Chemotactic drug-targeting

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Targeted drug delivery is one of many ways researchers seek to improve drug delivery systems' overall efficacy, safety, and delivery. Within this medical field is a special reversal form of drug delivery called chemotactic drug targeting. [1] [2] By using chemical agents to help guide a drug carrier to a specific location within the body, this innovative approach seeks to improve precision and control during the drug delivery process, decrease the risk of toxicity, and potentially lower the required medical dosage needed. [2] [3] [4] [5] The general components of the conjugates are designed as follows: (i) carrier – regularly possessing promoter effect also on internalization into the cell; (ii) chemotactically active ligands acting on the target cells; (iii) drug to be delivered in a selective way and (iv) spacer sequence which joins drug molecule to the carrier and due to it enzyme labile moiety makes possible the intracellular compartment specific release of the drug. Careful selection of chemotactic component of the ligand not only the chemoattractant character could be expended, however, chemorepellent ligands are also valuable as they are useful to keep away cell populations degrading the conjugate containing the drug. In a larger sense, chemotactic drug-targeting has the potential to improve cancer, inflammation, and arthritis treatment by taking advantage of the difference in environment between the target site and its surroundings. [6] [7] [8] Therefore, this Wikipedia article aims to provide a brief overview of chemotactic drug targeting, the principles behind the approach, possible limitations and advantages, and its application to cancer and inflammation.

Contents

Chemotactic drug-targeting Chemotactic drug-targeting.png
Chemotactic drug-targeting

Importance of Chemotaxis in Chemotactic Drug-Targeting

In general terms, chemotaxis is a biological process where living entities, such as cells or organisms, detect, maneuver, and react in response to a chemical signal in their environment. [1] Such a phenomenon is critical for many biological processes, including but not limited to wound healing, detection of food, and avoidance of many toxins. [2] Chemotaxis also plays an essential role in several diseases, such as tumor metastasis, the recruitment of T-lymphocytes during inflammation, and HIV-1 entry into T cells. [6] [9] [10] At the core of chemotaxis are specialized sensory cells called chemoreceptors. These cells allow an organism to detect chemical molecules within its environment and respond accordingly. Such chemical molecules are either known as chemoattractants or chemorepellents, which play a crucial role in attracting or repelling the organism towards or away from the source of the chemical signal, respectively. Thus, with this natural process of chemotaxis in mind, researchers have sought to apply the same phenomenon to targeted drug delivery, a medical technique aimed at delivering drugs to a specific cell, tissue, or organ within the body while minimizing its disruptive effects on healthy tissue. [4] By using both chemotaxes to help guide the drug delivery process, researchers aim to reduce toxicity by avoiding healthy tissues, improve drug efficacy by focusing only on the intended site, and decrease drug dosage by delivering the directly rather than throughout the whole body. [3] [11]

Chemotactic Drug Targeting Systems

Chemotactic drug delivery systems are an emerging field of drug delivery that aims to apply the natural phenomenon of chemotaxis in guiding and delivering a drug to a specific tissue or cell within the body. Thus, similar to how organisms use chemotaxis, researchers have designed drug delivery systems to detect, maneuver, and react to chemical molecules released by a desired cell or its surrounding area.

Microdroplets

Recent progress in the field of microfluidics has led to the development of microdroplets, a new drug-delivery system that uses uniform droplets to deliver drugs to specific locations within the body. [2] [12] These microdroplets allow researchers to load drugs during the polymerization step of their formation and provide variations in porosity, which can control the time it takes to release a therapeutic payload. [13] Thus, by using the natural process of chemotaxis, researchers aim to guide these tiny droplets by using chemical gradients released by a specific cell, tissue, or organ within the body. [2] [4] [12] In fact, a few examples of microdroplet systems that use chemotaxis are self-propelling, ionic liquid-based, and synthetic base. [2] [12] These microdroplet-based drug delivery systems offer several advantages over traditional drug delivery methods, which are talked about later in the advantage and limitations subsection of this article. Overall, the development of microdroplet-based drug delivery systems using the phenomenon of chemotaxis is just one of may avenues to potentially revolutionize the field of medicine and targeted drug delivery. [14]

Protocells

Another drug delivery system that has shown potential for chemotactic applicability is protocells. [15] In general, protocells are artificial cells that mimic living cells but cannot reproduce and have genetic mutations like living cells do. [15] Moreover, protocells combine the advantages of liposomes with that of mesoporous silica nanoparticles. [16] These advantages include but are not limited to stability, large capacity for various cargos, low toxicity, immunogenicity, and the ability to circulate the blood for long periods. [16] Thus, researchers aim to create a tunable chemotactic protocell that can move towards or away from a chemical signal. [17] [18] In fact, researchers have devised a way to use the enzymes catalase, urease, and ATPase to move the protocell closer or further away from the reactant, giving them direction and movement control of these protocells. [17] [18] Overall, the development of chemotactic controlled protocols holds great promise for the targeted delivery of drugs to specific areas of the body, potentially increasing treatment efficacy while minimizing side effects. However, more research is needed to fully understand the capabilities and limitations of protocells as drug delivery systems and optimize their design and functionality for specific applications.

Biological and Bio-hybrid drug carriers

Finally, biological and bio-hybrid drug carriers have shown potential for chemotactic applications. In general, these systems are inspired by microorganisms or cells to help design drug delivery systems that mimic their surface, shape, texture, and movement. [4] [19] One phenomenon that has become increasingly popular in improving the movement and release of bio-hybrid drug carriers is that of chemotaxis. Indeed, thanks to their natural chemotactic sensing property, bacteria can be used to locate a tumor, carry a therapeutic payload to the site, and release that drug in a controlled manner. [4] Researchers can also genetically modify these bacteria to produce a specific protein like anti-tumor cytotoxins for cancer treatment. [4]

Yet, this is not to say that they don't come with their own set of challenges and limitations. For one, the genetic modifications of the bacteria used can be manipulated by recent or unforeseen mutations, leading to a decrease in the efficacy of the drug and drug carrier. [4] Moreover, the therapeutic proteins produced may have incomplete protein folding, decreasing the drug's effectiveness or causing unforeseen side effects. [4] Generally speaking, using bacteria may provide some advantages, but further research and development are still needed to address their limitations.

Another example of bio-hybrid drug carriers is human cells, like macrophages, which offer compatibility with the human immune system and a simple way to load drugs as a bio-hybrid drug carrier. [4] Leukocytes demonstrate great promise because Tumor cells secrete large amounts of chemoattractants when the cell undergoes inflammation. [4] This secretion of chemoattractants naturally attracts leukocytes, such as macrophages, to the T cell location. [4] Thus, with their well-known chemotactic homing behavior to inflammation or pathogens' sites in mind, researchers can manipulate leukocytes to carry and deliver a therapeutic payload to the tumor site. However, this is not to say that Biological and bio-hybrid drug carriers do not have challenges and limitations of their own. For example, Leukocytes cannot penetrate deeply into the tumors, have a low capacity for carrying drugs, and slow down when the tumor size reduces. Thus, similar to bacteria drug carriers, further research and development are still needed to address their limitations and improve the overall drug delivery system.

Applications of Chemotactic Drug Targeting

The applications of chemotactic drug delivery systems include but are not limited to cancer therapy, wound healing, and inflammation. The ability to target specific cells and locations within the body through chemical cues has opened up new avenues for the field of drug delivery, allowing for increased drug efficacy and reducing harmful side effects.

Cancer

Cancer is not just one disease but a group of diseases involving abnormal cell growth and metastasis of such cells to other body parts. [20] [21] There are also several types of cancers, each with its own distinctive characteristics and stages that may require different treatment or targeted drug delivery approaches. [21] [22] Yet, even these treatments have their own advantages and disadvantages. Thus, since the discovery of cancer, researchers have constantly been developing new and innovative cancer treatments, including chemotactic drug delivery. For example, and as mentioned earlier in this article, researchers have sought to use microdroplets, protocells, and biological and bio-hybrid drug carriers to deliver drugs to cancer cells in a more effective manner, while reducing unwanted side effects. [2] [4] [12] [15] [19] In fact, the justification for using such systems, guided by chemotaxis, is that the environment inside a tumor has a higher resting temperature, higher peroxide concentration, lower pH, and a lower oxygen concentration than its surrounding tissue. [4] With these unique conditions, researchers can exploit chemotactic drug delivery to target tumor cells directly, avoiding healthy tissues, reducing toxicity, improving drug efficacy, and decreasing drug dosage. [12] [13]

Inflammation

Inflammation is the body's response to foreign objects, irritants, germs, and even pathogens. Although such a response is standard in some cases, if left untreated, chronic inflammation can lead to muscle degeneration, gastrointestinal disorders, and some types of cancers. [23] [24] While most treatments, such as anti-inflammatory drugs and steroid injections, can help relieve symptoms, they often fail to address the condition's underlying cause. Therefore, researchers have sought to explore new and innovative ways of inflammation treatment, such as chemotactic drug delivery.

One promising drug delivery system was based on engineered neutrophils that targeted inflammation sites through chemotaxis's unique properties. [4] [7] This approach took advantage of the concentration difference between iNOS and ROS for inflammatory disease sites and normal tissues. [7] By doing so, this drug delivery system provides the possibility to target areas of inflammation, increase drug efficacy, and minimize damage to the surrounding tissue. [3] [11] Moreover, because this concentration gradient is ubiquitous in the microenvironment of inflammatory diseases, common drug-targeting limitations such as individual differences can be avoided. [7] Another example of an innovative drug delivery system that uses the property of chemotaxis is leukocytes. [4] Indeed, during inflammation, the molecules on a cell that allows for adhesion are overly produced. [4] With this unique condition, researchers can modify leukocytes to quickly detect the cell, attach itself to the surface, and deliver a therapeutic payload. [4] Overall, many promising therapies and drug delivery systems are being developed to target inflammation more effectively. Chemotactic drug delivery systems are just one of many promising avenues that seek to increase target sites specifically, decreasing the needed drug dosage, reducing toxicity, and increasing drug efficacy. [3] [4] [11]

Advantages and limitations of Chemotactic Drug Targeting

While this emerging field of drug delivery shows excellent promise in targeting specific cells and locations within the body, understanding current challenges and drawbacks can allow researchers to optimize design, development, and delivery to improve the overall outcome of their medical treatment.

Microdroplets

Protocells

Biological and Bio-hybrid drug carriers

Conclusion

Generally speaking, chemotactic drug-targeting is a drug delivery strategy with promising avenues for treating diseases such as cancer and inflammation. This approach mimics the biological process of chemotaxis, which biological organisms use to detect, maneuver, and react to chemical signals in their environment. By applying this technique to targeted drug delivery, researchers aim to create drugs that can precisely reach their intended targets, minimizing the potential for side effects, improving drug efficacy, and decreasing drug dosage. Some examples include but are not limited to microdroplets, protocells, biological and bio-hybrid drug carriers, leukocytes, and neutrophils.

While chemotactic drug targeting holds great promise for drug delivery, there are key advantages and limitations that must be considered. One main advantage is that these systems can precisely target specific cells, tissues, or organs within the body while minimizing their disruptive effects on healthy tissue. Moreover, by delivering the drug directly to the desired target, researchers can effectively reduce the required drug dosage needed. However, some limitations to chemotactic drug targeting include issues with biocompatibility, drug-carrying capacity, and the life span of specific carriers. Another major challenge with this approach is motility, when either the chemical stimuli diminish, or the attached enzymes become oversaturated. This can limit the effectiveness of the drug delivery system and may require additional modifications to improve its performance. Thus, although these approaches have shown great promise, more research is still needed to fully understand chemotaxis mechanisms and optimize this property for targeted drug delivery strategies.

Related Research Articles

<span class="mw-page-title-main">Chemotaxis</span> Movement of an organism or entity in response to a chemical stimulus

Chemotaxis is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming toward the highest concentration of food molecules, or to flee from poisons. In multicellular organisms, chemotaxis is critical to early development and development as well as in normal function and health. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis. The aberrant chemotaxis of leukocytes and lymphocytes also contribute to inflammatory diseases such as atherosclerosis, asthma, and arthritis. Sub-cellular components, such as the polarity patch generated by mating yeast, may also display chemotactic behavior.

Nanomedicine is the medical application of nanotechnology. Nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

In the field of genetics, a suicide gene is a gene that will cause a cell to kill itself through the process of apoptosis. Activation of a suicide gene can cause death through a variety of pathways, but one important cellular "switch" to induce apoptosis is the p53 protein. Stimulation or introduction of suicide genes is a potential way of treating cancer or other proliferative diseases.

Haptotaxis is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or substrate-bound chemoattractants. These gradients are naturally present in the extracellular matrix (ECM) of the body during processes such as angiogenesis or artificially present in biomaterials where gradients are established by altering the concentration of adhesion sites on a polymer substrate.

An artificial cell, synthetic cell or minimal cell is an engineered particle that mimics one or many functions of a biological cell. Often, artificial cells are biological or polymeric membranes which enclose biologically active materials. As such, liposomes, polymersomes, nanoparticles, microcapsules and a number of other particles can qualify as artificial cells.

Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system releases the drug in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side-effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost, which makes productivity more difficult, and the reduced ability to adjust the dosages.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

<span class="mw-page-title-main">Sonodynamic therapy</span>

Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.

<span class="mw-page-title-main">Gold nanoparticles in chemotherapy</span> Drug delivery technique using gold nanoparticles as vectors

Gold nanoparticles in chemotherapy and radiotherapy is the use of colloidal gold in therapeutic treatments, often for cancer or arthritis. Gold nanoparticle technology shows promise in the advancement of cancer treatments. Some of the properties that gold nanoparticles possess, such as small size, non-toxicity and non-immunogenicity make these molecules useful candidates for targeted drug delivery systems. With tumor-targeting delivery vectors becoming smaller, the ability to by-pass the natural barriers and obstacles of the body becomes more probable. To increase specificity and likelihood of drug delivery, tumor specific ligands may be grafted onto the particles along with the chemotherapeutic drug molecules, to allow these molecules to circulate throughout the tumor without being redistributed into the body.

Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.

<span class="mw-page-title-main">Dextran drug delivery systems</span> Polymeric drug carrier

Dextran drug delivery systems involve the use of the natural glucose polymer dextran in applications as a prodrug, nanoparticle, microsphere, micelle, and hydrogel drug carrier in the field of targeted and controlled drug delivery. According to several in vitro and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV.

Conventional drug delivery is limited by the inability to control dosing, target specific sites, and achieve targeted permeability. Traditional methods of delivering therapeutics to the body experience challenges in achieving and maintaining maximum therapeutic effect while avoiding the effects of drug toxicity. Many drugs that are delivered orally or parenterally do not include mechanisms for sustained release, and as a result they require higher and more frequent dosing to achieve any therapeutic effect for the patient. As a result, the field of drug delivery systems developed into a large focus area for pharmaceutical research to address these limitations and improve quality of care for patients. Within the broad field of drug delivery, the development of stimuli-responsive drug delivery systems has created the ability to tune drug delivery systems to achieve more controlled dosing and targeted specificity based on material response to exogenous and endogenous stimuli.

<span class="mw-page-title-main">Reduction-sensitive nanoparticles</span> Drug delivery method

Reduction-sensitive nanoparticles (RSNP) consist of nanocarriers that are chemically responsive to reduction. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.

Protein nanotechnology is a burgeoning field of research that integrates the diverse physicochemical properties of proteins with nanoscale technology. This field assimilated into pharmaceutical research to give rise to a new classification of nanoparticles termed protein nanoparticles (PNPs). PNPs garnered significant interest due to their favorable pharmacokinetic properties such as high biocompatibility, biodegradability, and low toxicity Together, these characteristics have the potential to overcome the challenges encountered with synthetic NPs drug delivery strategies. These existing challenges including low bioavailability, a slow excretion rate, high toxicity, and a costly manufacturing process, will open the door to considerable therapeutic advancements within oncology, theranostics, and clinical translational research.

pH-responsive tumor-targeted drug delivery is a specialized form of targeted drug delivery that utilizes nanoparticles to deliver therapeutic drugs directly to cancerous tumor tissue while minimizing its interaction with healthy tissue. Scientists have used drug delivery as a way to modify the pharmacokinetics and targeted action of a drug by combining it with various excipients, drug carriers, and medical devices. These drug delivery systems have been created to react to the pH environment of diseased or cancerous tissues, triggering structural and chemical changes within the drug delivery system. This form of targeted drug delivery is to localize drug delivery, prolongs the drug's effect, and protect the drug from being broken down or eliminated by the body before it reaches the tumor.

<span class="mw-page-title-main">Ligand-targeted liposome</span> Ligand-targeted liposomes for use in medical applications

A ligand-targeted liposome (LTL) is a nanocarrier with specific ligands attached to its surface to enhance localization for targeted drug delivery. The targeting ability of LTLs enhances cellular localization and uptake of these liposomes for therapeutic or diagnostic purposes. LTLs have the potential to enhance drug delivery by decreasing peripheral systemic toxicity, increasing in vivo drug stability, enhancing cellular uptake, and increasing efficiency for chemotherapeutics and other applications. Liposomes are beneficial in therapeutic manufacturing because of low batch-to-batch variability, easy synthesis, favorable scalability, and strong biocompatibility. Ligand-targeting technology enhances liposomes by adding targeting properties for directed drug delivery.

<span class="mw-page-title-main">Artificial white blood cells</span> Alternative method of immunotherapy

Artificial white blood cells are typically membrane bound vesicles designed to mimic the immunomodulatory behavior of naturally produced leukocytes. While extensive research has been done with regards to artificial red blood cells and platelets for use in emergency blood transfusions, research into artificial white blood cells has been focused on increasing the immunogenic response within a host to treat cancer or deliver drugs in a more favorable fashion. While certain limitations have prevented leukocyte mimicking particles from becoming widely used and FDA approved, more research is being allocated to this area of synthetic blood which has the potential for producing a new form of treatment for cancer and other diseases.

Immunoliposome therapy is a targeted drug delivery method that involves the use of liposomes coupled with monoclonal antibodies to deliver therapeutic agents to specific sites or tissues in the body. The antibody modified liposomes target tissue through cell-specific antibodies with the release of drugs contained within the assimilated liposomes. Immunoliposome aims to improve drug stability, personalize treatments, and increased drug efficacy. This form of therapy has been used to target specific cells, protecting the encapsulated drugs from degradation in order to enhance their stability, to facilitate sustained drug release and hence to advance current traditional cancer treatment.

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