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The Second International Conference on Applications of Advanced Technologies (ICAAT2)
Smart drug delivery systems: Concepts and clinical applications
Saeideh Hosseini1
1Independent Researcher
*Email: hsaeideh@gmail.com
5
Abstract
Given that the production of a new drug molecule is time consuming and costly, pharmaceutical scientists seek to
create a drug delivery system that is safe, effective, stable, and has good patient compliance. Targeted drug
delivery is an advanced method of drug delivery that involves the controlled release of drugs at the target site
(organs / tissues / cells) over a period of time. Targeted drug delivery is also known as smart or Intelligent drug
10
delivery. In this method, the prescribed dose is reduced, which in turn improves the treatment by reducing the side
effects of the drug. In designing such systems, important factors that should be considered are: Chemical and
physical properties of drugs, Side effects or cytotoxicity for healthy cells, the route to be taken to deliver the
medicine, the desired location, disease, Specific properties of target cells, the nature of markers or transport
carriers or vehicles, which carry drugs to specific receptors and ligands and physically modulated components.
15
The various drug carriers that can be used in this advanced delivery system include: Polymer-drug conjugates and
nanoparticle systems such as Inorganic nanoparticles (e.g., magnetic nanoparticles, quantum dots), Dendrimers,
liposomes and lipoproteins are monoclonal antibodies, microspheres, microemulsions and neutrophils, fibroblasts,
artificial cells, micelles and immune micelles. These drug delivery systems are used in stem cell therapy,
regeneration methods and cancer treatments. In this review article, the drug delivery system and the importance
20
of targeting strategies as well as the basic aspects of targeted drug delivery were studied. Current approaches and
future perspectives on clinical applications are also presented.
Keywords: Targeted drug delivery, Magic bullet, Smart drug delivery systems, stimulant-sensitive materials
1. Introduction
25
Conventional drug delivery systems (DDS) often have systematic side effects Due to nonspecific biological
distribution and uncontrolled drug release characteristics. Since drug delivery technology can have commercial
and therapeutic value for health products, there has been rapid growth in drug delivery over the past three decades.
[1] Controlled drug delivery is an essential tool in controlling the release of the required amount of drug, increasing
the effectiveness of the drug in the body, protecting it from physiological degradation, the ability to control the
30
actual drug delivery site, and thus improving patient comfort [2-5]. The first generation of controlled drug delivery
systems is a type of controlled release system that uses a polymer matrix or pump as a speed control device to
deliver the drug in a fixed and predetermined pattern for an arbitrary period of time [6] These systems have the
following advantages over other prescription methods: (1) the possibility of maintaining the plasma drug levels,
which is therapeutically desirable, (2) The possibility of eliminating or reducing side effects from systemic
35
administration (3) The possibility of improving and facilitating drug administration in areas with poor medical (4)
Title of Manuscript
The possibility of prescribing drugs with a short half-life in the body, (5) Reduction of pain caused by high doses,
(6) the possibility of increasing in patient compliance, and (7) The possibility of producing a relatively low cost
product and less drug.
The design of drug delivery systems is difficult due to the existence of different mechanisms in drug secretion
40
processes. [7] Various factors such as drug uptake or limitations of drug release into the environment, drug
properties, method of administration, nature of vehicle, drug release mechanism, targeting ability, and
biocompatibility should be considered for effective treatment. these cases briefly Shown in Figure 1. In addition,
the reliability and reproducibility are the key points in the design of such a system. Achieving a system that
includes all of these is not easy due to the widespread independence of these factors.
45
Figure 1: Design requirement for a drug delivery system. [8]
2. Different Approaches (Systems) for Controlled Drug Delivery
Sustained Drug Delivery (Zero Order Release Profile)
Injectable or ingestible drugs have first-order kinetics, so that after administration, the initial level of the drug
50
in the body is at the highest possible value and then decreases in concentration, thus reducing the effect of the
drug. Therefore, it is considered an undesirable kinetics. Especially in cases where the distance between the
toxicity and the required level of therapeutic concentration is small. The graph of concentration changes is shown
in Figure 2.
55
Figure 2: Plasma concentration versus time curve for intravenous (IV) drug administration showing first-order
kinetic [8]
Title of Manuscript
Drug delivery systems with controlled release are characterized by a continuous drug release profile that
corresponds to zero-order kinetics. In this case, the blood level of the drugs remains constant during the delivery
period. Therefore, drug delivery systems with continuous release have significant therapeutic benefits and include
60
the following: Possibility of predicting in vivo release based on in vitro data; Decreased plasma peak levels and
the risk of toxic effects; Predictability of operation time and increased durability; Reduce discomfort by
administering repeated doses and thus improving patient compliance [9,10]. The constant plasma concentration,
which is desirable for many therapeutic agents, is shown in Figure 3.
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Figure 3: Plasma concentration versus time curve for sustained release profile of zero-order kinetics and
pulsatile release profile. [8]
Modulated Drug Delivery (Nonzero-Order Release Profile)
Creating a delivery system that has the ability to achieve a manipulable nonzero-order release profile is a
70
significant challenge in drug delivery. The drug release profile (curve) can take many forms, such as pulsatile or
ramp or some other pattern. Figure 2 shows pulsatile release profile within the therapeutic window. [8]
Feedback Controlled Drug Delivery.
The drug delivery system with feedback-controlled drug delivery that releases the drug in response to a
therapeutic marker is an ideal drug delivery system. modulated and triggered device are two classes of this system.
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A modulated device is characterized by the ability to monitor the chemical environment and the constant change
of drug delivery rate in response to a specific external marker, whereas in a triggered device the drug is released
only by stimulation by a marker. These different drug delivery approaches can be administered via oral,
pulmonary, pulmonary inhalation, transmucosal mucosa, and implantable systems. [8]
Implantable Controlled Drug Delivery Devices.
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Ideally, Implantable devices is electronically controlled with a long-life power source and follows a feedback-
controlled diffusion mechanism. Implantable devices are placed completely under the skin (usually in a
convenient but unspecified location) and are replaced by repeated IV catheters. These systems can be used in the
following cases: For the treatment of some diseases that require chronic medication. For a number of drugs that
cannot be delivered orally or are absorbed irregularly through the gastrointestinal tract (GI). (9). [11] These
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Title of Manuscript
systems are especially suitable for the pharmaceutical needs of insulin, steroids, chemotherapy, antibiotics,
painkillers, birth control pills and heparin.
Localized Drug Delivery.
In many cases, medications can be delivered to a specific location (tissue or organ). In this type of regional
treatment mechanism, systematic toxicity is reduced and the amount of drug in the desired location reaches the
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highest possible level. Medications such as anti-cancer drugs, anti-fertility drugs and anti-inflammatory steroids
need this type of treatment due to their many unwanted side effects. [8]
Targeted Drug Delivery
Ehrlich first introduced the concept of target drug delivery system based on the term "magic bullet" in 1906.
[12] The main idea of a targeted drug delivery system was based on three basic factors: namely finding the
95
particular target for the disease, finding the drug which will effectively treat the disease, and selecting appropriate
target vehicles to carry the drug in stable form while preventing other interactions and damage to the healthy
tissues. Targeted drug delivery is an intelligent drug delivery system in which a specific amount of a therapeutic
substance is delivered to a target area in the patient's body over a long period of time. [13,14] [15]. Cancers [16],
autoimmune diseases, neurological disorders, pulmonary diseases, cardiovascular diseases and most other
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conditions require effective, safe, specific targeting of drugs to certain receptors or direct delivery into the organ
[17] and TDD is expected to serve to these needs.
Ideally, TDD systems should have the following features: TDD systems should be biochemically inert (non-
toxic), non-immunogenic, physically and chemically stable in vivo and in vitro conditions. Additionally, they
should have restricted drug distribution to target cells or tissues or organs and should have uniform capillary
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distribution. TDD should have controllable and predictable rate of drug release and drug action should not depend
on the release kinetics. It should have therapeutic amount of drug release and minimal drug leakage during transit.
Carriers used should be bio-degradable or readily eliminated from the body without any problem. The preparation
of the delivery system should be easy or reasonably simple, reproductive and cost effective. [18-20]
3. Targeted Drug Delivery Carriers
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Targeted delivery requires special carrier systems. A TDD carrier is a special molecule, particle, composite, or
system that has the ability to hold the drug in or on them, either by encapsulation and / or by means of a separator.
[21, 22,19].
Drug Delivery Vehicles must meet several requirements: They must be able to pass through hard-to-reach
places, such as the blood-brain barrier, which can be easily identified by target cells, and in the case of tumor
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chemotherapy, tumor vessels. The drug ligand complex must be stable in biological fluids, plasma, interstitial and
other materials. It must be specifically and selectively identified by target cells and must retain the character of
Title of Manuscript
surface ligands. Once detected, the carrier system must release the drug into target organs, tissues, or cells. [21,
23, 24, 19].
The drug vehicle used must be non-toxic and non-immunogenic. high loading / encapsulation amount of the
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drug, [25] zero premature release of drug molecules, [26] cell type or tissue specificity and site directing ability,
and [27] proper controlled release rate of drug molecules to achieve an effective local concentration [25] are other
features of drug carriers.
At present, nanotechnology-based drug delivery systems have been studied due to the development and
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fabrication of various nanostructures. [16, 28]. These particles or structures can easily penetrate tissues (absorption
of nanoparticles is about 15-250 times higher than that of microparticles) and be absorbed by cells. They also
protect drugs from being destroyed by various gastrointestinal enzymes, so they can transport the drug to the target
as safely as possible. [29-31].
Nano-carrier-based TDDs have advantages such as higher surface-to-volume ratio, higher and more reactive
130
activity centers, stronger adsorption capacity, and other properties such as morphological preferences. The mode
of control and secretion of drugs by these carriers at the target sites is relatively unique and special, in that initially
an outbreak occurs and eventually leads to continuous release for a long time. Therefore, nanocarriers significantly
increase the efficacy of drugs in limited concentrations and also reduce the side effects of drugs and reduce the
suffering of patients from various diseases. [32]
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Figure 4: Targeted Drug Delivery Carriers [33,34]
4. Types of Targeted Drug Delivery
Increasing the therapeutic effectiveness and reducing the toxicity of the drug are among the benefits of targeting
the drug to an area of interest in the body. There are basically six strategies for drug targeting to the desired
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organ/tissue of interest: Passive Targeting, Active Targeting, Inverse Targeting, Physical Targeting, Dual
Targeting and Double Targeting. [35]
Title of Manuscript
4.1 Inverse Targeting
Reverse targeting of drugs means preventing inactive absorption of colloidal carriers by the Reticulo
Endothelial Systems (RES). This can be achieved by suppressing the regular function of RES by injecting large
145
amounts of empty colloidal carriers or macromolecules such as dextran sulfate. This method facilitates RES
saturation and suppresses the defense mechanism. This type is usually used as an effective way to target the drug
(s) to non-RES organs in the body. [36]
4.2 Physical Targeting
This approach can be achieved by changing some characteristics of environmental conditional changes such as
150
pH, system temperature, light intensity, magnetic field, electric field or ionic strength and other small and even
specific stimuli such as glucose concentration or gas concentration to localize the drug carrier at a predetermined
location. This method is used to target nanoparticles for tumors as well as in the cytosolic delivery of entrapped
drug or genetic materials. [37]
4.3 Dual Targeting
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In this system, the carrier molecule has therapeutic activity and therefore increases the therapeutic effect and
activity of the drug. For instance, the net synergistic effect of drug conjugate or the composite can be seen when
a carrier molecule with antibacterial or antifungal activity is loaded with an antibacterial or antifungal drug (e.g.,
loading antibacterial drugs on porous ZnO nanoparticles). [38]
4.4 Double Targeting
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The combination of temporal and spatial methodologies to target a carrier system is called dual targeting. Here,
it is possible to control the rate of drug delivery to the desired location by spatial placement targets drugs to
specific organs, tissues, cells or even subcellular containers and temporal delivery. [39]
4.5 Active Targeting
Active targeting is the specific interaction between the drug / drug carrier and target cells through specific
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ligand-receptor interactions for intracellular localization that occurs only after blood circulation and
extravasations. In this method, special modified nanosystems are used to identify and interact with specific cells.
Vitamins, carbohydrates, lipids, peptides and surface proteins, Antibodies and nucleic acids are among the various
targeting agents that are used in active targeting. [40-42]. The main reason for active targeting is the selectively
increase in the amount and size of drug delivery to target tumor cells due to the avid and specific interaction
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between nanocarriers and target cells. [43,42,44, 45]. This approach can be classified into three different levels
of targeting. 1) First order targeting, refers to the distribution of the drug in the capillaries of general target sites
such as compartmental targeting in lymphatics, peritoneal cavity, plural cavity, cerebral ventricles and eyes, joints.
Title of Manuscript
2) Second order targeting, selective drug delivery to specific cell types, such as tumor cells, rather than to normal
cells, for example, selective drug delivery to Kupffer cells in the liver. [46]. 3) Third order targeting is a specific
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type of drug delivery in which the drug is targeted intracellularly through endocytosis or through receptor-based
ligand interactions at the site. [22]
4.6 Passive targeting
Passive targeting is one of the natural phenomena that exists in the human body. Hormones, neurotransmitters,
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growth factors, etc. have a natural tendency to target receptors at their site of action, such as insulin and insulin
receptors. This concept also applies to drugs. Some tissues in disease conditions physiologically offer
opportunities that can be exploited by passively targeting nanocarriers. This is called the enhanced permeability
and retention (EPR) effect, in which nanocarriers accumulate in diseased tissues due to loosen fenestrations and /
or poorly formed lymphatic drainage (Figure 5). [47-49] [47,50-53,45]
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Accrual of drugs / drug-carrier systems at the site of operation leads to targeted drug secretion over a period of
time. [54,14,55]. Due to the clearance of nanocarriers by the reticulo-endothelial system (RES) consisting of
macrophages and mononuclear phagocytes, it can be used to passively target macrophages and even the lymph
nodes and spleen to treat infections that affect RES (e.g., Leishmaniasis and malaria). [56-59]. In order to create
features such as long-circulating, RES avoidance, and granting them time to accumulate at target sites in high
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amounts (long-circulating nanocarriers), Modifications (e.g., binding of polyethylene glycol; PEG) are often
performed on nanocarriers. [60]
Figure 5: A schematic representation of Passive targeting and Active Targeting [61]
internal stimuli, such as pH difference (e.g., low pH in tumor microenvironment [62]), redox systems (e.g.,
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exploiting high glutathione in cancer [63]), etc. are used in passive targeting. such stimuli provoke the Stimuli-
sensitive drug targeting systems and cause the drug to be released at the site. These systems have been widely
studied. [64-68]
Title of Manuscript
5. Stimuli and suitable smart DDSs
In controlled release systems, the activated drug can be released at the site in response to certain physical,
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chemical, or biochemical processes, some of which are induced internally and some externally. Therefore, they
can be classified into two main classes of responsive DDS: (1) Those that modulate or activate the release rate by
detecting changes in the biological environment (e.g., pH, temperature, or concentration of certain substances) are
termed closed-loop or self-regulating systems and (2) DDSs that release the drug (switch drug release on/off) as
a function of specific external stimuli (e.g., light, or electric or magnetic field) operate in open circuit and, if
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activated by an external agent, provide the drug pulse emission. [69,70]. Research into advanced excipients,
which can lead to responsive formulations, has provided an additional incentive to find suitable stimulant-sensitive
materials and increased the publication of articles on "smart" delivery systems.
Sensitivity to internal or external signals can be created in these systems by using synthetic or semi-synthetic
materials (mainly polymers) that have functional groups that change their properties as a function of signal
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strength. [71-73].
There may be various complications to these changes. For example, (i) the ability to change shape, solubility,
aggregation mode of individual components (e.g., assembly–disassembly of micelle unimers or sol–gel
transition); (ii) possible modifications in the conformation of chemically cross-linked networks that lead to the
volume phase transition in affinity towards other chemical or molecular species. (III) the Possibility to perform
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reversible stretching– shrinking of surface-immobilized chains or networks on inert substrates (Fig. 6). [70,74-
76]. These possible structural changes can be considered "intelligent" DDS behavior when they act reversibly and
in proportion to the intensity of the stimulus.
Figure 6: Some transitions associated with the responsiveness to a stimulus: (i) de-aggregation of amphiphilic
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polymers; (ii) volume phase transition; and (iii) helix to random coiling [77]
In many intelligent (smart) DDS, drug release requires structural changes throughout the carrier or in specific
layers or channels caused by the stimulus. [78-80]. These are designed to physically trap drugs. carriers made of
labile bonds or having the drug molecules conjugated through cleavable bonds, which are broken under the action
of the stimulus are affected by stimuli such as pH or enzymes [81].
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Title of Manuscript
Figure 7: Release of active agents from (a) supramolecular complexes like dendritic core–shell particles with a
cleavable shell and (b) dendritic scaffolds with attached solubilizing/stealth groups using cleavable linkers for the
drug conjugation. [81].
5.1 pH
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Because there are a variety of pH fluctuations in various organs and tissues of the body, such as the stomach
(pH≈ 2) and intestines (pH≈ 7), pH is one of the most widely used stimuli in smart DDS. [82-85]. Also, due to the
significant pH difference found at the cellular level between the cytosol (7.4), the Golgi apparatus (6.40), the
endosome (5.5-6.0) and the lysosome (4.5-5.5), They are especially suitable for design intracellular-specific
delivery. [86]. In addition, there is a difference between the extracellular pH of blood and healthy tissues (7.4)
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and damaged tissues such as tumor tissues (6.5-7.0) and inflammatory tissues (pH drop to 6.5). [87, 88]. Also,
healing progress index, is another application of pH-changes. [89] Although the pH stimulant is the most widely
used stimulant for drug secretion, but to achieve a very accurate and specific diffusion in the required places, it
must be combined with other stimuli such as temperature, oxidation. [90,67,91].
The use of polymers with weak acid (e.g., carboxylic acid) or base (e.g., primary and tertiary amines) groups
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that cause sharp changes in ionization at the desired pH is the basis for the development of pH-responsive systems.
In this way, changes in the conformation and affinity of the chains for the solvent, as well as the interactions
among them and resulting in either the disassembly of components or the swelling– shrinking of covalent networks
can be caused by increasing the degree of ionization. Changes in the nature of the co-monomers used to prepare
the polymer is a way to adjust the pH-responsiveness. [92]
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5.2 Redox conditions.
In nature, molecules containing sulfur (II) such as cysteine and cysteine-derived compounds (eg, glutathione,
GSH, etc.) are known as defense compounds. [93]. GSH – glutathione disulfide is the most important redox pair
in animal cells. Reduction of GSH by NADPH and glutathione reductase is a known redox system in cancer cells.
Also, since GSH is an intracellular substance present in different parts of the body and its amount in tumor tissues
250
is higher than healthy tissues (4 to 7 times more), therefore the role of GSH as a stimulus to stimulate drug release
in tumor cells Strengthens [94]. Thus, the design and fabrication of redox-responsive stimuli can be a promising
approach to the design of smart DDSs [95] and have received much attention for the treatment of diseases. [96,97]
Title of Manuscript
5.3 Molecule-responsiveness and imprinted systems
Stimulants such as pathological markers (e.g., enzymes and antibodies) that have the ability to precisely control
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and feed-back regulation of drug release have been extensively studied. Impaired regulation of enzyme function
causes many types of diseases, so it can be used to diagnose diseases. [98].
For example, overexpression of Capthesins, plasmin, urokinase-type plasminogen activator, prostate-specific
antigen, matrix metalloproteases, b-glucuronase, b-glucuronase carboxylesterases are a symptom of a tumor. [81].
The use of enzymes with distinctive features such as substrate specificity and high selectivity under mild
260
conditions has emerged as a stimulus in the design of smart DDS in recent years. [99-101].
Carriers prone to degradation by the relevant enzyme, drug–polymer conjugates with linkers as enzyme
substrates and Capped nanoparticles removable by enzyme function are considered as the basis for designing
enzymatically triggered DDSs. [103-106]
In addition, in another method, the internal (inner) pH of the network was changed by integrating the enzyme
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into the pH-responsive networks and the enzyme-substrate reaction. That is, in the absence of substrate, there is
no change in the conformation of the network, but at a certain concentration of the substrate, the reaction takes
place and the product causes a change in the local pH, and as a result will change the degree of swelling of the
network.
5.4 Temperature
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Temperature is one of the easiest and most effective stimulants to control drug secretion. [107-109]. In general,
thermo-sensitive nanocarriers are designed to store their payloads at a physiological temperature of 37° C and
when the temperature rises above 40-45 ° C, release the cargo quickly. Typically, pathophysiological conditions
such as inflammation, infarction or tumor, as well as infections caused by microorganisms cause a local increase
in temperature in the affected tissues [110,111]. Another temperature-responsive strategy is the concentrated
275
increase in temperature using external stimuli (e.g., ultrasound, magnetic field, etc.) that can be applied to the skin
or can be done by irradiating metals in DDS that heat energy. Converts, remotely created. [94].
5.5 Light
One way to stimulate drug release at the target by external light illumination are light-responsive systems.
Stimulation of formulations placed on the skin or that circulate through blood vessels close to the body surface
280
(e.g., eye structures) by ultraviolet (UV) rays and visible light causes the drug to be released. In Photo sensitive
carriers, excitation by one-time or repeatable light irradiation is accompanied by the opening or closing of the
nanostructure, resulting in the release of the drug. [95]. Knowledge related to Previously commercialized
photodynamic therapy-based treatments can be used to develop these responsive DDSs. However, limitation of
light wavelength is one of the drawbacks of practical treatment, which means that it inhibits non-invasive
285
programs for deep tissues. [112].
Title of Manuscript
5.6 Electrical field
Electrically sensitive networks can be created using polyelectrolytes with a high density in ionizable groups.
[113]. injectable drug-loaded microparticles or implants for subcutaneous insertion can be used to prescribe these
networks. In this way, by placing an electro-conducting patch on the skin through the implantation site and turning
290
on the battery, the protons move towards the cathode and by changing the pH near the electrodes, it causes the
network to shrink, thus the drug is released by squeezing. As the battery shuts off and the electric field is removed,
the hydrogel swells again. Therefore, it is possible to adjust drug release rate and duration by adjusting the
intensity of the electrical field and current application time.
5.7 Magnetic field
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Magnetite- and magmite-based nanoparticles are the most commonly used magnetic nanoparticles as contrast
agents for magnetic resonance imaging (MRI) [114]. Using magnetic stimuli, a non-invasive approach is possible
to temporally and spatially control of the carriers to the targets and Release of the drug is performed under
programmable exposure of external magnetic field. [115-117]. [94, 118-121] [122-128]. Compared to other
responsive systems that do not allow tissue guidance on their own, it is possible to guide and concentrate drug
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carriers with magnetic particles in a specific area using high-gradient magnetic fields. [114]. As a result, even at
low injectable doses, high local concentration occurs and when the alternating magnetic field is on, the drug is
released, resulting in site-specific treatment [129].
5.8 Ultrasound
Because ultrasound has high immunity and the ability to penetrate body tissues with low frequency and very
305
low scattering, it is widely used in clinics for diagnosis and treatment. Ultrasound can be applied to the body using
common physiotherapy equipment by adjusting the frequency, duty cycles and time of exposure to capture drug
carriers and trigger drug release. As a result, it can be used as a unique technique in the development of intelligent
nanocarriers (ultrasonic sensitive nanocarriers). [130-132]. In addition to identifying the effects of ultrasound on
cell apoptosis and genotoxicity, [133]. there are other barriers to the clinical use of ultrasound-responsive DDSs
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and theranostic systems that are being investigated. [134, 135]. For example, overcoming ultrasound attenuation
by bone is possible by combining modern imaging techniques, as a result, it is possible to deliver the drug through
the healthy skull to the target areas in the brain. [136].
5.9 Other responsive systems
Glucose and other Saccharide Sensitive Systems [137-139]. electro-responsive systems [113, 140-142] and
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Autonomous responsiveness are other stimuli used to control the release of payloads within nanocarriers. In
addition, the use of a hybrid stimulus can further improve the accuracy of drug delivery. Among these systems,
Dual stimuli-responsive DDSs have been extensively studied, such as thermo- and pH responsive systems
[143,144], thermo- and light responsive systems [145, 146], redox- and pH-responsive systems [67,91]. ultrasonic
Title of Manuscript
and magnetic responsive systems [147-151], In order to develop and use intelligent systems, a wide range of
320
stimuli with the ability to trigger the drug release at target place and expected time are included in nanostructures
(various nano-architectures). To ensure the sustainability and bioavailability of these strategies, it is necessary to
consider adjust the response to each stimulus both in vitro and in vivo.
Figure 8: Schematic illustration for stimuli-responsive DDSs. [152]
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Table1: Some medicines based on stimuli-responsive components that are in clinical trials or already
commercialized. [77, 152]
Product
Stimuli (Stimulus) /
Drug formulation
Structure
Clinical status
Opaxiot
Tumor enzyme
Paclitaxel poligumex
Approved orphan
drug for glioblastoma
multiforme
Trastuzumab-DM1
GSH concentration
Antibody–drug conjugate
Phase II/III in breast
cancer
Maytansine
GSH concentration
Antibody–drug conjugate
Phase II/III in
multiple myeloma
Nanocapsule
prototype
Dually responsive to
GSH and ROS
Camptothecin-based topoisomerase I
inhibitor conjugated to nanocapsules
In vivo tests with
breast tumor
xenograft models and
autochthonous colon
cancer models
Implant prototype for
antinflammatory
release
OH radicals
Lipoidal-chitosan-
poly(ecaprolactone) nanoparticles
coated with hyaluronic acid,
alginate and poly (acrylic acid)
Intraocular tests in
the rabbit model of
uveitis
Nanocarrier
prototype for tissue
plasminogen
activator (tPA)
Thrombin in the clot
tPA camouflaged with human serum
albumin via a thrombin cleavable
peptide, and coated with a homing
peptide that binds with GPIIb/IIIa
expressed on activated platelets
Rat thrombosis
model
Glucose biosensors
Guardian Real-
Times, Sevens,
Dexcoms G4t
Platinum, or Enlitet,
FreeStyle Navigators
Glucose
concentration
Glucose oxidase enzyme coupled to
other enzymes and transducers for
continuous monitoring of glucose
levels and regulation of insulin
release from pumps
Approved,
commercially
available
implantable
biosensors
Title of Manuscript
Table1: continued
Product
Stimuli (Stimulus) / Drug
formulation
Structure
Clinical status
Nanoparticles as
traps of bee venom
Melittin
Imprinted nanocarrier that
selectively captures melittin in
the bloodstream
Mice models
ThermoDoxs
Thermosensitive
(external source)
DPPC-based liposomes for
tumorspecific release of
doxorubicin
Phase III in liver cancer,
Phase II in chest wall
recurrence
of cancer, colorectal liver
metastases, lung cancer
and bone metastases
Phase II/III
Breast cancer, primary
liver cancer
Visudynes
UV light
NonPEGylated liposome
formulation of photosensitizer
verteporfin
Approved, commercially
available injectable
solution
Rotaxane-
functionalized
mesoporous silica
nanoparticles
UV light
Nanoparticles with pores
capped with chains of
triazole/ethylene glycol and
an azobenzene unit that
interact with a-cyclodextrin
Wild-type zebrafish
larvae
Cornell dots (C dots)
Near infrared radiation
Fluorescent core–shell
silicabased nanoparticles
Approved for human
stage I molecular
imaging of cancer
AuroShell
Near infrared radiation
Gold nanoparticles for solid
tumor hyperthermia
Phase I solid tumors
Thermosensitive
gold nanoshell
Nanospectra Biosciences
Phase I/ Intracranial
tumors
NanoXray products
X-rays
Hafnium crystals that amplify
the dose of radiation delivered
to the tumor
Phase I
Cochlear implants
coated with ICPs
Electrical stimulus
Coatings of intrinsically
conducting polymers that
switch neurotrophin release
on and off
Animal models
NanoTherms
Magnetic sensitive
(Magnetic field)
Water-dispersable iron oxide
nanoparticles coated with
aminosaline
Approved for
thermoablation of
glioblastoma; Phase I
prostate and pancreatic
carcinoma,
Phase I/II
www.magforce.de
Glioblastoma, prostata
cancer,eosphageal
cancer, pancreatic cancer
Nanocarrier prototype
for tissue
plasminogen
activator (tPA)
Ultrasound
tPA encapsulated in gelatin-
PEG nanoparticles for
localized thrombolysis
Rat thrombosis model
Opaxio
Enzyme-activated
polymeric NP
Cell Therapeutics, Inc.
Phase III/Ovarian cancer
Title of Manuscript
6. Applications
Targeted drug delivery systems in various diseases such as the treatment of various tumors (brain tumors, breast
330
cancer, ...), [153-155], cardiovascular diseases, [156, 157], neurological diseases such as depression, [158] oral
diseases (caries, oral cancer and gingivitis) [159] and also in the treatment of diseases Infectious diseases
(tuberculosis, malaria and immunodeficiency syndrome (AIDS)) have been used. [160]
7. Conclusion
Targeted drug delivery (TDD) is being developed as one of the most advanced medical science techniques in
335
the diagnosis and treatment of diseases. As the name implies, it means that the drug is delivered to the target cells
and tissues. This results in a lower dose as well as a significant reduction in side effects with maximum
bioavailability and high efficacy of the drugs. Nanoparticles are used as drug delivery systems due to their
chemical, physical and biocompatibility properties, which can improve the pharmacological and therapeutic
properties of drugs. There are countless nanoparticles that have been approved for clinical use. The inherent
340
advantage of this method has caused it to be considered as a highly preferred and facilitating field in the
pharmaceutical world.
Targeted drug delivery systems are faced with problems. For example, in most cases, drugs are synthesized in
poorly reproducible conditions and by non-standard methods. In addition, cytotoxicity, genotoxicity, antigenicity
and purification are the main topics to be clarified. The bioavailability of drugs embedded in smart DDS must be
345
measured in the target tissue or cell. Therefore, to do this, it is necessary to develop appropriate analytical
techniques. In this regard, guidance for the preparation and evaluation of materials by regulatory agencies is still
ongoing. Another problem attributed to targeting is the extrapolation of behavior from animal to human models.
Because small animals have pathologies, physiologies, anatomies, immune systems and host responses to
substances are significantly different compared to humans. [109]. This may include immune responses to
350
antibody-guided therapies and the inability to achieve consistent pharmacokinetics during the transition from
preclinical animal studies to clinical trials. There is also limited information on in vivo function. Evaluating the
cost-effectiveness of smart products is another important point in this regard. [161]. Despite the relevant concerns
mentioned above, TDDS is still an appropriate approach to achieving optimized design, easily translatable
production and evaluation in humans of more efficient formulations, and continued exploration will lead to the
355
development of successful treatments. Among the new plans for the future are the creation of multifunctional
devices that are able to meet different biological and therapeutic needs, as well as scaling processes that rapidly
bring innovative medical institutions to market.
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