Strategies of Drug Targeting.

 

Introduction.

  • Targeting drugs to specific cells and tissues of the body without allowing them to enter the systemic circulation is an innovative concept. 

  • The drug can be given in such a way that it reaches the receptor site in sufficient concentration without disrupting an extraneous tissue cell.  

  • These products are created by taking into account:

    • Specific properties of the target cells.

    • Nature of markers or transport carriers or vehicles which convey drugs to specific receptors.

    • Ligands and physically modulated compounds. 

Important Properties Influencing Drug Targeting:

  • The general properties influencing drug targeting can be divided into three broad categories, such as drug, carrier, and in vivo environment properties.

  1. Drug:

    1. Concentration, 

    2. Particulate location and Distribution 

    3. Molecular Weight, 

    4. Physicochemical properties 

    5. Drug Carrier Interaction.

  2. Carrier:

    1. Type and Amount of Excipients 

    2. Surface Characteristics, 

    3. Size 

    4. Density

  3. In vivo environment properties:

    1. pH, 

    2. Polarity, 

    3. ionic strength, 

    4. Surface Tension, 

    5. Viscosity, 

    6. Temperature, 

    7. Enzymes

    8. Electric Field

Strategies of Drug Targeting:

  • Different approaches are being identified and used successfully for the drug targeting, they are as follows.

    • Passive Targeting.

    • Inverse Targeting.

    • Active Targeting.

      • First Order Targeting.

      • Second Order Targeting.

      • Third Order Targeting.

    • Ligand Targeting.

    • Physical Targeting.

    • Dual Targeting.

    • Double TArgeting.

    • Combination Targeting.

  1. Passive Targeting:

  • This refers to the carrier's natural in-vivo distribution pattern

  • The particle size, shape, surface characteristics, surface charge, and particle number all play a role in the carrier's disposition.

  • For example, the ability of some colloids to be taken up by the ReticuloEndothelial Systems (RES), particularly in the liver and spleen, made them ideal substrates for passive hepatic drug targeting. 

  1. Inverse Targeting:

  • This type of targeting attempts to avoid passive uptake of colloidal carriers by RES; thus, the process is known as inverse targeting

  • To achieve inverse targeting, the normal function of the RES is suppressed by injecting large amounts of blank colloidal carriers or macromolecules such as dextran sulfate prior to injection.  

  • This strategy results in RES saturation and suppression of defense mechanisms. 

  • This type of targeting is an effective method for delivering drugs to non-RES organs.

  1.  Active Targeting:

  •  In this approach the carrier system bearing drug reaches a specific site on the basis of modification made on its surface rather than natural uptake by RES. 

  • Surface modification techniques include coating of surface with either a bioadhesive, non-ionic surfactant or specific cell or tissue antibodies (i.e. monoclonal antibodies) or by albumin protein. 

  • Active targeting can be affected at different levels:

    • First order targeting (organ compartmentalization) - Restricted distribution of the drug carrier system to an organ or tissue. 

    • Second order targeting (cellular targeting) - The selective drug delivery to a specific cell type such as tumor cells (& not to the normal cells)

    • Third order targeting (intracellular organelles targeting) - Drug delivery specifically to the intracellular organelles of the target cells 

  1. Ligand-mediated Targeting:

  • In this approach ligands are attached to the carrier surface as group(s), which can selectively direct the carrier to the pre-specified site(s)

  • Most carrier systems are colloidal in nature and can be specifically functionalized with a variety of biologically relevant molecular ligands such as antibodies, polypeptides, oligosaccharides, viral proteins, and fusogenic residues. 

  • The ligands provide recognition and specificity on the drug carrier, allowing them to approach the respective target selectivity and deliver the drug. 

  • e.g. 

    • Folate---> Folate receptor----> Overexpression of folate receptor.

    • Galactosamine---> Galactosamine receptors on hepatocytes---> Hepatoma.

  1. Physical Targeting: 

  •  This approach was found exceptional for tumor targeting as well as cytosolic delivery of entrapped drugs or genetic material. 

  • Characteristics of environment changes like pH, temperature, light intensity, electric field, and ionic strength are used for targeting the specific organ sites for delivering the drug molecules.

  1. Dual Targeting:

  • Carrier molecules have their own therapeutic activity in this targeting approach, which increases the therapeutic effect of the drug. 

  • For example, a carrier molecule with antibacterial activity can be loaded with an antibacterial drug, and the drug complex's net synergistic effect was observed

  1. Double Targeting:

  • When temporal and spatial methodologies are used to target a carrier system, this is referred to as double targeting. 

  • Spatial placement refers to targeting drugs to specific organs, tissues, cells, or even subcellular compartments, whereas temporal delivery refers to controlling the rate of drug delivery to the target site

  1. Combination Targeting: 

  • These targeting systems are outfitted with carriers, polymers, and molecularly specific homing devices that could provide a direct approach to the target site

Advantages of Drug Targeting:

  1. Protocols for drug administration could be made simpler.  

  2. Delivering a drug to its intended site reduces toxicity by minimizing negative systemic effects. 

  3. A smaller dose of the drug can be used to achieve the desired effect. 

  4. Avoidance of hepatic first pass metabolism. 

  5. Improved absorption of target molecules like peptides and particles. 

  6. Compared to traditional drug delivery methods, the dose is lower. 

  7. No peak and valley plasma concentration. 

  8. selectively focusing on infected cells in comparison to healthy cells 

Disadvantages of Drug Targeting.

  1. Targeted systems are quickly cleared. 

  2. Immune responses to carrier systems administered intravenously. 

  3. Targeted systems are not fully localized inside tumor cells. 

  4. Redistribution and diffusion of released drugs 

  5. High-end technology is needed for the formulation. 

  6. Skill for manufacturing, storage, and administration is needed. 

  7. At the target site, drug deposition could result in toxicological symptoms. 

  8. Maintaining dosage form stability can be challenging. For instance, erythrocytes that have been resealed must be kept at 4°C. 

  9. Since drug loading is typically legal, such as in micelles, it is challenging to foresee or fix the dosage regimen. 

Commonly Asked Questions.

  1. Discuss different strategies / approaches used for drug targeting. Give advantages and disadvantages of Drug Targeting.

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