Stimuli-responsive drug delivery systems

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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. [1] 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.

Contents

Endogenous stimuli consist of chemical, biological, and physical stimuli that occur naturally in the body, such as changes in pH, temperature, enzymatic action, pressure, and shear forces. More specifically, endogenous chemical stimuli include environmental pH, redox reactions, and chemical gradients, each of which are typically out of physiological range or unique to a specific or diseased tissue, which provides the ability to achieve target specificity using these particular stimuli for release. [2] Researchers have worked to develop numerous types of drug delivery systems that harness a response to endogenous chemical stimuli to achieve targeted delivery and controlled release of drug into a specific environment. These chemically responsive drug delivery systems can be created using a wide variety of materials and carriers, including lipid, protein, or polymeric materials to create degradable scaffolds or depots and micelles and nanoparticles. [3] An example of this includes the engineering of biopolymeric nanospheres that are triggered to release an encapsulated therapeutic when they enter the tumor microenvironment due to the drop in pH associated with the tumor microenvironment. Many of these systems rely on the application and manipulation of click chemistry to achieve stimulated response [2] The field of endogenous chemical-responsive systems has developed greatly within the last 20 years and continues to grow as researchers determine new applications for the field, including the development of chemically responsive systems for diagnostic purposes. [1]

Endogenous chemical stimuli-responsive drug delivery systems are important in the field of drug delivery because of their ability to harness chemical phenomena within the body to overcome traditional therapeutic release limitations such as temporal release and tissue permeability. These drug delivery systems can be applied both as diagnostic and treatment tools for diseases like cancer to achieve long-term action and maximize the therapeutic effect.

History

While the study of drug delivery methods and techniques has been around for centuries, the modern field of drug delivery we know today was not introduced until the 1960s, when the concept of controlled drug delivery systems was introduced by Judah Folkman, MD of Harvard. [4] He first introduced the idea of a prolonged drug release system as a means of constant rate delivery while experimenting with anesthetic gases and arterio-venous shunts on mice [4] This inspired the formation of a company called ALZA by a chemist named Alejandro Zaffaroni, whose primary focus was on the development of drug carrying systems that would increase the specificity and efficacy of drugs. [1] The introduction of this concept led to the development of the field we know today, with macro scale delivery devices being developed in the 1970s and 1980s before moving into more focused development of microscale and nanoscale devices in the late 1980s onward. [4] The concept of stimuli-responsive drug delivery systems can actually be seen as ahead of this time, since the first pH-responsive drug coating was used in the late 1950s in Europe. [4] These coatings were used on drugs delivered to the stomach, so that they would protonate and dissolve at low pH to release drug. [4] The development of stimuli-responsive drug carriers was not popularized until the mid-1980s by researchers at Utah University, who created thermally-responsive drug delivery systems. [4] Since the eruption of this field, substantial research has been conducted to tune stimuli-responsive drug delivery systems despite several limitations. As of 2013, a redox-responsive therapy targeting metastatic breast cancer had been approved by the FDA but was not yet currently in use. [1] Much work is still being done to continue the development of this field in hopes of one day making stimuli-responsive drug delivery systems commonplace in medical practice.

Type of stimuli and their mechanisms of action

pH-responsive

pH responsive drug delivery systems respond to the environmental pH of a tissue, which, when existing within a certain acidic range, can lead to structural and chemical changes of the drug delivery system. These changes can include conformational changes and surface interactions that can lead to the degradation or swelling/shrinking of the drug carrier. [1] pH responsive drug delivery systems are possible because of the tendency of diseased or cancerous tissues to maintain a lower pH value than is physiologically normal due to high rates of tumor cell metabolism (normal: 7.4, lower range: 5.0-6.5). [2] [5] These systems are governed by hydrophilic and hydrophobic interactions of self-assembled drug carriers within a certain pH range. [2] These hydrophilic and hydrophobic interactions can cause the destabilization of these systems, which lead to conformational changes that cause the drug carrier to breakdown or degrade. As a result, the drug is released from the system. pH responsive drug delivery systems are typically synthesized from pH-responsive polymers that have been conjugated with ionic residues that change charge based on the pH of the environment. [1] Systems used with pH-responsive polymers include implantable hydrogels and micro- and nanoparticles. pH-responsive drug delivery systems are particularly suitable for the design of chemotherapeutic delivery systems due to the naturally low pH found in tumor microenvironments, but can be applied in other disease settings where the pH of the varies from physiological pH. The highly targeted and controlled release ability, as well as their broad applications, make pH-responsive drug delivery systems some of the most well-researched and sought after clinical solutions in stimuli-responsive drug delivery. [3]

Redox-responsive

Example of intratumoral redox-responsive drug delivery Redox-Responsive Drug Delivery.png
Example of intratumoral redox-responsive drug delivery

Redox responsive drug delivery systems rely on the natural reduction-oxidation reactions that occur in the body and the availability of reducing or oxidative-agents in the extracellular and intracellular space. [2] In redox-stimulated responses, drug carriers enter the intracellular space through endocytosis and are destabilized by intracellular concentrations of reducing agents, leading to their disassembly and the delivery of the therapeutic intracellularly. [2] For example, the use of redox stimulated drug delivery is primarily attributed to the high intracellular concentration of glutathione (GSH) as compared to the much lower extracellular concentration of GSH. [6] GSH acts as a reducing agent in redox reactions, allowing it to cleave bonds like disulfide bonds. The increased level of GSH in tumor cells combined with its ability to cleave disulfide bonds has led to the development of drug delivery systems, such as polymeric micelles, synthesized with disulfide bonds that are subsequently cleaved by intracellular GSH, which cause the breakdown of the micelle and the intracellular release of the encapsulated therapeutic. [5]

Gradient-responsive

Gradient responsive drug delivery systems are stimulated to deliver therapeutics through contact with an endogenous chemical gradient. When the system comes into contact with its specific chemical gradient, increased concentration of the chemical can lead to the conformational change or degradation of a drug carrier to allow drug release.[ citation needed ] Gradient responsive systems also include gradients created by pH or redox reactants.

Applications

pH-responsive drug delivery systems are very popular subjects of research for their variability in application. Deviations from physiological pH occur in numerous disease states including infection, inflammation, and cancer, which makes this stimulus one of the most widely researched in the field of endogenous chemically responsive drug delivery systems. [3] Applications of pH-responsive drug delivery systems include the synthesis of pH-responsive polymers into carriers like hydrogels, micelles, and micro- and nanovesicles. [3] pH-responsive polymers can be selected for certain applications based on characteristics like the drug concentration, number of ionizable groups, and the type of carrier being used. Examples of widely used pH-responsive polymers include but are not limited to: poly(acrylamide), poly(acrylic acid), and poly(methacrylic acid) [3]

Redox-responsive drug delivery systems are also widely studied for a variety of applications, in particular their use in targeting cancer due to the increased levels of GSH in cancerous cells. Redox-responsive drug delivery systems are also used in the delivery of DNA and siRNA for gene therapy. [2] Redox-responsive drug carriers are primarily synthesized as micelles or polymersomes and are highly stable because they contain a high amount of cross-linking [2]

Gradient-responsive drug delivery systems do not have a substantial body of research as of yet. The primary applications of gradient-responsive drug delivery systems are usually referenced as pH or redox gradients, as opposed to the gradients of other hormones or factors found naturally in the body. Aside from pH and redox gradients, there are no published works on gradient-responsive drug delivery systems.

StimulusCarrierTherapeuticTargetStatusReference
Redox-ResponsiveAntibody drug conjugateDocetaxelMetastatic breast cancerApproved by FDA in 2013 [1]
MicellesDoxorubicinCancer cellsExperimental [7]
MicellesPaclitaxelBreast cancerExperimental [8]
Silica nanoparticlesDoxorubicinCancer cellsExperimental [9]
pH-ResponsiveNanovesiclesPaclitaxelMetastatic lung cancerExperimental [10]
NanovesiclesDoxorubicinCancer cellsExperimental [11]
MicelleplexCisplatin prodrugTumorsExperimental [12]

Limitations

This Venn Diagram compares the limitations faced by endogenous chemically responsive drug delivery systems. Limitations of Endogenous Chemically-Responsive Drug Delivery Systems.png
This Venn Diagram compares the limitations faced by endogenous chemically responsive drug delivery systems.

There are many limitations that exist within the field of endogenous chemically responsive drug delivery systems that prevent many of these products from approved to be used in a clinical setting. One of the primary challenges of endogenous chemically responsive drug delivery is the inability to address or overcome patient heterogeneity. Patient heterogeneity describes the naturally-occurring difference between patient biology, such as differences in tumor pH for the same cancer and blood concentrations of redox reagents. [1] The targeting of many chemical properties in pathological tissues is also restricted by a small range of fluctuation of the chemical property, which prevents researchers from being able to safely and specifically target that diseased tissue and stimulus due to small windows of sensitivity that have yet to be optimized. [5] [13] Other important limitations to consider include the formulation of the drug carrier, which can affect the clearance rate and biodistribution of the drug carrier and decrease therapeutic efficacy due to size, shape, or effective penetration of the tissue by the drug carrier. [5] [13] Biocompatibility and toxicity of the drug carrier formulation also poses a significant challenge to the development of the field, so future studies need to be conducted using inherently biocompatible materials to ensure feasibility and safety of these proposed delivery systems. Finally, cost of production and the scalability of the creation of stimuli responsive drug delivery systems remains an enormous barrier between the development and clinical use of these delivery systems.

Related Research Articles

<span class="mw-page-title-main">Dendrimer</span> Highly ordered, branched polymeric molecule

Dendrimers are highly ordered, branched polymeric molecules. Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt a spherical three-dimensional morphology. The word dendron is also encountered frequently. A dendron usually contains a single chemically addressable group called the focal point or core. The difference between dendrons and dendrimers is illustrated in the top figure, but the terms are typically encountered interchangeably.

A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration. Drug carriers are primarily used to control the release of drugs into systemic circulation. This can be accomplished either by slow release of a particular drug over a long period of time or by triggered release at the drug's target by some stimulus, such as changes in pH, application of heat, and activation by light. Drug carriers are also used to improve the pharmacokinetic properties, specifically the bioavailability, of many drugs with poor water solubility and/or membrane permeability.

<span class="mw-page-title-main">Drug delivery</span> Methods for delivering drugs to target sites

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.

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.

Magnetic-targeted carriers, also known as MTCs or magnetic vehicles, are micro- or nanoparticles that carry an anticancer drug to the target site by using an external magnetic field and field gradient to direct the desired drug. Usually, the complex involves microscopic beads of activated carbon, which bind the anticancer drug. A magnet applied from outside the body then can direct the drug to the tumor site. This can keep a larger dose of the drug at the tumor site for a longer period of time, and help protect healthy tissue from the side effects of chemotherapy.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

<span class="mw-page-title-main">Chemotactic drug-targeting</span>

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. 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. 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. 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.

Smart polymers, stimuli-responsive polymers or functional polymers are high-performance polymers that change according to the environment they are in.

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

A nanocarrier is nanomaterial being used as a transport module for another substance, such as a drug. Commonly used nanocarriers include micelles, polymers, carbon-based materials, liposomes and other substances. Nanocarriers are currently being studied for their use in drug delivery and their unique characteristics demonstrate potential use in chemotherapy. This class of materials was first reported by a team of researchers of University of Évora, Alentejo in early 1960's, and grew exponentially in relevance since then.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

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">Polymer-protein hybrid</span> Nanostructures of protein-polymer conjugates

Polymer-protein hybrids are a class of nanostructure composed of protein-polymer conjugates. The protein component generally gives the advantages of biocompatibility and biodegradability, as many proteins are produced naturally by the body and are therefore well tolerated and metabolized. Although proteins are used as targeted therapy drugs, the main limitations—the lack of stability and insufficient circulation times still remain. Therefore, protein-polymer conjugates have been investigated to further enhance pharmacologic behavior and stability. By adjusting the chemical structure of the protein-polymer conjugates, polymer-protein particles with unique structures and functions, such as stimulus responsiveness, enrichment in specific tissue types, and enzyme activity, can be synthesized. Polymer-protein particles have been the focus of much research recently because they possess potential uses including bioseparations, imaging, biosensing, gene and 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.

<span class="mw-page-title-main">Gated drug delivery systems</span> Method of controlled drug release

Gated drug delivery systems are a method of controlled drug release that center around the use of physical molecules that cover the pores of drug carriers until triggered for removal by an external stimulus. Gated drug delivery systems are a recent innovation in the field of drug delivery and pose as a promising candidate for future drug delivery systems that are effective at targeting certain sites without having leakages or off target effects in normal tissues. This new technology has the potential to be used in a variety of tissues over a wide range of disease states and has the added benefit of protecting healthy tissues and reducing systemic side effects.

Pullulan bioconjugates are systems that use pullulan as a scaffold to attach biological materials to, such as drugs. These systems can be used to enhance the delivery of drugs to specific environments or the mechanism of delivery. These systems can be used in order to deliver drugs in response to stimuli, create a more controlled and sustained release, and provide a more targeted delivery of certain drugs.

<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.

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.

Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.

Stretch-triggered drug delivery is a method of controlled drug delivery stimulated by mechanical forces. The most commonly used materials for stretch-triggered autonomous drug release systems are hydrogels and elastomers.

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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