Peptide Amphiphiles
Peptide amphiphiles fall under the category of nanomaterials, and many researchers have actively investigated them within the past decades. One of the most significant reasons for the amphiphilic peptides to receive so much attention is because they are simple in design and versatile in the application (Qui et al. 5005). Besides, this type of molecules can self-assemble, which represents a significant measure of creating nanomaterials (Qui et al. 5005).
In such a way, due to their functions, peptide amphiphiles present high interest for the scholars within healthcare research. This part of the paper will investigate the role of amphiphilic peptides, their application and its advantages, and their use in cancer diagnosis or treatment.
First, it is essential to understand what the amphiphilic peptides (PAs) are. The definition states that they are “small molecules that contain hydrophobic components covalently conjugated to peptides” (Hendricks et al. 2440). Today, PAs are used in different projects because they create an effective and advanced platform to design hybrid materials (Hendricks et al. 2440). Hence, possessing various biomedical functions and having a structure that can be used for the creation of nanomaterials, Pas can be applied in different studies and lead to discoveries in the medical industry.
It is crucial to look at the features that the self-assemble function provides to the medical industry. The self-assembly of molecules is defined as “the spontaneous aggregation of molecules into well-ordered nanostructures, which are usually driven by non-covalent bonds” (Qui et al. 5003).
Therefore, to successfully design the materials that self-assemble, it is critical to understand and control the molecules. According to Qui et al., nature itself has already provided numerous paradigms for the design of self-assembling molecular materials, such as how the lipids shape the bilayer membrane (5003). It is possible to say that with taking natural paradigms, the researchers managed to develop other systems that self-assemble, like amphiphilic peptides.
The self-assembly feature of the PAs has several goals that it can achieve because the role of the peptides is integral in many biological processes. Existing evidence states that peptide self-assembly aims to unravel the principles or to generate the nanomaterials that possess biocompatibility and specific functions (Zhao et al. 115). Moreover, the fragments of the peptides and their derivatives represent the “building blocks for self-assembly” (Zhao et al. 115). Again, it shows that the peptide amphiphiles can have diverse applications and play a crucial role in the design of nanostructures and nanomaterials.
Peptide amphiphiles possess other features besides self-assembly, which creates extra attention around them as the molecular building blocks. The researchers emphasize that versatility, tunable structures, the simplicity of manufacturing, diversity, and low costs significantly contribute to the numerous applications of those peptide groups (Sun et al. 79). In such a way, peptide amphiphiles, as a self-assembled peptide structure, are widely used in medicine. Some of the amphiphilic peptides are commonly used in drug delivery, tissue engineering, as antibacterial agents, or as nanosensors (Sun et al. 75).
Despite active use in various medical applications, this group of peptides, like other structures that self-assemble, impose challenges for the researchers. The scientists believe that amphiphilic peptides can not only contribute to the investigations of complex phenomena in biology but also influence the way the diseases are treated and improve health (Sun et al. 78). Consequently, those peptides require further research to bring more significant outcomes to the healthcare industry.
One of the examples of how peptide amphiphiles can contribute to conquering the diseases can be their use in treating fungal keratitis. There is a study that investigated the effect of the peptides on the fungus keratitis due to their antimicrobial features (Wu et al. 1). The importance of this study is evident because it is one of the steps in applying amphiphilic peptides towards the treatment of diseases that currently have ineffective solutions. The study revealed that the peptides that had optimal composition “demonstrated higher propensity and improved antifungal activity” (Wu et al. 1). Thus, the integration of the self-assembling system of this peptide group into the fungus keratitis treatment therapeutics can have a positive influence on the results with the patients who suffer from this disease.
Besides the advantages that the PAs bring to the fight against fungal keratitis, they also contribute to the research with such diseases as atherosclerosis, group A streptococcus, or cardiovascular illnesses. Thus, amphiphilic peptides can also be used for the “multimodal imaging of atherosclerotic lesions” (Yoo et al. 996). The study found a way to incorporate the PAs with various Gd-chelating molecules to describe the generated fibrin-targeting micelle (Yoo et al. 996). Therefore, with the implementation of this technique, imaging tools, such as MRI, can provide more precise results for the professionals to have a bigger picture of the presence of the disease.
The next essential point would be to investigate the possibility of PAs use in the diagnosis or treatment of cancer. Cancer is a severe disease that represents a problem of public health at the international level. Although the death rate from cancer has significantly decreased within the last two decades, it remains to be an issue that requires though clinical research to find the way to combat the disease (Kuang et al. 85). Various advances in nanomedicine have been used within this field, including the implementation of the peptide amphiphiles. The PAs are used for the development of the peptide-functionalized liposomes that are actively used in cancer therapy (Kuang et al. 87). In such a way, continuous medical research brought significant progress to the fight with cancer.
Besides, the use of the peptide amphiphiles is related to the liposomal drugs that have several advantages, including lower side effects and improved pharmacokinetics. There are several ways to functionalize liposomes with targeting the peptides. Hence, the insertion of the PAs into preformed liposomes or the mixture of PAs with lipids are the techniques to give necessary functions to liposomes (Kuang et al. 88).
Those ways through the use of amphiphilic peptides can provide the desired level of functionality to the liposomes used in the pharmacotherapy. Still, further efforts should be made within the field of clinical research to propose more effective strategies. They will hopefully offer drugs that improve the effects of tumor treatment.
The paragraphs above describe the functions of peptide amphiphiles, its advantages and various biomedical applications, and the possibility of integrating them into cancer therapy with the help of further research. Self-assembly represents one of the essential functions of this peptide group because it provides the ability to participate in the design of nanostructures and nanomaterials. Various techniques of the implementation of the PAs into the therapeutic process allow their use in the treatment of such illnesses as fungal keratitis, cardiovascular diseases, and others. It is critical to mention that the use of the amphiphilic peptides with the liposomes can generate an effective liposomal drug for the antitumor effect.
Inositol Triphosphate Pathway
Calcium signals that are generated in different channels regulate various cellular functions. Inositol triphosphate represents one of such pathways that operates through two mechanisms that can be primary or modulatory (Berridge 1267). The formation process of IP3 is a process that includes various external stimuli. In such a way, stimuli, like hormones or neurotransmitters stimulate the IP3 generation through the activation of G protein-coupled receptors (GPCRs) or protein tyrosine kinase-linked receptors that are attached with phospholipase isoforms (Berridge 1269).
Thus, the principle of IP3 work goes through the binding to the IP3 receptors “to release calcium from endoplasmic reticulum” (Berridge 1261). It shows that IP3 helps to increase the level of intracellular calcium due to the entry of non-cellular calcium into the cell and to its mobilization from the endoplasmic reticulum.
It is essential to look through the inositol triphosphate (IP3) mechanism of work. IP3 is dissoluble, and it disperses through the cell, from where it attaches to the receptor that is a calcium channel (Berridge 1268). Those features lead to a critical role of inositol triphosphate in different biological processes. The primary aim can be observed in the cell where it produces calcium signals to control “metabolism, secretion, fertilization, proliferation, and smooth muscle contraction” (Berridge 1261).
In such a way, the fact that the IP3 pathway is significant in numerous cellular processes implies that the changes in the mechanisms can lead to various diseases. Among the illnesses, the researchers highlight the possibility of Alzheimer’s disease, diabetes, epilepsy, bipolar disorder, Huntington disease, pancreatitis, schizophrenia, osteoarthritis, Duchenne muscular dystrophy, and others (Berridge 1270). Expansive role of IP3 in many processes requires careful control and implies the significance of this pathway for human health.
As far as IP3 serves as a pathway for the generation of calcium signals, it is crucial in the regulation of various processes. The paragraph above mentions different diseases that can be caused by the pathologies in the calcium signals due to the deterioration in the process of IP3 regulation. Among those diseases, there are autoimmune and metabolic illnesses, but besides those, IP3 deregulation can also lead to cancer.
One of the recent researches has investigated the possible creation of the therapeutic agent against cancer. The study suggests that the targeting of the interaction between Bcl-2 and IP3 receptors can lead to the development of a chemical compound that will have a cancer therapeutic effect (Distelhorst and Bootman 13). Thus, current medical research aims to investigate this type of interaction and perform a continuous search for new cancer treatment solutions.
The field of drug discovery is an important and complicated area, and the IP3 plays a significant role in the findings of drugs connected to the diseases possibly caused by IP3 deregulation. According to Jacob, the earliest and the essential step in the process of drug discovery is “the elucidation of a drug target” (235). The search suggests that more than half of the identified targets belong to the three families of the receptors, where GPCRs represent the most common drug target (Jacob 236). The description of the IP3 formation process above shows that it includes the activation of this receptors’ group, which highlights the significance of IP3 in drug targeting.
The paper has already discovered that IP3, as water-soluble molecules, are responsible for the regulation of various aspects of cell physiology. The study shows that all eukaryotic genomes have enzymes that are accountable for the synthesis of inositol polyphosphate (Saiardi et al. 73) The researchers emphasize that “the identification of inositol kinase inhibitors, specifically targeting the kinases of a pathogenic microorganism,” is highly desirable and can be achieved (Saiardi et al. 74).
It implies that medical research aims to study metabolic pathways in different illnesses in order to find the most effective solution. Some of the studies investigating pathogenic fungi or protozoa highlight the importance of IP3 in the virulence of the pathogens. Therefore, the significance of the IP3 role as pathway research in the context of diverse diseases is unquestionable and highly desirable.
The three most essential features point out the possibility of viewing IP3 as the drug development target. According to Saiardi, the first of those features is the significance of highly phosphorylated IP “for the fitness of pathogenic organisms’ ‘ (75). The next two features include the existence of alternative pathways that lead to IP3 in human cells and “the low amino acid homology between human and pathogenic kinases (Saiardi, 75).”
Thus, those features explain why the development of new therapeutic agents with inositol triphosphate is so challenging. Besides, the researchers emphasize that there is drug resistance emerging and that it is urgent to find new targetable pathways (Saiardi 76). It explains the high focus on the research to generate new drugs in the era of its high availability and growing resistance to the existing ones.
There are two main classes of cell-surface receptors responsible for InsP3 formation: (1) the G protein-coupled receptors (GPCRs) and the protein tyrosine kinase-linked receptors (PTKRs) that are coupled to different phospholipase C (PLC) isoforms (Dana et al. 655). The difference between the two classes lies in their use of isoforms: while for the GPCRs, it is the PLCβ isoforms, the receptor tyrosine kinases (RTKs) couple with the PLC-γ isoforms. The transduction process is characterized by the hydrolyzation of the precursor lipid PtdIns4,5P2 by PLC, which results in the production of InsP3 and diacylglycerol (DAG). The InsP3 is then released from the membrane and diffused into the cytosol. What follows is the engagement of the InsP3 receptors (InsP3Rs) and the release of Ca2+ from the endoplasmic reticulum.
The termination of the Ca2++ mobilizing function of InsP3 is achieved through its metabolism by one of the two compounds: InsP3 3-kinase or InsP3 5-phosphatase. The result of this chemical reaction is InsP2 and InsP4: they enter an inositol phosphate metabolic pathway and reverted back to free inositol. The DAG is converted back to the precursor CDP-DAG, which then is coupled with inositol to transform the phosphatidylinositol (PtdIns) (Dana et al. 656).
The latter finds its way back to the plasma membrane to start the process of phosphorylation to the PtdIns4,5P2 precursor. All the aforementioned processes and reactions serve the maintenance of the InsP3 signalling pathway.
InsP3 / Ca2++ signalling pathway plays an essential role in the highly versatile and dynamic cellular Ca2++ signalling system and controls many of the cellular processes. One of the defining and useful features of InsP3/ Ca2++ signalings is its behavior during the development of multiple human diseases. The harmful alterations in the InsP3/ Ca2++ signalling pathway may be treated with Vitamin D. It has the potential of maintaining the phenotypic stability of both the Ca2++ and other signalling pathways.
If a patient is Vitamin D deficient, there is an observable increase in the resting state of these pathways (Dana et al. 659). This, in turn, improves the activity of the InsP3/ Ca2++ signalling pathway. The role of InsP3/ Ca2++ signalling differs depending on cell types and membranes and contributes to different disease states.
Another explanation as to how the analyzed metabolic signaling pathway behaves in the case of disease lies in its contribution to the regulation of autophagy. Studies show that autophagy can be induced by the release of Ca2++ from the ER. Subsequently, further research indicated that InsP3/ Ca2++ signalling pathways play an essential role in regulating autophagy. However, of a special note is the ambivalence of Ca2++ pathways as they can both impede and facilitate autophagy (Dana et al. 654). An increase in various pathological aggregates such as amyloid, tau, synucleins, and mutant Huntington fragments may occur due to a decline in autophagy. This phenomenon is indicative of neurodegenerative diseases such as AD, Parkinson’s disease, and HD.
The visualization and measurement of biological processes at the cellular and subcellular levels in living systems is achievable via molecular imaging. Of increased importance in diagnosing and managing disease is targeted molecular imaging that helps to quantify target expression. As of late, molecular imaging of tumor cells has been employing selective receptor-targeting peptide based agents. The rationale for such use was their unique properties: rapid clearance from circulation, increased affinities, and specificities for their targets (Sun 40).
The rapid development of advanced chemistry modification techniques has given rise to the design and development of different peptide-based imaging agents. Their key characteristics include metabolic stability, desired pharmacokinetics, enhanced binding affinity and selectivity (Sun 40). Besides, they display a better imaging ability and biosafety. Various radiolabeled peptides have already gained recognition for their precision and sensitivity and have been adopted in the clinical practice.
One of the most useful molecular imaging methods is calcium imaging. Thirty years ago, the design and development of organic fluorescent Ca2+ indicators created plenty of opportunities for imaging with a high degree of high degree of temporal and spatial resolution. Over the last few decades, discoveries regarding Ca2++ imaging have transformed clinical approaches for tissue-level spatiotemporal analysis of functional organization.
This type of imaging has become a powerful tool for in situ cellular activity imaging in humans. Later, in vivo Ca2+ imaging characterized by temporal resolution at the millisecond and spatial resolution at micrometer ranges has become achievable due to novel designs of Ca2++ sensors. Other factors that have contributed to the scientific advancements were development of modern microscopes and powerful imaging techniques such as two-photon microscopy. The new approaches are poised to open doors for physiological experiments and for pharmacological approaches in the field of oncology.
Taking all these facts into account, one may assume that Ca2++ signalling and imaging offer promising opportunities in cancer diagnosis and treatment. Stewart et al. report that their research suggests that deregulated Ca2++ signaling be linked to the so-called cancer hallmarks. Namely, the researchers have discovered that altered Ca2++ transporter protein expression is related to some cancers (Stewart et al. 2509). Some cancer cells may display altered Ca2++ signals, which helps with initial cancer diagnosis. However, the nature of altered Ca2++ signaling in cancer has yet to be clarified. Once it is, the new discovery will guide more precise therapeutic targeting.
Giant Cells
Modern science has now recognized that cells of the the monocyte/macrophage lineage are able to fuse and form the so-called multinucleated giant cells (MGCs). Yet, what has yet to be clarified is their identification, adhesion, fusion, and activation. Another unknown aspect is the specific intercellular and intracellular pathways of MGCs. Moreover, the local environment and the chemical and physical character of the agent to which the MGCs and their monocyte/ macrophage precursors are responding account for a great degree of variation in cell phenotypes. This part of the paper will address the various phenotypes of MGCs, their peculiar survival mechanism and death program, and treatment methods.
To properly answer the question as to how exactly MGCs rise, it is only reasonable to pay attention to the particularities of each phenotype discovered. One way in which MGCs may rise in humans is from mycobacterium-induced granulomas (Kleinschmidt-DeMasters 100).
Recent studies employing an in vitro model of human tuberculous granulomas have demonstrated that high virulence mycobacterium such as M. tuberculosis is capable of triggering the rise of multinucleated giant cells. As compared to low virulence mycobacterium species such as M. avium and M. smegmatis that induce MGCs with less than seven nuclei per cell, high virulence mycobacterium can lead to the formation of cells with more than 15 nuclei (Kleinschmidt-DeMasters 89). Of special note is that MGCs with greater numbers of nuclei per cell are now considered the last stage of formation and differentiation of giant cells. These cells lose their capacity for phagocytosis while retaining a strong antigen presentation capability.
MGCs are also found in meta-epiphyseal regions of bone tumors that form after skeletal maturity. After the initial tumor formation, mononuclear histiocytic cells reach the site of tumor where they later fuse and form giant cells. Neoplastic giant cell tumor stromal cells serve as the receptor activator of nuclear factor kB ligand; they enable fusion with macrophage colony stimulating factor.
Another phenotype with a distinct formation method of MGCs is osteoclasts. They consist of multinucleated bone-resorbing cells that given the normal functioning, regulate bone homeostasis and remodelling. The origin of osteoclast precursors is bone marrow: after derivation, they enter the blood flow and bind to the surface of bone. As of now, the mechanism of recognition and target binding are not that well-researched. One thing that is known for a fact is that osteoclast formation is enabled primarily by two cytokines: RANKL and M-CSF (Kleinschmidt-DeMasters 125). The fourth and the last most common MGCs phenotype is foreign body giant cells (FBGC).
FBGCs are typically found at the tissue/ material interface of implanted medical devices, prostheses, and biomaterials. In this case, adherent macrophages and foreign body giant cells are a part of the body’s reaction to the implantation of a foreign object. It should be noted that FBGCs often rise in tissues that cannot adapt to foreign particulates of large size because the latter does not permit normal macrophage phagocytosis.
The life, death, and survival mechanisms of giant cells have long been of interest for researchers. Some time ago, they believed that giant cells were doomed to die, and it was the only feasible outcome of their fusion and formation. However, recent findings suggest that giant cells can survive and remain active for extended periods of time. Some registered instances demonstrated giant cells’ evolution to smaller size cancer cells (Gao 3810). The most common event that leads to giant cell death is mitotic catastrophe, a premature or improper entry of cells into mitosis because of chemical or physical stresses. Other fatal events include apoptosis, necrosis, or sometimes even a combination of two cell death pathways such as aponecrosis or necroptosis.
Of a special note is giant cells’ survival and death programmes as opposed to normal cells. When treated with cytostatics, there are two different outcomes for MGCs. One outcome is the arrest and resistance of giant cells since chemotherapy and irradiation only affect the cycling cells. Not only do giant cells become resistant to medication or radiation, they also give rise to new cells that are inherently resistant to these two forms of treatment (Gao 3810).
The second outcome also results in giant cells’ survival: they reenter the cell cycle, which leads to multinucleation and polyploidization (Gao 3810). Further treatments might also be non-effective against giant cells as they produce new cells or even go back to the parental cell type. What remains unclear about giant cells’ functioning is the very purpose of their formation. They might be appearing to avoid cell death or give rise to new, smaller cells.
Methods of treatment of giant cells depend on their phenotype. In the case of giant cell arteritis, the appropriateness of strategy depends on the results of biopsy or imaging. If a patient returns with a positive biopsy or imaging result, the most common treatment plans include high-dose systemic glucocorticoids soon after the confirmation of the diagnosis. If patients are at risk of developing adverse side effects of prednisone, the strategy should include the addition of tocilizumab (TCZ) or methotrexate (MTX) (Ponte 484). If the clinical scenario of GCA is suggestive of this diagnosis, but biopsy and imaging results are negative, it makes sense to run more tests: temporal artery biopsy or biopsies and/or color-coded duplex ultrasonography.
Giant cell tumor is a rare aggressive non-cancerous tumor, a condition that occurs in adults between the ages of 20 and 40. Diagnosis methods vary and typically include biopsy, radionuclide scans, and x-rays. The appropriateness of existing treatment strategies is evaluated based on a patient’s background information: age, overall health, medical history, extent of the condition, and tolerance for specific procedures and medications. The goal of the treatment is to remove the giant cell tumor and avert bone damage. Depending on the aforementioned characteristics, one of the following options may help with that:
- amputation (in severe cases);
- bone grafting;
- bone reconstruction;
- physical therapy; and
- surgery (Sobti 2).
Some tumors are impossible to remove surgically; in this case, radiation therapy might be considered.
A foreign body granuloma is a non-allergic chronic inflammatory reaction that leads to the formation of multinucleated giant cells (Lee and Kim 237). The primary method of foreign body granuloma treatment is intralesional corticosteroid injections. These injections have been found to be disruptive to the activities of fibroblasts, macrophages, and giant cells. Recurring foreign body granulomas can be treated with systemic steroid therapy.
Systemic steroid therapy differs from the aforementioned injection treatment method in the higher doses of steroids. As with other giant cell conditions, the use of oral prednisone is recommended to prevent the recurrence. The starting dose is 30 mg/ day, and the maintenance dose is 60 mg/ day. Lastly, one more option is surgical excision of foreign body granulomas, even though this is often not the first choice. Granulomas are invasive and do not have defined borders with the surrounding tissue. Surgery may lead to complications such as abscess; the latter is treated with incision and drainage.
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