Targeted drug delivery system 1_44299_BP704T_03-12-2024.pptx
- 2. 2 Learning Outcomes o At the end of the topic, the students should be able to o Identify potential targets for drug delivery o Describe the barriers to targeted drug delivery o Types and attributes of targeted systems o Discuss how these systems can reach intracellular targets
- 3. 3 Introduction o A specialised drug delivery system that selectively targets only a diseased tissue, organ, or a group of cells to localize the right amount of drug for maximum therapeutic affect and minimizing side-effects o Obviously it leaves out the non-diseased tissue o It is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others o E.g cancer therapy, Alzheimer's therapy, colon specific therapy, ocular therapy
- 4. 4 Rationale Pharmaceutical reasons Pharmacodynamics issues Pharmacokinetic issues Low solubility Drug instability • Poor bioavailability • Short half life • Large volume of distribution • Drug metabolism Low therapeutic index Low specificity
- 5. 5 What are we really achieving? Advantages o Simplified drug administration. o Reduced toxicity o Minimum therapeutic dose o Avoidance of hepatic first pass metabolism. o Biological molecules can be administered o Reduced dose fluctuations o Selective targeting to infected cells leaving aside normal cells. Disadvantages o Rapid clearance o Immune reactions are common o Insufficient localization into tumour cells is sometimes a problem o Requires highly sophisticated technology for the formulation. o Requires skill for manufacturing storage, administration. o Drug dumping at the target site may produce toxicity symptoms. o Stability issues exist with some delivery systems. o E.g.: Resealed erythrocytes have to be stored at 40 C. o Drug loading is usually low. o E.g. As in micelles
- 6. 6 Four principles to a successful dosage form Retain • Proper loading of the drug into an appropriate drug delivery vehicle Evade • Possess an ability to escape the body’s immune system Target • Long residence time in circulation to reach the site of interest Release • Release the drug at the specific site within time for effective drug functioning
- 7. 7 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 eg. prodrug Controlling the input of the drug into bioenvironment to ensure a programmed and desirable biodistribution
- 8. 8 Ideal targeted drug delivery system o Should be biochemically inert (non-toxic) o Should be non-immunogenic. o Should be physically and chemically stable in vivo and in vitro conditions. o There should be no specific interaction with the target tissue. o Should have controllable and predictable rate of drug release o It should retain the drug during drug transit o The drug should be able to access the target site and be retained for therapeutic action o Carriers used should be bio-degradable or readily eliminated from the body without any problem. o The preparation of the delivery system should be easy or reasonably simple, reproducible and cost effective.
- 9. 9 Important considerations o Drugs o Drugs with high total clearance are better suited o Drugs already targeting the same tissue would benefit less o Molecular Weight, Physiochemical properties, Drug Carrier Interaction o Target o Specific organ such as brain for Parkinson’s, Crueutzfeldt-Jakob disease, lungs for cystic fibrosis o Tissues such as tumours, inflamed areas o Organisms such as bacteria, viruses, etc o Specific cells such as human epidermal growth factor in breast cancer o Cellular components such as cytoplasmic proteins and nucleic acids
- 10. 10 Classes of carriers Basic concept for design Soluble carriers Natural and synthetic water soluble polymers and antibodies Drug is conjugated to the carrier Particulate systems Liposomes Microspheres Nanoparticles Drug is surface bound or trapped into the system
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- 12. 12 Targeting strategies o Passive targeting makes use of the disease site condition to target the drug. For example, in case of cancer cells, the blood vessels and lymphatic system is already flowing in and out the area. o Injecting the drug into the blood vessels will go the area and be taken up by lysosomes and the drug can be released when the carrier breaks down o The size and surface properties of drug delivery nano- particles must be controlled specifically to avoid uptake by the reticuloendothelial system (RES), to maximize circulation times and targeting ability. o For attaining such conditions the optimal size should be less than 100 nm in diameter and the surface should be hydrophilic to circumvent clearance by macrophages o Other examples include targeting of antimalarial, drugs for treatment of leishmiansis, brucellosis, candiadsis https://www.youtube.com/watch?v=emEua2eJp1U
- 13. 13 Targeting strategies o Active targeting includes specific modification of a drug/drug carrier nano systems with active agents having selective affinity for recognizing and interacting with a specific cell, tissue or organ in the body. o In case of cancer, the drug is bound to the carrier and is injected into the blood stream. The carrier is formulated to target specific cells o Such a system include lectin- carbohydrate, ligand-receptor, and antibody-antigen o This active targeting approach can be further classified into three different levels of targeting. o First order targeting: refers to restricted distribution of the drug carrier systems to the capillary bed of a predetermined target site, organ or tissue. Example includes compartmental targeting in lymphatics, peritoneal cavity, plural cavity, cerebral ventricles, eyes, joints, etc. o Second order targeting refers to selective delivery of drugs to specific cell types such as tumour cells and not to the normal cells .E.g. include selective drug delivery to kupffer cells in the liver. o Third order targeting is defined as drug delivery specifically to the intracellular site of targeted cells. E.g. receptor based ligand mediated entry of a drug complex into a cell by endocytosis. https://www.youtube.com/watch?v=SX-XmqINUKM
- 14. 14 Targeting strategies o Ligand mediated targeting o 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 ‘homing device’ to the carrier/drug. o 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. o The ligands confer recognition & specificity upon drug carrier & endow them with an ability to approach the respective target selectivity & deliver the drug https://www.youtube.com/watch?v=iBz5kfLIynY https://www.youtube.com/watch?v=u0E7TDmHBqM https://www.youtube.com/watch?v=5AXApBbj1ps
- 15. 15 Targeting strategies o Inverse Targeting o In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES and hence the process is referred to as inverse targeting. o To achieve inverse targeting, RES normal function is suppressed by pre injecting large amount of blank colloidal carriers or macromolecules like dextran sulphate. o This approach leads to saturation of RES and suppression of defense mechanism. o This type of targeting is a effective approach to target drug(s) to non- RES organs. o Physical Targeting o In this type of targeting some characteristics of environment changes like pH, temperature, light intensity, electric field, ionic strength small and even specific stimuli like glucose concentration are used to localize the drug carrier to predetermined site o This approach was found exceptional for tumour targeting as well as cytosolic delivery of entrapped drug or genetic material.
- 16. 16 Physical Targeting Strategy 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 https://www.youtube.com/watch?v=Z6BMYNXbwLU
- 17. 17 Targeting strategies o Dual targeting o In this targeting approach carrier molecule itself have their own therapeutic activity and thus increase the therapeutic effect of drug o For example, a carrier molecule having its own antiviral activity can be loaded with antiviral drug and the net synergistic effect of drug conjugate was observed. o Mingxin Wang, Chaoqun You, Zhiguo Gao, Hongshuai Wu, Baiwang Sun, Xiaoli Zhu & Renjie Chen (2018) A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles, Journal of Biomaterials Science, Polymer Edition, 29:11, 1360-1374 o Double targeting o Combining two methods to deliver drug to target area
- 18. 18 Targeting strategies o Combination targeting o These targeting systems are equipped with carriers, polymers and homing devices of molecular specificity that could provide a direct approach to target site. https://www.youtube.com/watch?v=C45L8A4oB_g&list=PLIoGb_hvwOjdAgkVw2A V-9vXL7YXEvF1A&index=22
- 19. 19 Carriers for drug delivery o Liposomes o Liposomes are small artificially designed vesicles composed of phospholipid bilayers surrounding with the size ranging from 20 to 10 000 nm. o Many liposome formulations are rapidly taken up by macrophages and this can be exploited either for macrophage-specific delivery of drugs or for passive drug targeting which allow slow release of the drug over time from these cells into the general circulation.
- 20. 20 Liposomes o These are vesicles composed of an aqueous core bounded by a hydrophobic lipid bilayer. o Solutes in the core, such as drugs, cannot overcome the hydrophobic barrier. However, the bilayer allows for the absorption of hydrophobic molecules and therefore, liposomes are known to be ampiphilic carriers. o A new variety of liposomes known as ‘stealth’ liposomes has recently been developed by incorporating polyethylene glycol (PEG) which was considered to prevent liposome recognition by phagocytic cells. o Such liposomes have longer circulation times and increased distribution to peripheral tissues in the body.
- 21. 21 Liposomes o Advantages o Biodegradable, biocompatible, flexible, Non ionic o Can carry both water soluble and lipid soluble drugs o Increased efficacy. o Increased stability via encapsulation. o Reduces toxicity of the encapsulated agents. o Disadvantages o Production cost is high o Leakage and fusion of encapsulated drug/molecules
- 22. 22 Liposomes o Preparation of liposome o Hydration of lipids in presence of solvent o Ultrasonication o French Pressure cell o Solvent injection method o a) Ether injection method o b) Ethanol injection o Detergent removal o Detergent can be removed by o a) Dialysis o b) Column chromatography o c) Bio-beads o Reverse phase evaporation technique o High pressure extrusion o Miscellaneous methods o a) Removal of Chaotropic ion o b) Freeze-Thawing Marketed liposomal preparations https://www.youtube.com/watch?v=04SP8Tw3htE https://www.youtube.com/watch?v=vGz-qDE3Go4&list=PLQh_yj SFsDFm0pRDkAgoNxOtnY-P65pAg https://www.youtube.com/watch?v=vUqwIL5lgS8&list=PLQh_y jSFsDFm0pRDkAgoNxOtnY-P65pAg&index=6
- 23. 23 Drug delivery mechanisms of liposomes
- 24. 24 Monoclonal Antibodies and Fragments o Since the development of monoclonal antibodies by Köhler and Milstein in 1975, they have proven immensely useful in combating diseases especially cancer o Antibody-drug conjugates (ADC) combine a drug with a monoclonal antibody which provides selective targeting for tumoral cell masses or lymphomas o The drug is released by enzymatic cleavage of the linker under physiological conditions o The high selectivity greatly reduces the toxic side effects of traditional chemotherapy, and also makes possible the use of newer actives with a high toxicity profile o Monoclonal antibodies characteristics: o Their ability to be produced in unlimited quantities, specificity of binding, their homogeneity o Additionally, one unique advantage of hybridoma production is that impure antigens can be used to produce specific antibodies.
- 25. 25 mAB
- 26. 26 Assignment 1. What are the major types of targeting mechanisms used in targeted drug delivery. 2. What is targeted drug delivery, and how does it differ from conventional drug delivery systems? 3. How do nanoparticles enhance the efficiency and specificity of targeted drug delivery systems? 4. What are the main advantages and limitations of targeted drug delivery in cancer treatment? 5. What role do ligands and receptors play in achieving active targeting of drugs to specific tissues or cells?
- 27. 27 References o Gujral SS, Khatri S. A Review on Basic Concept of Drug Targeting and Drug Carrier System. IJAPBC – Vol. 2(1), 2013. o Rani K, Paliwal S. A Review on Targeted Drug Delivery: its Entire Focus on Advanced Therapeutics and Diagnostics. Sch. J. App. Med. Sci., 2(1C):328- 33, 2014. o Perrie Y, Rades T. Site targeted Drug targeting In Fasttrack Pharmceutics- Drug Delivery and Targeting. Pg 141-160. Pharmaceutical Press: London; 2010. o Perrie Y, Rades T. Carriers for Drug Targeting In Fasttrack Pharmceutics-Drug Delivery and Targeting. Pg 161-214. Pharmaceutical Press: London; 2010. o Mishra N, Pant P, Porwal A, Jaiswal J, Samad MA, Tiwari S. Targeted Drug Delivery: A Review. Am. J. PharmTech Res. 6(1); 2016
- 28. 28 THANK YOU