Stimuli-Responsive Drug Delivery Systems (PDF)

 Advanced Drug Delivery Systems (PT 707) Mohammed Fawzy, PhD Pharmaceutics and Pharmaceutical Technology Department, Egyptian Russian University STIMULI-RESPONSIVE DRUG DELIVERY SYSTEMS  DEFINI...

 Advanced Drug Delivery Systems (PT 707) Mohammed Fawzy, PhD Pharmaceutics and Pharmaceutical Technology Department, Egyptian Russian University STIMULI-RESPONSIVE DRUG DELIVERY SYSTEMS  DEFINITION Stimuli-responsive drug delivery systems release the carried drug when specific stimuli are sensed, preferably at the diseased site to maximize efficacy and minimize adverse effects of the active pharmaceutical ingredient.  ADVANTAGES 1. Drug delivery systems providing a stimuli-triggered drug release, allow for a decrease in dosing frequency, which lead to a higher patient adherence. 2. Furthermore, the targeting properties of novel drug delivery systems in comparison to conventional formulations provide a higher bioavailability of the given drug and allow for reducing drug doses, leading to a safer and more efficient therapy with lower adverse drug reactions. 3. Using stimuli-responsive drug delivery systems overcame the problem of premature drug release in nonspecific sites.  CONCEPT In order to release an active pharmaceutical ingredient at a specific location, stimuli-responsive drug delivery relies on materials that can undergo a physicochemical change when exposed to changes in the surrounding microenvironment. The term “stimuli” refers to factors that can cause this environmental change.  CLASSIFICATION Two approaches can be used in designing stimuli- responsive DDS. In one approach, endogenous stimuli which are mainly unique for diseased tissue, can be utilized for enhancing drug action specificity. In the second approach, physical stimuli are applied externally to targeted tissue after administration of drug-loaded specific carriers. A) ENDOGENOUS STIMULI-RESPONSIVE DDS  A) ENDOGENOUS STIMULI-RESPONSIVE DDS The endogenous stimulus of biochemical and chemical origin includes redox-responsive, enzyme responsive, pH-responsive, and ionic microenvironment responsive drug delivery systems. These DDS trigger the delivery of drugs by regulating the microenvironment tissues, over-expression of specific enzymes, antibody-antigen interaction, and recognition of host-guest moieties in a specific state.  1) REDOX-RESPONSIVE DDS Redox-responsive agents such as disulfide bond (-S-S-), thioether bond (-S-), and thiol group (-SH) are frequently used in drug delivery systems for targeting the redox responsive sites. The redox-sensitive property of the DDSs can be used to formulate a prodrug, where role of linkers in the delivery of drug is highly important.  1) REDOX-RESPONSIVE DDS (CONT.) The difference between the extra- and intra-cellular redox environments has been used for drug delivery using redox- sensitive linkers. Macromolecular prodrugs have been developed which contain disulfide-based linkers that remains stable in the extra-cellular space while undergo some changes upon cellular uptake.  APPLICATIONS 1) Gene-delivery systems containing disulfide linkages were prepared and taken by endocytosis then undergo disulfide cleavage in the lysosomal compartments. The glutathione pathway which controls the intracellular redox potential was significantly involved in this stimuli mechanism. The use of these reducible polymers for gene delivery result in the efficient gene transfection in vivo while limiting the toxicity.  APPLICATIONS (CONT.) 2) These systems are also helpful to deliver nucleic acid therapeutics to tumors with altered redox state. 3) Redox-sensitive DDS is most suitable for sustained delivery of dopamine to brain. 4) Redox-sensitive chemical delivery system is helpful for delivery of steroids.  2) ENZYME-RESPONSIVE DDS Enzyme-responsive DDS is a system that undergoes macroscopic transitions in its physicochemical properties upon the biocatalytic action of the enzyme. In enzyme-responsive DDS, the drugs are released out of the drug-loaded carriers upon enzyme-assisted degradation of polymeric moiety. Among different enzymes, proteases are of supreme interest to fabricate novel DDS, since they are often over-expressed in infectious diseases, such as cancer and inflammation.  APPLICATIONS 1) Dual enzyme-responsive nanocapsules was developed to deliver anticancer agents specifically inside cancer cells. The degradation of nanocapsule walls in the presence of trypsin or hyaluronidase leads to the release of the encapsulated drug molecules at a rapid rate. The integration of two or more enzymes synchronously, for enzyme-mediated DDS, could increase the accuracy and sensitivity of the method. 2) Also, Oxidoreductases have been considered as therapeutic targets due to their central role in oxidative stress and their involvement in diseases such as Alzheimer’s and cancer.  3) pH-SENSITIVE (RESPONSIVE) DDS pH of the human body varies and can be utilized for various pH-responsive DDS. While considering oral DDS, there is a pH difference between the stomach and intestine. Cancer and inflammatory tissues are slightly acidic with pH 6.5 – 7.2, whereas intracellular cytosol, endosome, and lysosome have pH values of 7.4, 5.0 – 6.5, and 4.5 – 5.0, respectively.  3) pH-SENSITIVE (RESPONSIVE) DDS The pH is an important signal, which can be addressed through pH- responsive materials. Weak acids and bases like carboxylic acids, phosphoric acid, and amines exhibit a change in the ionization state upon variation of the pH. This leads to a change in the conformation for the soluble polymers. Swelling behavior of the hydrogels also changes when these ionizable groups are linked to the polymer structure. This behavior induces controlled release of carried drug.  3) pH-SENSITIVE (RESPONSIVE) DDS The extracellular and intracellular pH profile of biological system is greatly affected by diseases. The pH at systemic sites of infections, primary tumor, and metastasized tumor are lower than the pH of the normal tissue. So, pH sensitive preparations have been designed in order to overcome such diseases.  APPLICATIONS 1) The pH-sensitive liposomes have been designed to deliver highly hydrophilic molecules or macromolecules into the cytoplasm. 2) The intracellular delivery of pH-sensitive polymeric micelles release anticancer drug doxycycline in response to acidic pH at endosomes (pH 5.0 – 6.0) and lysosomes (pH 4.0 – 5.0), which may be helpful for the treatment of tumor. B) EXOGENOUS STIMULI-RESPONSIVE DDS  B) EXOGENOUS STIMULI-RESPONSIVE DDS Unlike endogenous stimuli-responsive DDS, the exogenous one has the potential benefit of overcoming inter-patient variability since, in these systems, drug release is controlled by external factors, which can be controlled precisely. Different external stimuli have been reported, which can be used to control drug releases such as temperature, magnetic field, light, electrical field, and ultrasound. In designing these DDS, thermo-responsive polymers have a significant role since most of these stimuli respond by heat generation.  1) TEMPERATURE-RESPONSIVE DDS Temperature or thermo-responsive DDS are one of the widely explored exogenous stimuli-responsive DDS. Overall, thermo-responsive drug carriers retain drug in normal physiological temperature and release drug upon exposure of higher temperature of diseased tissue. Two strategies have been reported for thermo- responsive drug release:  1) TEMPERATURE-RESPONSIVE DDS (STRATEGIES) First, thermo-responsive drug carriers are designed to respond to internal higher temperature for drug release. This higher temperature is an intrinsic characteristic of diseased/tumor tissue (internal stimulus). E.g. Polycaprolactone nanoparticles loaded with 5-Fluorouracil and Quercetin for tumor treatment. These dual drugs loaded NPs exhibited thermo-responsive behavior and a significant increase in drug release was reported at a higher temperature (40◦C) of diseased tissue as compared normal tissue temperature.  1) TEMPERATURE-RESPONSIVE DDS (STRATEGIES) In the second approach, drug carriers were designed for drug release in response to a higher temperature, which is achieved by external stimulus over targeted tissue. This strategy is also used for inducing hyperthermia for thermal-based therapy along with chemotherapy. Commonly employed external stimuli for this purpose are a magnetic field, light, ultrasound.  THERMO-RESPONSIVE POLYMERS Thermo-responsive polymers are the key members of these systems as they can respond to temperature change. There are two types of reported behaviors for thermo- responsive materials including lower critical solution temperature (LCST) and upper critical solution temperature (UCST).  THERMO-RESPONSIVE POLYMERS In the case of LCST, the decrease in temperature below LCST is responsible for increase swelling and leading to the increase in hydrophilicity. In contrast, for polymers with UCST character, an increase in temperature above UCST leads to an increase in hydrophilicity. This alteration in hydrophilicity controls swelling behavior of drug carriers, which lead to controlled drug release.  2) PHOTO/LIGHT-RESPONSIVE DDS Photo/light responsive DDS are widely explored systems which released the carried drug in response to light. The different wavelength range of light (ultraviolet, visible, and near-infrared) were reported to be used for controlling drug release. However, due to poor penetration, visible and UV light are not considered suitable for in vivo therapeutic applications while the NIR range is the potential source of light for controlling drug release due to safety and better tissue penetration.  2) PHOTO/LIGHT-RESPONSIVE DDS (TYPES) Photo-related therapy includes photodynamic therapy (PDT) and photothermal therapy (PTT). 1) PDT is a new clinical treatment for superficial tumors and age-related muscular degeneration. This technique involves the systemic administration of a photosensitive drug and light irradiation to the affected tissue. This photosensitizer generates singlet oxygen after light irradiation and causes oxidative damage to cells. PDT affects only the irradiated areas because singlet oxygen is short-lived, making it a site- specific and noninvasive treatment. VIDEO 1  2) PHOTO/LIGHT-RESPONSIVE DDS Hypericin is a powerful naturally occurring photosensitizer which is considered a promising agent in PDT of cancer due to its minimal toxicity, low concentration necessary to trigger photocytotoxicity, high clearance rate from the host body and due to its large absorption in the visible spectrum.  2) PHOTO/LIGHT-RESPONSIVE DDS 2) PTT involves the systemic administration of gold nanoparticles and light irradiation of the affected tissues, similar to PDT with photosensitizers. Gold nanoparticles generate heat after light irradiation and this damages the cells. VIDEO 2  3) MAGNETIC-RESPONSIVE DDS The magnetic field can penetrate in the body tissue and is commonly employed for body imaging in MRI. Controlling drug release from magnetic field responsive carriers through external magnetic field stimulus have also been explored. Two mechanisms have been reported in this regard: a) The magnetic field induced hyperthermia for drug release and b) the magnetic field guided drug targeting.  3) MAGNETIC-RESPONSIVE DDS Hyperthermia-based magnetic nanoparticles have been widely explored in the recent decade for drug delivery applications. In addition, local hyperthermia can also cause tumor inhibition along with the provision of imaging opportunity due to the presence of a magnetic response.  4) ULTRASOUND-RESPONSIVE DDS Due to safety, tissue penetration, non-invasiveness, and better control, ultrasound waves have been explored as an external stimulus on target-controlled drug release by many researchers. Thermal, mechanical effects, and radiation forces produced by ultrasound waves are responsible for stimulating drug release for carriers.  4) ULTRASOUND-RESPONSIVE DDS (EXAMPLE) Mesoporous silica nanoparticles (MSN) PEGylated by a thermo-responsive linker was developed. Applied external ultrasound (US)-induced heat cleaved thermo-responsive linker leading to the removal of the protecting PEGylation and exposed the Positively charged MSNs which exhibited enhanced cellular uptake. E.g. Tepotecan-loaded US responsive MSNs showed a significant reduction in viability of human osteosarcoma cells in the presence of ultrasound.  DUAL/MULTI-RESPONSIVE DDS Apart from single stimulus responsive DDS, some DDS have been reported that can respond to dual or multi-stimuli to enhance the efficiency of targeting. These stimuli may be endogenous or exogenous or a combination of both. Examples: 1) pH and redox (dual endogenous stimuli) responsive micelles for tumor targeting. 2) Cisplatin loaded NIR and redox-responsive (exogenous and endogenous stimuli) reactive smart nanoparticles for tumor targeting. THANK YOU