid lipid NPs are composed of a solid lipid core that sustains a solid form both at room temperature and human body temperature [12]. Additionally, they have the capacity to absorb and disperse drugs, making them highly biocompatible and increasing their overall drug trapping capabilities [13]. Overall, SLNs provide many advantages, such as the ability to issue controlled drug release over a prolonged time period [14] (i.e. several weeks) as a result of the increased mass transfer resistance provided by the lipid’s solid structure [12, 13]. A recent application of solid lipid NPs uncovered its ability to enter a brain tumor when delivering resveratrol, a drug used to treat cancer [4, 15].
Liposomes are comprised of spherical sacs that encompass phospholipid molecules. Cholesterol is also commonly included in the fabrication of liposomes, as it has been demonstrated to contribute to the NPs’ stability in-vivo [16]. Liposomes range in size and lamellae count, and therefore classified under varying subcategories. Small unilamellar vesicles (SUVs) span up to 100 nanometers with one lipid bilayer, large unilamellar vesicles (LUVs) exceed 100 nanometers with one lipid bilayer, and multilamellar vesicles (MLVs) frequently surpass 500 nanometers in diameter and involve multiple concentric bilayers (Fig 3).
Fig. (3)) Classification of liposomes based on the lamellarity: Multilamellar Vesicles (MLV) are composed of many lipid bilayers and ranges from 1-5 µm in size. Large Unilamellar Vesicles (LUV) are in the size range of 100-250 nm with single lipid bilayer. Small Unilamellar Vesicles (SUV) consist of a single phospholipid bilayer surrounding the aqueous phase with a size range of 20-100 nm.Liposomal delivery of anticancer medication was the first nanotherapeutic method to be approved for cancer treatment by the Food and Drug Administration (FDA) [14]. Through modification of the liposome surface, it has demonstrated extreme effectiveness in breaching the blood-brain barrier. This is attributable to its likeness to the lipid bilayer of the endothelial cell membrane itself [17]. Liposomes ordinarily adopt either receptor-mediated transcytosis (RMT), or adsorptive-mediated transcytosis (AMT) to transport drug delivery across the blood-brain barrier.
3.2. Polymeric NPs
Polymeric NPs are subdivided into polymeric micelles, dendrimers, nanocapsules, and nanospheres. Micelles make up a collection of amphiphilic molecules that are dispersed in an aqueous solution [18]. Research has found micelles to be successful in crossing the blood-brain barrier in human astrocyte cell culture when conjugated to transcriptional activators peptides [19]. This same peptide has helped to facilitate selective brain penetration through adsorptive-mediated transcytosis (AMT), helping to concentrate the NPs within the astrocyte and around the neuron’s nucleus [19, 20]. Further research has affirmed the benefits of micelles usage, including the enhanced transportation of a drug into functional tissues including the caudate putamen, hippocampus, substantia nigra, and cortical layer of the brain [21].
Dendrimers are unique in that they consist of three domains: the core, radially concentric interior shells, and a multivalent exterior. Drug molecules are able to attach to the surface covalently to form dendrimer prodrugs or can become encapsulated internally through supramolecular formation [22]. Dendrimers are highly beneficial for transporting drugs on account of their low toxicity, high loading capabilities, and water solubility [23], which makes them easily malleable in response to their environment. Additionally, they have been adopted as a favourable method for penetrating cells within the neurovascular unit (NVU) through both neurosurgical and intravenous administration [24]. The composition of a polymeric nanosphere is made up of a closely-packed polymer matrix that aids the adsorption and binding of drugs. In comparison, polymeric nanocapsules take on a polymeric shell composition (although the capsule may also consist of lipids) [14]. Both NPs types are currently under investigation for their drug delivery abilities.
3.3. Inorganic NPs
Inorganic NPs embody a wide variety of substances, several of which can be utilised for neurological drug delivery. These include gold NPs (AuNPS), fluorescent nanodiamonds (FNDs), magnetic NPs (MNPs) ceramic NPs, and upconversion NPs (UCNPs). Gold NPs are nanoscopic in size with a sizable surface area to mass ratio. These features, combined with their proficient functionalisation, make them incredibly valuable carriers for drug delivery [25]. The same may be said for fluorescent nanodiamonds, which can enhance drug precision and retention through conjugation to various drugs and high levels of biocompatibility [26]. Magnetic NPs also denote significant benefits, as their magnetic properties enable them to be utilised as magnetic resonance imaging (MRI) contrast agents as well as carriers for nanotherapeutic drugs. This is due to their magnetic core that consists of two material forms: paramagnetic and super-paramagnetic properties. The latter material is beneficial in that does not manifest any magnetic properties beyond the external magnetic field, therefore it is highly functional for biomedical applications [27]. In contrast, ceramic NPs maintain a small, porous structure, which helps to aid water solubility. These NPs are often appointed for anticancer treatment due to their stability in biological environments and high molecular weight compounds [28].
Upconversion NPs constitute a selective inorganic substance and can serve as a neuroprotective unit for drug transportation. Their distinct features set them apart from other inorganic NPs, as they possess magnetic resonance imaging and upconversion luminescence (UCL) imaging features. The development of nanoprobes, synthesized to traverse the blood-brain barrier, has greatly assisted upconversion NPs in anticancer treatment. One application of this was a study whereby glioblastoma-affected mice were observed following intravenous nanotherapeutic treatment. These nanoprobes were successful in crossing the blood-brain barrier via receptor-mediated transcytosis [29]. The results obtained strongly indicated that the targeting efficacy of the nanoprobes surpassed that of single-mode imaging agents currently implemented in clinical practice [29]. Furthermore, the likelihood of incorporating upconversionnanoprobes for tumor radiotherapy and has been regarded as a strong possibility for future applications [30].
4. NEUROLOGICAL DISORDERS AND TREATMENT STRATEGIES
4.1. Parkinson’s Disease
Parkinson’s Disease is characterised by the progressive loss of dopaminergic neurons, which leads to slow movement (bradykinesia), tremors, and stiffness. Dopamine plays a crucial role in coordination and movement; therefore, a deficiency presents adverse neuronal effects. An additional marker of Parkinson’s is an increase in Lewy bodies, although little is known about their processes. Currently, there is no cure for Parkinson’s disease, but the initial stages may be treated with levodopa (L-DOPA), the precursor for dopamine. If the delivery of levodopa is untargeted however, the peripheral system may be compromised, generating dyskinesia and harmful cardiovascular effects [31]. For that reason, encapsulating neurotransmitters used for Parkinson’s treatment would guarantee an appropriate delivery system and allow for blood-brain barrier diffusion.
4.2. Alzheimer’s Disease
Alzheimer’s Disease is the most prevalent form of dementia (roughly 70% of cases) [32], signalised by memory loss and a difficulty in executing familiar tasks. Pathologically, the aggregation of insoluble amyloid-beta (Aβ) peptide deposits and neurofibrillary tangles incite neuroinflammation [33], which results in widespread brain atrophy. While no cure currently exists for Alzheimer’s, many therapeutic approaches and clinically approved drugs exist to mitigate its progression. Amyloid-beta and tau proteins within the cerebrospinal fluid (CSF) have been utilised diagnostically as they are considered to be significant biochemical markers [3]. The inhibition of amyloid-beta plaque and tau neurofibrillary tangle formation has been the focal point for recent remedial approaches. Transition metals exist as a foundation for amyloid-beta aggregation; therefore, it has been speculated that chelating agents could bind to these select metals [34]. Chelating agents are chemical compounds that help to lower blood and tissue levels of heavier metals (national institute of diabetes), and so could be seriously regarded for Alzheimer’s treatment [34]. Unfortunately, due to the blood-brain barrier’s selective permeability, the chelators’ potential is severely diminished. This is where NTs are advantageous, as they may be conjugated to iron chelators [34]. One NPs prototype, Nano-N2PY, was synthesized to impede Aβ aggregate formation, thus protecting the human brain from neurotoxicity.
4.3. Glioblastoma
Among the primary brain tumors, glioblastomas are regarded as the most common and most aggressive. It is accompanied by a grim prognosis, with only 25% of affected individuals possessing a 2-year survival rate following treatment [35]. Additionally, clinical treatment is inhibited by the formation of the blood-brain tumor barrier (BBTB). This structure, combined with blood-brain barrier, produces an additional hindrance for drug delivery to the glioblastoma cells, thus requiring newer drug development strategies so as to aid delivery to the tumor site. Extensive research has exhibited that the blood-brain tumor barrier may be breached through the utilization of non-toxic NPs that are no larger than 11.7-11.9 nm in diameter and possess prolonged blood half-lives [36]. Further studies have affirmed the correlation between glioblastoma targeting efficacy and nanotherapeutic treatment, such as conjugated liposomes binding to glioblastoma multiforme tissue which resulted in reduced tumor volume [37]. Additionally, magnetic resonance imaging (MRI) assessment showed that the dual-functionalized liposomes exerted significant tumor suppressive effects on glioblastoma cells, resulting in the reduced size of select tumor regions [20]. A selection of nanomaterials has displayed a range of favourable effects, including liposomes, polymeric micelles, and iron oxide NPs (IONP) 38. Overall, the nanomaterials have exhibited enhanced permeability and retention (EPR) through the implementation of positive targeting, which in turn evokes retention of the NPs within the tumors [38]. To supplement EPR, active targeting is administered in order to enhance drug delivery to tumor tissues.
4.4. Vascular Occlusion
Cardiovascular disease continues to claim one of the leading causes of death worldwide, despite being one of the most thoroughly researched and progressive. Various methods such as cellular therapy have been introduced to mitigate long-term effects, however, poor cell retention has posed as a severe hindrance [39]. A solution to this was the introduction of superparamagnetic iron oxide NPs, which demonstrated no adverse effects on cell viability and differentiation, nor functional capacity [39]. Further practical nanotherapeutic methods have included mechanically-activated biomimetic drug carriers, a synthetic implementation through which biochemical processes may be imitated. These drug carriers target sites for vascular occlusion, whereby a blockage in the blood vessel occurs. A vital component and determining factor for vascular pathophysiology is shear stress, a frictional force that is generated by blood flow. High levels of shear stress assist in promoting vasodilation, anticoagulation, and endothelial cell survival 40, whereas low levels correlate to high prothrombotic and inflammatory [41]. Our bodies are able to regulate shear stress levels ordinarily, however, they are compromised in the presence of arterial vascular diseases and hemodynamic conditions [41].
5. BIOLOGICAL BARRIERS FOR DRUG DELIVERY
Although NPs are able to distribute therapeutic agents in a safe and effective manner, they still come with their setbacks (Table 1). In spite of these barriers, however, great opportunities still remain for drug targeting by NTs. The vascular arrangement of tumors is incredibly heterogenous when it comes to dispersal, with certain areas being more permeable than others [44]. However, poor perfusion is a also a common occurrence in tumors. When lymphatic drainage in tumors is compromised, interstitial fluid pressure (IFP) is augmented [45], thus establishing another obstacle for drug delivery. Increased IFP is a leading source for the restriction of extravasation and transvascular macromolecule transport, while additionally impeding molecule transportation within the interstitial tumor space [46]. By increasing the cell density of the tumor, drug transportation may be affected [44]. For that reason, the targeted tissue area requires thorough investigation in order to ascertain permeability prior to administering nanotherapeutic drug delivery. Another challenge that NPs are faced with is their susceptibility to aggregate during formulation, storage, and application. This is due to their considerable surface area to volume ratio and may be resultant of external factors or simply their own inherent chemical properties. There are several proceedings through which this issue can be mitigated, however, including lyophilisation (or ‘freeze-drying’). This stabilises the NPs for a short period of time, after which they are able to assume their original structure for administration [47]. It does not stop there, unfortunately, as the NPs are still prone to aggregating, which interferes with their ability to redisperse when placed into an aqueous solution. For that reason, a non-reducing saccharide known as trehalose can be utilized, as it is able to undertake a cryoprotectant role 43. Trehalose has the ability to lower NP aggregation and increase their rate of separation, while placing no effect on their size, morphology, or yield [43]. Small NPs that were treated with trehalose went on to demonstrate more efficient brain tissue penetration than NPs who had not received cryoprotection [43].
Further studies have evidenced that administering trehalose at nanoscale levels contributed to micromolar concentration efficacy and successful brain targeting [48]. Conclusively, it could be applied to preventative and therapeutic methodologies for a number of neurodegenerative disorders.
CONCLUDING REMARKS
The blood-brain barrier has long been attested as a significant hindrance to successful drug delivery to the central nervous system. The research and development of engineered and multifunctional NPs as pharmaceutical drug carriers has spurred exponential growth in applications to medicine throughout the last decade, proving them to be highly relevant, and indeed advantageous, for the treatment of neurological diseases. This is evident for an abundance of reasons. Firstly, their substances are able to permeate the blood-brain barrier, a common deterrent for central nervous system-targeted therapies. NPs also possess the ability to be engineered to interact with defined cellular subgroups and/or molecules, thereby affording specificity of treatment. Additionally, the materials are multifaceted in that numerous features may be applied to the NPs so as to ensure concurrent targeting, bioactivity, and successful delivery.
Many existing drug treatments have proven to be ineffective at healing, or even mitigating the progression of much neurological pathology. Again, this is accredited in large part to the role of the blood-brain barrier. Moreover, many central nervous system disorders’ disease mechanisms remain unmarked. Looking forward, however, NTs has every indication of advancing positively, particularly with the development of successful strategies to permeate the blood-brain barrier. As we continue to broaden our knowledge and comprehension on neuropathology and etiology, we will be able to continue applying it to NPs engineering and the vital role it holds in deriving original therapeutic treatments and approaches. Overall, NTs hold a great promise to deliver treatment for neurological diseases due to their beneficial features and imparts substantial opportunities for targeting by NPs.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.
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ACS Appl Mater Interfaces 2017; 9(28): 24126-39.[http://dx.doi.org/10.1021/acsami.7b06510] [PMID: 28632387]Molecular Mechanism of Therapeutic Actions of Some Nanoparticles in Some Diseases
Bello Aminu Bello1,*,Ibrahim Khalil Adam1,Sani S. Usman2,Yahaya Saidu Gwarzo1,Luqman Shah3,Fatima Sulaiman Abdullahi4Abstract
This chapter covers a detailed description of various molecular mechanisms of therapeutic actions of silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), Iron Oxide nanoparticles (FeO-NPs), Titanium Dioxide nanoparticles (TiO2-NPs), Cerium Oxide Nanoparticles (CNPs), Zinc Oxide nanoparticles (ZnO-NPs), Nitric oxide releasing nanoparticles (NO-NPs) among others in cancer, diabetes, bacterial, fungal, viral and inflammatory diseases. The mechanisms of anticancer activity of the nanoparticles (NPs) range from ultra-structure disruption, generation of reactive oxygen species (ROS), induction of DNA damage, inactivation of proteins that regulate signalling pathways, inhibition of migration and angiogenesis as well as induction of apoptosis. The mechanism of anti-diabetic activity of the NPs is through inhibition of α-amylase and protein tyrosine phosphatase 1B. The antibacterial and anti-fungal activities of the NPs are by disruption of membrane and induced DNA damage as a result of generation of ROS and dissolved metal ions. The diseases associated with viral infections are treated by restricting the entrance of the virus into the host and by binding to the ap120 site on the viral membrane, thereby regulating its function. The therapeutic mechanism of the NPs in inflammatory diseases is through blocking the production of pro-inflammatory cytokines, inhibiting mast cell proliferation, suppressing lipopolysaccharides (LPS) induced cyclooxygenase (COX-2) gene expression, reducing vascular endothelial growth factor level, decreasing Hypoxia-Inducible Factor (HIF) 1 α -gene expression, suppressing the inducible nitric oxide synthases (INO) gene expression as well as preventing mucin hypersecretion. Therefore, it is clear that the NPs possess various effective and efficient mechanisms of action against both infectious and degenerative diseases.
1. INTRODUCTION
The field nano-biotechnology is considered one of the most dynamic and rapidly growing research fields with diverse applications. It deals with synthesis, strategy and manipulation of new materials at a scale between 1nm and 100 nm [1]. Therefore, the major product of nano-biotechnology called nanoparticles which can be synthesized through different methods that range from physical, chemical, electrochemical, photochemical, biological as well as the use of irradiative techniques [2]. In physical and chemical methods, the involvement of high radiation and high concentrations of both the reductants and stabilizing agents are extremely harmful to the environment, humans and other living organisms, thereby limiting their vast applications [3]. Even though these methods were recorded for being successful in generating pure and well defined NPs, they are highly expensive and release dangerous products to the environment [4]. The biological method, on the other hand, involves a single step bio-reduction process which is cost-effective, can be operated easily at an industrial scale, requires less energy and eco-friendly products (NPs) that are safe for humans with therapeutic importance are generated [5, 6]. Many bio-based substances such as plant extracts, fungi, bacteria, algae and enzymes act as reducing and protecting agents in the green synthesis of NPs [7, 8]. The plant based NPs synthesis is one of the emerging fields of nanotechnology in the recent era [8] that has been continuously drawing the attention of more researchers due to their numerous applications in different fields as a result of their inherent properties and pose no harmful effects to the environment. It is usually carried out at a neutral pH and ambient temperatures [4, 9]. These plant materials or extracts served as both reducing and capping agents for metallic ions have more advantages than other biological material [10]. Because of their safer applications, plant-based metallic NPs are the most demanding and most effective in the field nano-biotechnology. The different metallic NPs are synthesized using metallic ions such as silver, gold, zinc, copper, titanium, magnetite and nickel (Fig. 1) and different parts of the plants or extracts such as stem, roots, fruits, leaves and flowers are largely investigated with various biological potentials [4].
Due to their completely new and enhanced properties such as their high surface-to-volume ratio and small size, distribution and morphology which allow for the ability to surpass barriers and gain access to biological molecules and, particularly in microorganisms [11], NPs are continuously gaining applications in many fields such as health care, implants, prosthetics, in-vitro diagnostics, cosmetics, biomedical, food and feeds, drug-gene delivery, environmental study, mechanics, optics, optoelectronic devices, bio-imaging devices, sensors and many others [12]. The metallic NPs have been widely used in these fields because of their high stability, solubility, multi-functionality, bio compatibility, adhesive as well as therapeutic properties. The current trend is the development of nanoparticles which have better therapeutic properties as well as being environment-friendly [13-15]. Among these metallic NPs, the NPs from noble metals such as gold (Au), silver [1] and platinum (Pt) are well studied and reported to have significant applications in electronics, magnetic, optoelectronics and information storage. Recently, it was reported that, NPs could serve as drug carriers either by active or passive mechanism [1]. The most studied among the metallic NPs are the AgNPs and were reported to be used in producing products that have direct contact with human systems such as shampoos, soaps, detergents, cosmetics, toothpaste, medical, pharmaceuticals, among others [16]. The nanoparticles (NPs) are reported to exhibit a wider range of superior physical, chemical, mechanical, thermal as well as biological properties when compared with the bulk or starting materials. All of these properties are important to the biological and research fields because they influence their antibacterial [17], antifungal [4], anti-inflammatory [18, 19], antiviral [20], anti-diabetic [21], antioxidant [22] and anti-angiogenic potential with improved catalytic activities [15, 23, 24]. AgNPs are reported to have potential applications in cancer diagnosis and treatment [25-27]. They are reported to be used in the treatment of ulcer [28-30] and cardiovascular disorders [31].
Fig. (1)) The metallic-nanoparticles synthesized from different plant extracts.
