INTRODUCTION:

Targeted drug delivery as an event where, a drug-carrier complex/conjugate, delivers drugs exclusively to the pre-selected target cells in a specific manner. Targeted drug delivery implies selective and effective localization of pharmacologically active moiety at pre-identified target in therapeutic concentration, while restricting its access to non-target normal cellular linings, thus minimizing toxic effects and maximizing therapeutic index^1-4.

Figure 1: Emerging Formulation Theory of Targeted Drug Delivery

The site-specific targeted drug delivery negotiates an exclusive delivery to specific pre-identified compartments with the maximum intrinsic activity of drugs and concomitantly reduced access of drug to irrelevant non-target cells. The targeted delivery to previously inaccessible domains, e.g. intracellular sites, viruses, bacteria, and parasites offers distinctive therapeutic benefits. The controlled rate and mode of drug delivery to the pharmacological receptor and specific binding with target cells; as well as bioenvironmental protection of the drug en route to the site of action are specific features of targeting. Invariably, every event stated contributes to higher drug concentration at the site of action and a resultant lower concentration at non-target tissue where toxicity might crop up. The high drug concentration at the target site is a result of the relative cellular uptake of the drug vehicle, the liberation of a drug, and efflux of free drug from the target site^5-8.

The restricted distribution of the parent drug to the non-target site with effective access to the target site could maximize the benefits of targeted drug delivery. Drug targeting is a phenomenon in which the distribution of the drug in the body in such a manner that the major fraction of the drug interacts exclusively with the target tissue at a cellular or sub-cellular level. The objective of drug targeting is to achieve a desired pharmacological response at a selected site without undesirable interactions at other sites. This is especially important in cancer chemotherapy and enzyme replacement treatment. Drug targeting is the delivery of drugs to receptors or organs or any other specific part of the body to which one wishes to deliver the drug exclusively. The targeted or site-specific delivery of drugs is indeed a very attractive goal because this provides one of the most potent ways to improve the therapeutic index of the drugs. Several technological advances have since been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines. At present, drug targeting is achieved by one or two approaches. The first approach involves chemical modification of the parent compound to a derivative which is activated only at the target site^9-11.

The second approach utilizes carriers such as liposome’s, niosomes, microspheres, nanoparticles, antibodies, cellular carriers (erythrocytes and lymphocytes), and macromolecules to direct the drug to its site of action. Recent advancements have led to the development of several novel drug delivery systems that could revolutionize the method of medication and provide several therapeutic benefits. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug content. The ideal drug delivery system delivers drugs at a rate^11-14.

1. Nanoparticles:

Nanoparticles are one or several types of systems known collectively as colloidal drug delivery systems. Also included in this group are microcapsules, nanocapsules, macromolecular complexes, polymeric beads, microspheres, and liposomes. A nanoparticle is a particle-containing dispersed drug with a diameter of 200 to 500nm. Materials used in the preparation of nanoparticles are sterilizable, non-toxic, and biodegradable. They usually are prepared by a process similar to the coacervation method of microencapsulation. Nanoparticles are also called nanospheres or nanocapsules depending upon whether the drug is in a polymer matrix or encapsulated in a cell. The polymers used are the usual biodegradable ones. The main advantage of this system is that it can be stored for up to one year and can be used for selective target via the reticuloendothelial system to the liver and to cells that are active phagocytically¹⁵.

2. Niosomes:

Nonionic surfactant vesicles known as niosomes are used as carriers to deliver drugs to target organs and modify drug disposition. Niosomes are found to improve the therapeutic efficacy of drugs in cancer therapy, parasitic, viral, and microbial diseases. Many nonionic surfactants like cetrimide, sodium dodecyl sulfate are used with cholesterol to entrap drugs in vesicles. Livers can act as a depot for many drugs where niosomes containing drugs may be taken up by the liver where they are broken down by lysosomal lipase slowly to release the free drug to the circulation. Niosomes slowly degraded providing a more sustained effect. Niosomes are capable of releasing entrapped drugs slowly. Niosomes are found to have selective drug delivery potential for cutaneous application of 5- α – dihydro Testosterone triamcinolone acetamide and intravenous administration of methotrexate for cancer treatment and sodium stibogluconate in the treatment of leishmaniasis etc¹⁶.

Figure 2: Physical Structure of Niosomes¹⁶

3. Resealed Erythrocytes:

When erythrocytes are suspended a hypotonic in a hypotonic medium, they sell to about one and half times their normal size and the membrane ruptures result in the formation of pores with diameters of 200- 5000A⁰ . The pores allow equilibration of the medium that are adjusted to iso-tonicity and the cells are incubated at 370C, the pores will close and cause the erythrocytes to reseal. Using this technique with a drug present in the extracellular solution, it is possible to entrap up to 40% of the drug inside the resealed erythrocyte and to use this system for targeted delivery via intravenous injection. The advantage of using resealed erythrocytes as a drug carrier is that they are biodegradable, fully biocompatible, and non -immunogenic, exhibit flexibility in circulation time depending on their physicochemical properties, the entrapped drug is shielded from immunologic detection and chemical modification of drug is not required. Resealed erythrocytes can be targeted selectively to either the liver or spleen, depending on their membrane characteristics. The ability of resealed erythrocytes to deliver drugs to the liver or spleen can be viewed as a disadvantage in that other organs and tissues are inaccessible¹⁷.

Figure 2: Resealed Erythrocytes¹⁸

4. Microspheres:

Microspheres are free-flowing powders consisting of spherical particles of size ideally less than 125 microns that can be suspended in a suitable aqueous vehicle and injected. Each particle is a matrix of drugs dispersed in polymer from which release occurs by a first-order process. The polymers used are biocompatible and biodegradable ex. Polylactic acid, poly lactidecoglycolide, etc. Drug release is controlled by the dissolution/degradation of the matrix. The system is ideally suited for the controlled release of peptide/ protein drugs. To overcome uptake of intravenously administered microspheres by the reticuloendothelial system and promote drug targeting to tumors with good perfusion, magnetic microspheres were developed. They are prepared from albumin and magnetite and have the size of 1µ g to permit intravascular injection¹⁹.

Figure 3: Microspheres Encapsulation¹⁹

5. Monoclonal Antibodies:

Monoclonal antibodies can have monovalent affinity, binding only to the same epitope (the part of an antigen that is recognized by the antibody). In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different antibody secreting plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one monoclonal antibody to two epitopes. It is possible to produce monoclonal antibodies that specifically bind to virtually any suitable substance; they can then serve to detect or purify it. This capability has become an important tool in biochemistry, molecular biology, and medicine. Monoclonal antibodies are being used on a clinical level for both the diagnosis and therapy of several diseases²⁰.

Figure 3: Monoclonal Antibodies²¹

Monoclonal antibodies are exceptionally high-quality antibodies that consist of one molecular species and may be obtained in a virtually homogeneous state. Once monoclonal antibodies for a given substance have been produced, they can be used to detect the presence of this substance. Proteins can be detected using the Western blot and immuno dot blot tests. In immunohistochemistry, monoclonal antibodies can be used to detect antigens in fixed tissue sections, and similarly, immunofluorescence can be used to detect a substance in either frozen tissue section or live cells²².

6. Liposomes:

It is defined as a spherule vesicle of a lipid bilayer enclosing an aqueous compartment. The lipid most commonly used is phospholipids, sphingolipids, glycolipids, and sterols have been used to prepare liposomes. In recent years, liposomes have been extensively studied for their potential to serve as carriers for the delivery of drugs, antigens, hormones, enzymes, and other biologicals. Because liposomes are composed of naturally occurring substances they have the distinct advantage of being nontoxic and biodegradable. Biologically active materials encapsulated within liposomes are protected to various extents from immediate dilutions or degradations in vivo. This protective property promotes the delivery of entrapped drugs to the target organ by preventing a premature drug release after administration. Liposomes have two standard forms. Multilamellar vesicles (MLV’s) are made up of several lipid bilayers separated by fluid. Unilamellar vesicles (ULV’s) consist of a single bilayer surrounding an entirely fluid core. The ULV’s are typically characterized as being small (SUVs) or large (LUV)²³.

Figure 3: Example of Liposome Structure²³

Limitations of TDDS:

TDDS such as liposomes, resealed erythrocytes, and platelets suffer serious stability problems. Although monoclonal antibodies show a very high degree of site-specificity the selection and isolation procedures are too tough. If the particle size of TDDS is high, they may be rapidly cleared by RES. Magnetically controlled TDDS shows high specificity to superficially located organs and tissues but cannot be targeted to deep-seated organs. Monoclonal antibodies may sometimes cause an unwanted antigen-antibody reaction which leads to serious consequences. Microspheres of particle size more than 50µg can lead to a problem of thromboembolism in general circulation. One administered drug cannot be removed if an undesirable action is precipitated or if the drug is no longer needed. Most of such systems are administered by subcutaneous or intraperitoneal route. The vehicles polymer employed should be sterile, hydrogen-free, nonirritating, biocompatible biodegradable, and biodegradable into nontoxic compounds within an appropriate time, preferably close to the duration of action. The products which tend to remain intact may become lodged at some sites. If these occur slow release of drug from dosage form leads to a high localized concentration of drug which caused local irritation. Drugs having a biological half-life of 1 hr or less are difficult to formulate as controlled release formulation. The high rates of elimination of such drugs from the body need an extremely large maintenance dose which provides 8-12 hrs of continuous therapy. As these products normally contain a large number of drugs there is the possibility of unsafe overdosage if the products are improperly made. If it is once administered it may be difficult to stop the therapy due to toxicity or any other reasons²⁴.

Merits of TDDS:

Targeting of the drug molecule towards the issue or organ reduces the toxicity to the normal tissues. Increase bioavailability. Improved treatment of many chronic illnesses where symptom breaks through occurs when the plasma level of the drug falls below the MEC. The drug is protected from first-pass metabolism and GI degradation. Improved patient compliance can be achieved due to a decrease in the amount and frequency of dose administered. Biocompatibility can be well achieved. Maintenance of therapeutic action of the drug overnight. Systemic and local side effects are successfully reduced due to the reduction in the total amount of the drug. Magnetically controlled systems can be used for targeting the drug towards superficial tissues. Economic savings can be claimed due to the reduction of the total amount of drugs used²⁴.

Applications of TDDS:

Red blood cells, leukocytes, lymphocytes, and fibroblasts have also been used as potential delivery vehicles for drugs. They have the advantage of inherent biocompatibility, but they cannot cross barriers and cannot easily fuse with other cells erythrocytes have been explored as possible carriers for Methotrexate and Adriamycin. Many of the more biocompatible polymers can be used as small soluble molecular drug carriers or they can be assembled as both soluble molecular drug carriers or they can be assembled as soluble and particulate drug vehicles. A large number of drugs or agents can be incorporated through noncovalent forces in the assembled polymers. These particulate systems are best utilized as sustained-release vehicles. Bovine albumin or bovine serum albumin and human serum albumin have been extensively investigated for target-specific and sustained delivery of cancer chemotherapeutic agents. The intraperitoneal administration of micro-spheres sustained the drug release over a while²⁵.

Carrier Systems used for Targeted Drug Delivery^26-29:

1. Colloidal Carriers:

a) Vesicular system Liposomes; Niosomes; Pharmacosomes; Virosomes; Immuno liposomes.

b) Microparticulate systems Microparticles; Nanoparticles; Magnetic-micro spheres; Albumin microspheres; Nano-capsules.

2. Cellular Carriers:

Resealed erythrocytes; serum albumin; antibodies; platelets; leukocytes.

3. Supramolecular Delivery Systems:

Micelles; reverse micelles; mixed micelles; polymeric micelles; Liquid crystals; Lipoproteins (chylomicron; VLDL; LDL) Synthetic LDL mimicking Particles (supramolecule bio vector system).

4. Polymer Based Systems:

Signal sensitive; Muco-adhesive; Biodegradable; Bio-erodible; soluble synthetic polymeric carriers.

5. Macromolecular Carriers:

a) Proteins, glycoproteins; neo glycoproteins, and artificial viral envelopes (AVE).

b) Glycosylated water-soluble polymers (poly-L-lysine).

c) Mabs; Immunological Fab fragments; antibody-enzyme complex & bispecific Abs.

d) Toxins, immunotoxin & rCD4 toxin conjugates.

e) Lectins (Con A) & polysaccharides.

Levels of Drug Targeting^30-32:

Targeted drug delivery may be achieved by using carrier systems, where reliance is placed on exploiting both, the intrinsic pathway(s) that these carriers follow, and the bio-protection that they can offer to drugs during transit through the body³⁰. The various approaches of vectoring the drug to the target site can be broadly classified as:

1. Passive targeting

2. Inverse targeting

3. Active targeting (Ligand mediated targeting and physical targeting)

4. Dual targeting

5. Double targeting

6. Combination targeting

Passive Targeting:

Systems that target the systemic circulation are generally characterized as “passive” delivery systems (i.e. targeting occurs because of the body’s natural response to the physicochemical characteristics of the drug or drug-carrier system. It is a sort of passive process that utilizes the natural course of (attributed to inherent characteristics) bio-distribution of the carrier system, through which; it eventually accumulates in the organ compartment of the body.

Inverse Targeting:

It is essentially based on successful attempts to circumvent and avoid passive uptake of colloidal carriers by the reticuloendothelial system (RES). This effectively leads to the reversion of the biodistribution trend of the carrier and hence the process is referred to as inverse targeting. One strategy applied to achieve inverse targeting is to suppress the function of RES by a pre-injection of a large amount of blank colloidal carriers or macromolecules like dextran sulfate. This approach leads to RES blockade and as a consequence impairment of the host defense system.

Active Targeting:

Active targeting exploits modification or manipulation of drug carriers to redefine its fate. The natural distribution pattern of the drug carrier composites is enhanced using chemical, biological and physical means so that it approaches and is identified by particular sites. The facilitation of the binding of the drug carrier to target cell through the use of ligands or engineered homing devices to increase receptor-mediated (or in some cases receptor-independent but epitope-based) localization of the drug and target-specific delivery of the drug is referred to as active targeting.

Dual Targeting:

This classical approach of drug targeting employs carrier molecules, which have their intrinsic antiviral effect thus synergies the antiviral effect of the loaded active drug. Based on this approach, drug conjugates can be prepared with a fortified activity profile against viral replication. A major advantage is that the virus replication process can be attacked at multiple points, excluding the possibilities of resistant viral strain development.

Double Targeting:

Drug targeting may be combined with passive and active targeting for the drug delivery system. The combination is made between spatial control and temporal control of drug delivery. The temporal control of drug delivery has been developed in terms of control drug release before the development of drug targeting. If spatial targeting is combined with temporal control release results in an improved therapeutics index by the following two effects. First, if drug release or activation is occurred locally at therapeutic sites, selectivity with the local release/activation. Second, the improvement in the therapeutic index by a combination of a spatially selective delivery and a preferable release pattern for a drug, such as zero-order release for a longer period of drugs.

Combination Targeting:

These targeting systems are equipped with carriers, polymers, and homing devices of molecular specificity that could provide a direct approach to the target site. Modification of proteins and peptides with natural polymers, such as polysaccharides, or synthetic polymers, such as poly (ethylene glycol), may alter their physical characteristics, and favor targeting the specific compartments, organs, or tissues within the vasculature. Further vectorization of these modified proteins and peptides into vesicular or micro-particulate carriers may take advantage of the intrinsic of inherited (through homing devices) properties of the carrier to achieve a site-specific active targeting of encapsulated contents.

CONCLUSION:

Pharmaceutical development of drug delivery system is being pursued enthusiastically in many laboratories in India. These are being investigated in vitro for release pattern and in some cases in vivo in animals for pharmacokinetics but less frequently for efficacy. There is a paucity of data on clinical studies and utility of the DDS in patients. It is necessary that pharmacologists should be involved in the investigation of pharmacokinetics and pharmacodynamics of DDS if the products have reached their meaningful outcome - the clinical use.

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Received on 25.03.2022 Modified on 17.06.2022

Asian J. Pharm. Res. 2022; 12(4):335-340.

DOI: 10.52711/2231-5691.2022.00053