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Presented by: Anvita
M. Pharm (IP)
What is drug targeting
 The therapeutic response of a drug depends upon the interaction of drug
molecules with cell on ce...
Reasons for Drug Targeting
Drug instability
Low absorption
Short half-life
Large volume of distribution
Low specificity
Lo...
Common Approaches of Targeted Drug
Delivery
Controlling the distribution of drug by incorporating it in a carrier system
A...
Properties of Ideal Targeted Drug Deliver
 Nontoxic, biocompatible and physicochemical stable in vivo and invitro.
 Rest...
Important Properties Influencing
Drug Targeting
Drug Concentration, Particulate location and Distribution
Molecular Weight...
Drug
Targeting
strategies
Passive
Targeting
Inverse
Targeting
Active
Targeting
Ligand-
mediated
TargetingPhysical
Targetin...
Passive Targeting
 It utilizes the natural course of biodistribution of the carrier.
 The colloids which are taken up by...
Inverse Targeting
 It is a result of the avoidance of passive uptake of colloidal carriers
by the RES.
 It can be achiev...
Active Targeting
 It involves the modification or functionalization of the drug carriers
so that the contents are deliver...
Active Targeting
First Order
Targeting
Second
Order
Targeting
Third Order
Targeting
Restricted distribution of the drug
ca...
Strategies for Drug Targeting
Ligand-mediated Targeting
 Ligands are carrier surface group(s), which can selectively direct the
carrier to the pre-spec...
Examples of Ligands
Ligands Target Tumor target
Folate Folate receptor Overexpression of folate
receptor
Transferrin Trans...
Physical Targeting
Characteristics of environment changes like pH,
temperature, light intensity, electric field, and
ionic...
Physical Targeting
Physical Targeting Formulation System Mechanism for Drug
Delivery
Heat Liposome Change in Permeability
...
Dual Targeting
 In this targeting approach, carrier molecule,
itself have their own therapeutic activity and
thus increas...
Double Targeting
Spatial
Control
Temporal
Control
Double
Targeting
Targeting drugs to specific
organs, tissues, cells or e...
Combination Targeting
 These targeting systems are equipped with
carriers, polymers and homing devices of
molecular speci...
Components for Drug
Targeting
Target
• Specific organ or a cell or group of cells,
which in chronic or acute condition nee...
Carriers
Liposomes
Microspheres
Nanoparticles
Quantum Dots
Dendrimers
Nanoerythrocytes
Resealed Erythrocytes
Targeted Nanoparticles
Platform Targeting ligand Drug Stage
PEGylated liposome F(ab ¢ ) 2 fragment of human
antibody GAH
D...
Applications of Resealed Erythrocytes
Diseases Name of Drug(s) Purpose
Liver tumors Bleomycin, Adriamycin,
Carboplatin,Gen...
Other Approaches of Drug
Targeting
1. Magnetically modulated drug targeting
2. Monoclonal antibody based targeted drug del...
Magnetically modulated drug targeti
 An interesting approach of targeting carrier system has been to
magnetize the carrie...
Magnetic
Drug /Carrier
Circulation
Major Pathway
Minor Pathway
RES Organs
( liver/spleen/ bone
marrow)
N
S
Target Tissues
...
ADVANTAGES
 Therapeutic responses in target organs at
only 1/10th of the free drug dose.
 Controlled drug release within...
 Magnetic microspheres
 Magnetic nanoparticles
 Magnetic liposomes
 Magnetic emulsion
 Magnetic resealed erythrocytes...
Monoclonal antibody based targeted
drug delivery
 The recognition site for the monoclonal antibody should be located on t...
Approved Monoclonal Antibodies
Antibody Target Indication
Trastuzumab HER2 Breast Cancer
Bevacizumab VEGF Lung Cancer
Cetu...
Immunoconjugates
 The possibility of raising monoclonal antibodies against cell surface markers allow
tumor site targetin...
Bispecific antibodies
 The approach has been mainly suggested for immunotherapy of
immunological disorders especially tho...
Immunotoxins
 These are conjugates of antibody (Mab & Fab) fragments & toxins, in which cell
binding moieties of the toxi...
Immunotoxins under clinical trials
Immunotoxin Target antigen Target malignancy Stage
LMB-2 CD25 Leukemia Phase II
SSIP Me...
Prodrugs
 Prodrug is an inactive pharmacological moiety developed to optimize
pharmacokinetics or site selectivity of a d...
Enzymes & prodrugs used for ADEPT
Enzymes Prodrug Reactivity
Alkaline Phosphatase Doxorubicin Hydrolysis of Phosphate Grou...
Conclusion
Targeted drug delivery essentially implies for selective and effective
localization of the pharmacologically-ac...
Reference:
 Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, Editors: Roop Khar, SP Vyas, Farhan Ahmad...
 R. Panchagnula and C. S. Dey, Monoclonal Antibodies in Drug Targeting, Journal of Clinical
Pharmacy and Therapeutic, 22,...
Drug targeting
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Drug targeting

Drug Targeting

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Drug targeting

  1. 1. Presented by: Anvita M. Pharm (IP)
  2. 2. What is drug targeting  The therapeutic response of a drug depends upon the interaction of drug molecules with cell on cell membrane related biological events at receptor sites in concentration dependent manner.  Selective and effective localization of the pharmacologically-active moiety at preidentified target(s) in therapeutic concentration, while restricting its access to non-target(s) normal cellular linings, thus minimizing toxic effects and maximizing the therapeutic index. Target cell Normal Cell Normal Cell
  3. 3. Reasons for Drug Targeting Drug instability Low absorption Short half-life Large volume of distribution Low specificity Low therapeutic index
  4. 4. Common Approaches of Targeted Drug Delivery Controlling the distribution of drug by incorporating it in a carrier system Altering the structure of the drug at molecular level Controlling the input of the drug into bioenvironment to ensure a programmed and desirable biodistribution
  5. 5. Properties of Ideal Targeted Drug Deliver  Nontoxic, biocompatible and physicochemical stable in vivo and invitro.  Restrict drug distribution to target cells or tissue or organ or should have uniform capillary distribution.  Controllable and predictable rate of drug release.  Minimal drug leakage during transit.  Carrier used must be biodegradable or readily eliminated from the body without any problem.  Its preparation should be easy or reasonably simple, reproductive and cost effective.
  6. 6. Important Properties Influencing Drug Targeting Drug Concentration, Particulate location and Distribution Molecular Weight, Physiochemical properties Drug Carrier Interaction Carrier Type, Amount of Excipients, Surface Characteristics, size, Density In Vivo Environment PH, Polarity, Ionic Strength, Surface Tension, Viscosity, Temperature, Enzyme, Electric Field
  7. 7. Drug Targeting strategies Passive Targeting Inverse Targeting Active Targeting Ligand- mediated TargetingPhysical Targeting Dual Targeting Double Targeting Combination Targeting
  8. 8. Passive Targeting  It utilizes the natural course of biodistribution of the carrier.  The colloids which are taken up by the reticulo-endothelial system (RES) can be ideal vectors for passive targeting of drugs to RES predominant compartments.  Passive capture of colloidal carriers by macrophages offers therapeutic opportunities for the delivery of anti-infective agents.
  9. 9. Inverse Targeting  It is a result of the avoidance of passive uptake of colloidal carriers by the RES.  It can be achieved by suppressing the function of RES by pre- junction of a large amount of blank colloidal carriers or macromolecules like dextran sulphate.  Other strategies include modification and defined manipulation of the size, surface charge, composition, surface rigidity & hydrophilicity characteristics of carriers for desirable biofate.
  10. 10. Active Targeting  It involves the modification or functionalization of the drug carriers so that the contents are delivered exclusively to the site corresponding to which the carrier is architected.  Active targeting can be affected at different levels – 1. First order targeting (organ compartmentalization) 2. Second order targeting (cellular targeting) 3. Third order targeting (intercellular organelles targeting)
  11. 11. Active Targeting First Order Targeting Second Order Targeting Third Order Targeting Restricted distribution of the drug carrier system to the capillary bed of a pre-determined target site, organ or tissue. The selective drug delivery to a specific cell type such as tumor cells (& not to the normal cells) Drug delivery specifically to the intracellular organelles of the target cells
  12. 12. Strategies for Drug Targeting
  13. 13. Ligand-mediated Targeting  Ligands are carrier surface group(s), which can selectively direct the carrier to the pre-specified site(s) housing the appropriate receptor units to serve as ‘homimg device’ to the carrier/drug.  Most of the carrier systems are colloidal in nature & can be specifically functionalized using various biologically-relevant molecular ligands including antibodies, polypeptides, oligosaccharides, viral proteins & fusogenic residues.  The ligands confer recognition & specificity upon drug carrier & endow them with an ability to approach the respective target selectivity & deliver the drug
  14. 14. Examples of Ligands Ligands Target Tumor target Folate Folate receptor Overexpression of folate receptor Transferrin Transferrin receptor Overexpression of transferrin receptor Galactosamine Galactosamine receptors on hepatocytes Hepatoma
  15. 15. Physical Targeting Characteristics of environment changes like pH, temperature, light intensity, electric field, and ionic strength. This approach was found exceptional for tumor targeting as well as cytosolic delivery of entrapped drug or genetic material.
  16. 16. Physical Targeting Physical Targeting Formulation System Mechanism for Drug Delivery Heat Liposome Change in Permeability Magnetic Modulation Magnetically Responsive Microspheres Containing Iron oxide Magnetic Field can retard fluid Flow of particles. Ultrasound Polymers Change in Permeability Electrical Pulse Gels Change in Permeability Light Photo responsive Hydro gels Containing Azo- Derivatives Change in Diffusion Channels, Activated by Specific Wavelength
  17. 17. Dual Targeting  In this targeting approach, carrier molecule, itself have their own therapeutic activity and thus increase the therapeutic effect of drug.  A carrier molecule having its own antiviral activity can be loaded with antiviral drug and for the synergistic effect of drug conjugate.
  18. 18. Double Targeting Spatial Control Temporal Control Double Targeting Targeting drugs to specific organs, tissues, cells or even sub cellular compartment Controlling the rate of drug delivery to target site
  19. 19. Combination Targeting  These targeting systems are equipped with carriers, polymers and homing devices of molecular specificity that could provide a direct approach to target site.
  20. 20. Components for Drug Targeting Target • Specific organ or a cell or group of cells, which in chronic or acute condition need treatment. Carrier • Special molecules or system essentially required for effective transportation of loaded drug up to the pre selected sites
  21. 21. Carriers Liposomes Microspheres Nanoparticles Quantum Dots Dendrimers Nanoerythrocytes Resealed Erythrocytes
  22. 22. Targeted Nanoparticles Platform Targeting ligand Drug Stage PEGylated liposome F(ab ¢ ) 2 fragment of human antibody GAH Doxorubicin Phase I NGPE liposome Transferrin Oxaliplatin Phase I/II Liposome Single-chain antibody fragment p53 gene Phase I PEGylated PLGA NP Peptide Docetaxel Phase I
  23. 23. Applications of Resealed Erythrocytes Diseases Name of Drug(s) Purpose Liver tumors Bleomycin, Adriamycin, Carboplatin,Gentamycin Targeting to hepatic carcinoma Parasitic diseases Pentamidine loaded, IgG coated erythrocytes, Glutaraldehyde treated erythrocytes Macrophage containing leshmania, liver targeting of primaquine phosphate, metronidazole
  24. 24. Other Approaches of Drug Targeting 1. Magnetically modulated drug targeting 2. Monoclonal antibody based targeted drug delivery 3. Prodrug
  25. 25. Magnetically modulated drug targeti  An interesting approach of targeting carrier system has been to magnetize the carrier so that these particles can be retained at or guided to the target site by the application of an external magnetic field of appropriate strength.  Retention of magnetic carrier at the target site will delay reticuloendothelial clearance, facilitate extravasation & thus prolong the systemic action of drug.
  26. 26. Magnetic Drug /Carrier Circulation Major Pathway Minor Pathway RES Organs ( liver/spleen/ bone marrow) N S Target Tissues Principle of Magnetic Drug Targering
  27. 27. ADVANTAGES  Therapeutic responses in target organs at only 1/10th of the free drug dose.  Controlled drug release within target tissues for intervals of 30 min to 30 h, as desired.  Avoidance of acute drug toxicity directed against endothelium & normal parenchymal cells.  Adaptable to any part of the body. DISADVANTAGES  It is expensive  It needs miniaturized specialized magnet for targeting, advanced techniques for monitoring, & trained personnel to perform procedures.  Magnet must have relatively constant gradients, in order to avoid focal overdosing with toxic drugs.  A large fraction (40 – 60 %) of the magnetite, which is entrapped in the carriers, may be deposited permanently in target tissues. Magnetic Drug Targeting
  28. 28.  Magnetic microspheres  Magnetic nanoparticles  Magnetic liposomes  Magnetic emulsion  Magnetic resealed erythrocytes Magnetic delivery systems
  29. 29. Monoclonal antibody based targeted drug delivery  The recognition site for the monoclonal antibody should be located on the surface of the cell.  The antibodies should have sufficient tumor tissue specificity.  The extent of localization of the antibody at the target site. Biodistribution of the drug–antibody conjugate in the body relative to that of the parent antibody.  Stability of the drug–antibody conjugates in blood.  The host toxicity of the conjugate. The conjugate must be biodegradable and non-immunogenic. Drugs should be released upon interaction between the carrier molecule and the cell.
  30. 30. Approved Monoclonal Antibodies Antibody Target Indication Trastuzumab HER2 Breast Cancer Bevacizumab VEGF Lung Cancer Cetuximab EGFR Colorectal carcinoma Panitumumab EGFR Colorectal carcinoma
  31. 31. Immunoconjugates  The possibility of raising monoclonal antibodies against cell surface markers allow tumor site targeting discretely.  Many cytotoxic drugs have been conjugated with monoclonal antibodies. These conjugates have been used to study drug localization in tumors and modulation of drug toxicity. They have been found to be useful in the management of various types of carcinomas.  The conjugation of antibodies developed against a specific tumor determinant with another recognition component provides them dual specificity to target the drug or toxin intracellularly.
  32. 32. Bispecific antibodies  The approach has been mainly suggested for immunotherapy of immunological disorders especially those related to lack of MHC restricted recognition by immune effectors cells.  Bispecific antibodies against tumor endothelium & tissue factors (the initiator of the intrinsic pathway of blood conjugation) have also been proposed for synergistic effects.
  33. 33. Immunotoxins  These are conjugates of antibody (Mab & Fab) fragments & toxins, in which cell binding moieties of the toxins are replaced with specific binding chain of the antibodies. Advantages  The naturally occurring toxins used have very specific biological pathways in producing their cytocidal effects.  The cytotoxic activity of the toxin that is conjugated to the antibody does not involve any other secondary agent(s).  Theoretically, immunotoxins should not bind to non-malignant cells, and even if they do bind, the internalization of the agent should not be sufficient to neutralize the therapeutic effect.
  34. 34. Immunotoxins under clinical trials Immunotoxin Target antigen Target malignancy Stage LMB-2 CD25 Leukemia Phase II SSIP Mesothelin Pancreatic cancers Phase I UCHT1 CD3ε Leukemia Phase II RFT5-dgA CD25 Melanoma Phase I/II
  35. 35. Prodrugs  Prodrug is an inactive pharmacological moiety developed to optimize pharmacokinetics or site selectivity of a drug.  Since the prodrug has low cytotoxicity prior to its activation, it has very few chances of its encounter with healthy cells.  In general, selective enzyme expression, hypoxia, & low extracellular pH at tumor site is utilized for prodrug activation.  ADEPT has been investigated in the treatment of tumors, where an antibody- enzyme conjugate is administered systemically, where it clears from the circulation & localizes to its target by virtue of the antibody binding to its specific biomarker on the tumor.
  36. 36. Enzymes & prodrugs used for ADEPT Enzymes Prodrug Reactivity Alkaline Phosphatase Doxorubicin Hydrolysis of Phosphate Group Etoposide β lactamase Mitomycin Cleavage of Lactam Ring Paclitaxel Schematic representation of ADEPT
  37. 37. Conclusion Targeted drug delivery essentially implies for selective and effective localization of the pharmacologically-active moiety at preidentified target(s) in therapeutic concentration, Various strategies such as active targeting, passive targeting etc. can be applied to achieve efficient drug targeting. The targeted delivery is of great importance in cancer chemotherapy which always demands for reduction in adverse effect. .
  38. 38. Reference:  Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, Editors: Roop Khar, SP Vyas, Farhan Ahmad, Gaurav Jain, Chapter 25 Targeted Drug Delivery Systems, Pg. No. 907-943, 2014.  Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, Editors: Roop Khar, SP Vyas, Farhan Ahmad, Gaurav Jain, Chapter 24 Novel Drug Delivery Systems, Pg. No. 872-906, 2014.  Mrs Jaya Agnihotri, Dr.Shubhini Saraf, Dr.Anubha Khale, Targeting : New Potential Carriers for Targeted Drug Delivery System, International Journal of Pharmaceutical Sciences Review and Research, Volume 8, Issue 2, Pg. No. 117-123, May – June 2011.  Vidyavati S, Koppisetti and Sahiti. B, Magnetically Modulated Drug Delivery Systems, International Journal of Drug Development & Research, Vol. 3, Issue 1, Pg. No. 260 - 266, Jan-March 2011.  Priyanka Lokwani, Magnetic Particles for Drug Delivery: An Overview, International Journal of Research in Pharmaceutical and Biomedical Sciences, Vol. 2 (2), Pg. No. 465 – 473, Apr – Jun 2011.
  39. 39.  R. Panchagnula and C. S. Dey, Monoclonal Antibodies in Drug Targeting, Journal of Clinical Pharmacy and Therapeutic, 22, Pg. No. 7 – 19, 1997.  Gupta Manish and Sharma Vimukta, Targeted drug delivery system: A Review, Research Journal of Chemical Sciences, Vol. 1 (2), Pg. No. 135 – 138, May 2011.  Archana Swami , Jinjun Shi , Suresh Gadde , Alexander R. Votruba , Nagesh Kolishetti , and Omid C. Farokhzad, Chapter 2 Nanoparticles for Targeted and Temporally Controlled Drug Delivery, Multifunctional Nanoparticles for Drug Delivery Applications: Imaging, Targeting, and Delivery, Nanostructure Science and Technology, Pg. No, 9 – 29, 2012.  Andrew M. Scott1, James P. Allison and Jedd D. Wolchok, Monoclonal Antibodies in Cancer Therapy, Cancer Immunity, Vol. 12, Pg. No. 14 – 21, 2012.  Nurit Becker and Itai Benhar, Antibody-Based Immunotoxins for the Treatment of Cancer, Antibodies, 1, Pg, No. 39 – 69, 2012.  Tirupathi Rao K, Suria Prabha K and Muthu Prasanna, Resealed Erythrocytes: As a Specified tool in Novel Drug Delivery Carrier System, Research Journal of Pharmaceutical, Biological and Chemical Sciences, Vol. 2, Issue 4, Pg. No. 496 – 512, October – December 2011.  Theresa M. Allen, Ligand-Targeted Therapeutics in Anticancer Therapy, Nature Review – Cancer, Vol. 2, Pg. No. 750 – 763, October 2002.

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