Targeted Drug Delivery Systems PDF

UNIT-4 TARGATED DRUG DELIVERY Points to be covered in this topic OINTRODUCTION OAPPROACHES ’0ADVANTAGES >ODISADVANTAGES OLIPOSOMES >ONIOSOMES >ONANOPARTICLES OMONOCLONAL ANTIBODIES  TARGATED DRUG...

UNIT-4 TARGATED DRUG DELIVERY Points to be covered in this topic OINTRODUCTION OAPPROACHES ’0ADVANTAGES >ODISADVANTAGES OLIPOSOMES >ONIOSOMES >ONANOPARTICLES OMONOCLONAL ANTIBODIES  TARGATED DRUG DELIVERY OINTRODUCTION: In conventional drug delivery systems such as oral ingestion or intravascular injection, The medication is distributed throughout the body by means of systemicblood circulation. For most therapeutic agents, only a small portion of the medication reaches the affected organ or tissue, Targeted drug delivery sue to deliver medication in the tissues of interest while reducing the relative concentration of the medication inthe remaining tissues. For example, by avoiding the host's defence mechanisms and inhibiting non-specific distribution in the liver and spleen, a system can reach the intended site of action in higher concentrations. Targeted delivery is believed to improve efficacy while reducing side effects. Targeted Drug Delivery System Functdonalized Nanocarrlers Drug loaded Nanocarrlers Targeted Cell Drug Release oj o Potynes Gol Nanele Me Dendrlme Wonoprdes ML Nanoparticles /Nanocarriers What is drug targeting? The therapeutic response of adrug depends upon the interaction of drug molecules with cell on cell membrane related biological events at receptor sites in concentration dependent manner. V Selective and effective localization of the 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 the therapeutic index. DAPPROACHES The basic approaches for targeting the drug to specific site based different research outcomes may be categorized broadly in to followings, I. Controlling the distribution of drug by incorporating it in a carrier system II. Altering the structure of the drug at molecular level III. Controlling the input of the drug into bioenvironment to ensure a programmed anddesirable biodistribution OADVANTAGES " Drug administration protocols may be simplified. Toxicity is reduced by delivering a drug to its target site, thereby reducing harmful systemic effects. Drug can be administered in a smaller dose to produce the desire effect. Avoidance of hepatic first pass metabolism. " Enhancement of the absorption of target molecules such as peptides and particulates. Dose is less compared to conventional drug delivery system. " No peak and valley plasma concentration. Selective targeting to infections cells that compare to normalcells. ODISADVANTAGES Rapid clearance of targeted systems. Immune reactions against intravenous administered carrier systems. Insufficient localization of targeted systems into tumour cells. " Diffusion and redistribution of released drugs. Requires highly sophisticated technology for the formulation. Requires skill for manufacturing storage, administration. Drug deposition at the target site may produce toxicity symptoms. Difficult to maintain stability of dosage form. E.g.: Resealed erythrocytes have to be storedat 4°C. DLIPOSOMES Liposome is derived from the Greek word, where lipo means "fatty" constitution and soma means "structure". Liposome Liposome are relatively small in size and it Nutrient ranges from 50nm to several micrometres in diameter. (Vitanin C) These are spherical vesicle in which aqueous core is entirely enclosed by one or more phospholipid bilayers. It having the unique ability toentrap both lipophilic and hydrophilic compounds. The hydrophobic or lipophilic molecules are inserted into the bilayer membrane, Whereas hydrophilic molecules can be entrapped Liposome Liposome (hydrophobic load) (hydrophilic load) in the aqueouscentre.  Advantages: Suitable for delivery of hydrophobic (e.g. amphoterícin B) hydrophilic (e.g. cytrabine) and amphipathic agents. Liposome increases efficacy and therapeutic indexof drug (actinomycin D) Liposome increase stability viaencapsulation Suitable for targeted drug delivery V Suitable to give localized action in particular tissue Suitable to administer via various routes Liposomes help to reduce the exposure of sensitive tissue to toxic drug. Disadvantages: Once administrated, liposome cannot be removed. Possibility of dumping, due to faulty administration. Leakage of encapsulated drug during storage. Low solubility / Productioncost is high. * Applications: > Cancer chemotherapy: Liposome are successfully used to entrap anticancer drugs. Thisincreases circulation life time, protect from metabolic degradation. º Liposome as carrier of drug in oral treatment: Steroids used for arthritis can be incorporated into large MLVs. Alteration in blood glucose levels in diabetic animals was obtained by oral administration ofliposome encapsulated insulin. Liposome for topical application: Drug like triamcinolone, methotrexate, benzocaine, corticosteroids etc. Can be successfullyincorporated as topical liposome. º Liposome for pulmonary delivery: V Inhalation devises like nebulizers are used to produce an aerosol of droplets containingliposome. ONIOSOMES Niosomes areone of the novel drug delivery system of encapsulating the meicament in a vesicular system. The vesicle composed of a bilayer of non-ionic surfactants and hence the name niosomes. Non aqucous, The niosomes are very small. surfactant non-ionic bilayer and microscopic in size (in nanometric scale). Although being structurally similar to liposomes, they Aqueous Compartment have several advantages over them. Structure of Niosome Hydrophilc drug Hydrophob1c drug Amptiphiic drug Advantages: The vesicles may act as a depot, releasing the drug in a controlled manner, They are osmotically active and stable, They improve the therapeutic perfornnance of the drug molecules by delayed clearance from the circulation, Protecting the drug from biological environment,  They improveoral bioavailability of poorlyabsorbed drugs. Niosomal dispersion in an aqueous phase can be emulsified in a non aqueous phase to regulate the delivery rate of drug and administer normal vesicle in external non-aqueous phase. * Disadvantages V Physical instability of the noisome vesicles is major disadvantage of the noisome drug delivery system. Aggregation: Aggregation of the noisome vesicles can be another disadvantage to be considered. Fusion: Fusion of the niosomal vesicles to form loose aggregates Leaking of entrapped drug: affect the intended properties of the niosomnes. Hydrolysis of encapsulated drugs which limiting the shelf life of the dispersion. * Applications Anti-neoplastic Treatment: Niosomes can alter the metabolism, prolong circulation and half-life of the drug, thus decreasing the side effects of the drugs. Use in Studying Immune Response: / Due to their immunological selectivity, low toxicity and greater stability. Niosomes as Carriers for Haemoglobin: The niosomal vesicle is permeable to oxygen and hence can act as a carrier for haemoglobin in anaemic patients.  ONANOPARTICLES Asite specific drug delivery system consisting of poly metacryclic nanoparticles. " The main goal in designing nanoparticles as a delivery system is to control size of particle, surface characteristics and discharge of pharmacologically active agents. " In order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen. Advantages: Increases the stability of any volatile pharmaceutical agents. They offer a significant improvement over traditional oral and intravenous methods of administration in terms of efficiency and effectiveness. Delivers a higher concentration of pharmaceutical agent. The choice of polymer and the ability to modify drug release from polymeric nanoparticles have made them ideal candidates for cancer therapy, delivery of vaccines, contraceptives and delivery of targeted antibiotics. Disadvantages: Smallsize &large surface area can lead to particle aggregation. V Physical handling of nano particles is difficult in liquid and dry forms. Limited drug loading. V Toxicmetabolites may form. Etc.  Application Internalization: Internalization within mammalian cells can be achieved by surface functionalized carbon nanotubes Vaccine delivery: Conjugation with peptides may be used as vaccine delivery structures. º Gene delivery: carbon nanotubes has been modelled in such a way so that they can be convenienty utilized as small molecule transporters in transporting DNA, indicatingpotential use as a gene delivery tool. > Transport of peptides, nucleic acids and other drug molecules Incorporation of carboxylic or ammonium groups to carbon nanotubes enhances their solubility. > Cancer therapy: This technology is being evaluated for cancer therapy. > Diagnostic purposes: Inwhole blood immunoassays e.g. coupling of gold nanoshells to antibodies to detect immunoglobulins in plasma and whole blood. etc. DMONOCLONAL ANTIBODIES An antibody is a protein used by immun system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. The high specificity of antibodies makes them an excellent tool for detecting andquantifying a broad array of targets, from drugs to serum proteins to microorganisms. With in-vitro assays, antibodies can be used to precipitate soluble antigens, agglutinate (clump) cells,opsonize.  How monoclonal antibodies work Kill bacteria with the assistance of complement, and neutralize drugs, and viruses. toxins, Y Monoclonal antibodies once attached, bind to their target they make it harmiess Advantages Though expensive, monoclonal antibodies are cheaper to develop than conventional drugs because it is based on tested technology. Side effects can be treated and reduced by using mice-human hybrid cells or by using fractions of antibodies. They bind tospecific diseased or damaged cells needing trea They treat a wide range of conditions. Disadvantages Time consuming project - anywhere between 6 -9 months. Very expensive and needs considerable effort to produce them. Small peptide and fragment antigens may not be good antigens monoclonal antibody may not recognize the original antigen. Hybridoma culture may be subject to contamination. VSystem is only well developed for limited animal and not for other animals. More than 99% of the cells do not survive during the fusion process reducing the range of useful antibodies that can be produced against a.. antigen Itis possibility of generatingimmunogenicity * Application º DiagnosticApplications: Monoclonal antibodies have revolutionized the laboratory diagnosis of various diseases. For this purpose, MAbs may be employed as diagnostic reagents for biochemical analysis or as tools for diagnostic imaging of diseases. (A) MAbs in Biochemical Analysis: / Diagnostictests based on the use of MAbsas reagentsare routinely used in radioimmunoassay (RIA) and enzyme-linked immunosorbent assays (ELISA) in the laboratory. V These assays measure the circulating concentrations of hormones (insulin, human chorionic gonadotropin, growth hormone, progesterone, thyroxine, triiodothyronine, thyroid stimulating hormone, gastr renin),and several other tissue (B) MAbs in Diagnostic Imaging: Radiolabeled-MAbs are used in the diagnostic imaging of diseases, and this technique is referred to as immunoscintigraphy. The radioisotopes commonly used for labelling MAb are iodine-13 andtechnetium-99. 2. Therapeutic Applications: (A) Cardiovascular diseases: Myocardial infarction: The cardiac protein myosin gets exposed wherever myocardial necros1s (death of cardiac cells) occurs. Antimyosin MAb labelled wt.. radioisotope indium chloride (111 In) is used for detecting nyosin and thus the site of myocardial infarction. Imaging of radiolabeled MAb, is usually done after 24-48 hours of intravenous administration. Deep vein thrombosis (DVT): DVT refers to the formation of blood clots (thrombus) within the blood veins, primarily in the lower extremities. For the detection of DVT, radioisotope labelled MAb directed against fibrinor platelets can be used. The imaging is usually done after 4 hours of injection. Fibrin specific MAbs are successfully used for the detection of clots in thigh, pelvis, calf and knee regions.