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. 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. 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. 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 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.
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. 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 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. 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. 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. These coatings were used on drugs delivered to the stomach, so that they would protonate and dissolve at low pH to release drug. 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. 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. 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. 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). These systems are governed by hydrophilic and hydrophobic interactions of self-assembled drug carriers within a certain pH range. 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. 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.
Redox-responsive
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