logging in or signing up DRUG TARGETING nikitaverma1988 Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 6556 Category: Science & Tech.. License: All Rights Reserved Like it (10) Dislike it (0) Added: December 10, 2010 This Presentation is Public Favorites: 11 Presentation Description My first presentation at my college . Comments Posting comment... By: mirrormirror (8 month(s) ago) good Saving..... Post Reply Close Saving..... Edit Comment Close By: manzoorahmed5661 (9 month(s) ago) send me mail. email@example.com Saving..... Post Reply Close Saving..... 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To avoid distribution of drug to other tissues which seems to be unnecessary, wasteful and a potential cause of toxicity. 3 The Concepts of Targeting : The Concepts of Targeting HISTORY: The concept of designing specified delivery system to achieve selective drug targeting has been originated from the perception of “ Paul Ehrlich”, who proposed drug delivery to as ‘magic bullet’ . He described targeted drug delivery as an event where, “ a drug –carrier complex/conjugate , delivers drug exclusively to the preselected target cells in a specified manner”. Bangham’s observation on phospholipid hexagonal liquid crystals , that they are premselective to the ions in a manner similar to biomembrane , led to the discovery of artificial vesicular system based on phospholipid amphiphiles. Gregoriadis , 1981 described drug targeting using novel drug delivery systems as ‘old drug in new clothes’ . 4 Principle and Rationale of Drug Targeting : Principle and Rationale of Drug Targeting free drug Drug In carrier Target site Facilitated transport (effect : targeting) Bioenvironmental factors Target site Bioenvironmental factors No access, no affinity (limited effect ) No access, no affinity (limited effect ) Non target site Non target site Access , affinity (effect : toxicity) Inactivation/less Therapeutic effect Sequestration and Improved therapeutic availability 5 : Controlled rate and mode of drug delivery to 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. Every event stated contributes to higher drug concentration at the site of action and resultant lower concentration at non-target tissue where toxicity might crop-up. The restricted distribution of the parent drug to the non-target site with effective accessibility to the target site could maximize the benefits of targeted drug delivery. 6 Carriers : Carriers Carrier is one of the most important entities essentially required for successful transportation of the loaded drug. They are drug vectors, which sequester , transport and retain drug en route , which elute or deliver it within or in the vicinity of the target. Carriers can do so either through an inherent characteristics or acquired (through structural modification), to interact selectively with biological targets , or otherwise they are engineered to release the drug in the proximity of the target cell lines demanding optimal pharmacological action (therapeutic index). 7 Requirement of drug carriers : Requirement of drug carriers 8 An ideal drug carrier should have the following features : : An ideal drug carrier should have the following features : It must be able to cross anatomical barriers and in case of tumour chemotherapy tumour vasculature. It must be recognized specifically and selectively by the target cells and must maintain the avidity and specificity of the surface ligands. The linkage of the drug and the directing unit ( ligand) should be stable in plasma , interstitial and other biofluids. Carrier should be non-toxic , non-immunogenic and biodegradable particulate or macromolecule and after recognition , and internalizaton,the carrier system should release the drug moiety inside the target organs , tissues or cells. The biomodules used for carrier navigation and site recognition should not be ubiquitous otherwise it may cross over the sites, defeating the concept of targeting. 9 Based on the nature of their origin carriers are categorized as: : Based on the nature of their origin carriers are categorized as: Endogenous ( low density lipoprotein, high density lipoprotein, chylomicrons , serum albumin, erythrocytes). Exogenous ( microparticulates, soluble polymeric and biodegradable polymeric drug carriers ). 10 Carrier Systems Used for Targeted Drug Delivery : Carrier Systems Used for Targeted Drug Delivery 1. Colloidal carriers a) Vesicular systems Liposomes; Niosomes; Pharmacosomes; Virosomes; Immunoliposomes b) Microparticulate systems Microparticles; Nanoparticles; Magnetic microspheres; Albumin microspheres; nanocapsules 2. Cellular carriers Resealed erythrocytes; serum albumin; antibodies; platelets; leukocytes 11 : 3. Supramolecular delivery systems Micelles; reverse micelles; mixed micelles; polymeric micelles; liquid crystals; lipoproteins ( chylomicron; VLDL; LDL ) Synthetic LDL mimicking particles (supramolecule biovector system) 4. Polymer based systems Signal sensitive; Muco-adhesive; Biodegradable; Bioerodible; Soluble synthetic polymeric carriers 5. Macromolecular carriers a) Proteins, glycoproteins; neo glycoproteins and artificial viral envelopes (AVE) 12 : b) Glycosylated water soluble polymers (poly-L-lysine) c) Mabs; Immunological Fab fragments ; antibody-enzyme complex and bispecific Abs d)Toxins , immunotoxin and rCD4 toxin conjugates e) Lectins ( Con A ) and polysacchrides 13 Examples of some drug carrier systems : Examples of some drug carrier systems 14 LIPOSOMES They are spherical vesicles with a phospholipid bilayer. Liposomes help improve : Therapeutic index Rapid metabolism Unfavorable pharmacokinetics Low solubility Lack of stability Irritation Niosomes : Niosomes They are non ionic surfactant vesicles. They enhance the penetration of drug. They are used for: Targeting of bioactive agents. Delivery of peptide drugs. Transdermal delivery of drug . 15 Micelle : Micelle Micelle is an aggregate of amphipathic molecules in water, with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water. Hydrophobic drugs can be encapsulated/ solubalized, into inner core. 16 Microspheres : Microspheres Microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers which are biodegradable in nature and ideally having a particle size less than 200 µm. 17 Polymeric Nanoparticles : Polymeric Nanoparticles In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in drug targeting to particular organs/tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through a per oral route of administration 18 Resealed erythrocytes : Resealed erythrocytes Erythrocytes have been extensively studied for their potential carrier capabilities for the delivery of drugs and drug-loaded microspheres. Such cells could be used as circulating carriers to disseminate a drug within a prolonged period of time in circulation or in target-specific organs, including the liver, spleen, and lymph nodes. 19 Levels of Drug Targeting : Levels of Drug Targeting The various approaches of vectoring the drug to the target site can be broadly classified as : Passive targeting Inverse targeting Active targeting ( Ligand mediated targeting and Physical targeting ) Dual targeting Double targeting Combination targeting 20 Passive 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 physiochemical characteristics of the drug or drug-carrier system). The ability of some colloids to be taken by the RES vectors for passive hepatic targeting of drugs to these compartments. Passive capture of colloidal carriers by macrophages offers therapeutic opportunities for the delivery of anti- infectives for disease conditions that involve microphage cells of the reticuloendothelial system. e.g. leishmaniasis,brucellosis and candidiasis. Delivery into lyosomal compartment can also be affected for the treatment of certain lyosomal storage diseases, macrophage neoplasms and macrophage activation. 21 : This category of targetable devices includes drug bearing bilayer vesicular systems as well cellular carriers of micron or submicron size range. The passive targetability of microparticulate drug carriers is due to the recognition of these particulates either in the intact or in the opsonized form, by the phagocytic cells of the RES and this sensing behaviour is exploited to target MPS associated cell lines. A major disadvantage of miacroparticulate carriers is that they cannot pass the endothelial cell lines , as a result extravasation is generally poor. Although some investigations claim that slow transcellular ( vesicular) transport of liposomes and microspheres is possible through endothelia. 22 Inverse targeting : Inverse targeting It is based on successful attempts to circumvent and avoid passive uptake of colloidal carriers by reticuloendothelal system (RES). This effectively leads to the reversion of 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 sulphate. This approach leads to RES blockade and as a consequence impairment of host defense system. Alternative strategies include modification of the size, surface charge , composition , surface rigidity and hydrophilicity of carriers for desirable biofate. 23 : Modification of the surface by imparting distinctive hydrophilicity to the carrier particles , as an effective mode of targeting of drug to non-RES organs. Phospholipid microspheres emulsified with Polaxamer 338 showed the lowest RES uptake in mouse peritoneal macrophages in vitro. Poloxamine 908, is another hydrophilic nonionic surfactant, which diverts normal RES uptake of coated emulsion and coated nanoparticles (polystyrene microsphere) to inflammatory sites in rabbits. Lee and coworkers ,1995 suggested inverse targeting of drugs to the sites other than RES rich organs by coating the lipid microemulsion with polaxamer 308. it has been suggested that surface hydrophilicity may reduce or even eliminate the adhesion of opsonin materials/HDL on the surface of lipid microemulsion , which is an important step in the process of phagocytosis responsible for ultimate uptake of LM by RES system. 24 Active Targeting : Active Targeting Active targeting exploits modification or manipulation of drug carriers to redefine its biofate The natural distribution pattern of the drug carrier composites is enhanced using chemical, biological and physical means, so that it approaches and identified by particular biosites. The facilitation of the binding of the drug –carrier to target cells through the use of ligands or engineered homing device to increase receptor mediated localization of the drug and target specific delivery of drug is referred to as Active Targeting. 25 : This targeting approach can further be classified into three different levels of targeting: First order targeting ( organ compartmentalization) Second order targeting ( cellular targeting) Third order targeting ( intracellular targeting ) 26 First order targeting : First order targeting It refers to restricted distribution of the drug carrier system to the capillary bed of a predetermined target site, organ or tissue. Compartmental targeting in lymphatics, peritoneal cavity , plural cavity ,cerebral ventricles , lungs , joints, eyes,etc. Represents first order targeting. The ability of liposomes to extravasate and penetrate into diseased states other than MPS is directly related to their size. Large liposomes (10 µ or above ) are rapidly removed via mechanical filtration of lungs and from this size range down upto 150 nm are removed by tissue macrophages originated in the liver and spleen , which are the natural target for these vesicles. 27 Slide 28: 28 : In order to achieve significant levels in other tissues, liposomes of smaller size (≤ 100 nm ) with a homogeneous distribution have been developed. They could penetrate into either normal tissue having sinusoidal or fenestrated epithelium or otherwise into diseased tissue having altered capillary permeability. This has in turn increase the chances of achieving targeting in vivo to non-MPS cell linings. 29 Second order targeting : Second order targeting The selective delivery of drugs to a specific cell type such as tumour cells and not to the normal cells as referred to as second order targeting. The selective drug delivery to the Kupffer cells in the liver exemplifies this approach. 30 Third order targeting : Third order targeting The third order targeting is defined as drug delivery specifically to the intracellular site of target cells. An example of third order targeting is the receptor based ligand –mediated entry of a drug complex into a cell by endocytosis , lysosomal degradation of carrier followed by release of drug intracellularly or gene delivery to nucleolus. 31 Ligand mediated targeting : Ligand mediated targeting Targeting components which have been studied and exploited are pilot molecules themselves (bioconugate) or anchored as ligands on some delivery vehicle (drug carrier system) , All the carrier systems in general are colloidal in nature. they can be specifically functionalized using various biologically relevant molecular ligands including antibodies , ploypeptides , oligosaccharides , viral proteins and fusogenic residues. The ligands afford avidity to drug carrier. The cascade of events involved in ligand negotiated specific drug delivery is termed as ligand driven receptor mediated targeting. 32 : Ligand mediated active targeting could be achieved using specific uptake mechanisms such as : 1) receptor dependent uptake of natural low density lipoproteins (LDL) particles 2) synthetic lipid micro emulsions of partially reconstituted LDL particles coated with the apoproteins. The apoprotein coat serves as a ligand for the LDL receptors expressed in the body. The ability of an immunoglobulin coated carrier to promote its accelerated interception by the liver and spleen , possible via pathways involving Fc and C3B receptor mediated uptake, is one of the approaches that exemplifies and signifies active targeting. 33 : Recently Balley and coworkers ,1997 described active targeting of the proten coated liposomes using different targeting approaches : a) two step targeting approach b)Direct approach The stusy was based on the specificity of biotin binding to avidin and streptividin. Biotinylated molecules can be targeted in complex mixtures using the appropriate avidin or streptividin conjugates with carrier system. In the two step targeting approach, the first sttepprebels target cells with biotinylated antibodies specific for alignad on the target cell. At a predtermined time that was sufficient to allow for plasma elimination of free antibody , streptividin conjugated liposomes specific for biotin onj the antibody prelabelled cells were administered. 34 : The active targeting is referred to as two step targeting approach for the fact that it requires the administration of the both the intermediate protein and liposomes separately , the former to allow accumulation and binding to target cells and latter to bind with the intermediate protein labeled target cells. The direct targeting approach exploits specificity by using liposomes linked with targeting ligands via a biotin –avidin bridge. 35 Slide 36: 36 Targeting Ligands Physical Targeting ( Triggered release ) : Physical Targeting ( Triggered release ) The selective drug delivery programmed and monitored at the external level with the help of physical means is referred to as physical targeting. In this mode of targeting , some characteristics of the bioenvironment are used either to direct the carrier to a particular location or to cause selective release of its contents. The first approach reported is the temperature sensitive liposomes , which were developed and applied to tumour by Weinstein and co –workers, 1979 . The release of drug from temperature sensitive liposomes in the vicinity of a tumour(temperature status higher or equal to the phase transition temperature of constitutive lipids ) is brought about by serum components mostly the lipoproteins, which at phase transition induce release of the entrapped drug. 37 : It has been suggested that weakly anionic drugs, e.g. methotrexate, be released from liposomes preferentially at low ph regions of tumours. Yatwin and coworkers ,1980 have reported ph sensitive liposomes for selective release of contents at low ph. This approach was further modified with antitumour antibody anchored as a site directing ligand with ph sensitive components of the liposomes. The approach was found exceptional for tumour targeting as well as cytosolic delivery of entrapped drugs or genetic materials ( shown in diagram ). In another approach , the application of external magnetic field has been suggested for localization of magno-responsive liposomes and microspheres within a preselected capillary bed. 38 Slide 39: ph sensitive Cytosolic Delivery of Contents. ph sensitive immunoliposomes bind with receptors via its Mabs component . 2,3 and 4 indicates receptor mediated internalization. 5 indicates cytosolic drug release at endosomal ph (4.5) and 6 indicates the fate of the system without the ph sensitive components. 39 Dual Targeting : Dual Targeting This classical approach of drug targeting employs carrier molecules, which have their own intrinsic antiviral effect thus synergies the antiviral effect of the loaded active drug. Based on this approach, drug conjugates can be prepared with fortified activity profile against the 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. 40 Double Targeting : Double Targeting Drug targeting may be combined with another methodology , other than passive and active targeting for drug delivery systems. The combination is made between spatial control and temperature control of drug delivery. The temporal control of drug delivery has been developed in terms of control drug release prior to the development of drug targeting. If spatial targeting is combined with temporal control release results in an improved therapeutic index by the following two effects. First, if drug release or activation is occurred locally at therapeutic sites , selectivity is increased with the local release /activation. 41 : 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 time period of the drugs. When these two methodologies are combined ,it may be called “Double targeting ” . ( as shown in figure) 42 Slide 43: The Concept of Double Targeting 43 : In order to achieve a double targeting effect ,site specificity of the drug, by virtue of targeting moiety , a high specificity module ( mainly a photosensitizer ) is linked to antibodies. Mew and coworkers in a series of studies on such double targeting systems reported haematoporphyrin (HP)-anti-M-1 antibody conjugates for the suppression of tumour following incandescent light exposure. Further Hp-monoclonal antibody conjugates against a leukemia-associated antigen was shown to have selective toxicity. Conjugates of monoclonal antibody and photosensitizers were prepared using a spacer arm in order to circumvent direct coupling of drug and antibody molecules. Similar double targeting systems were reported using different combinations of photosensitizer and antibody specific either to a particular antigen or to cell lines expressing cell specific receptors. 44 Combination Targeting : Combination Targeting Petit and Gombtz ,1998 have suggested the term combination targeting for the site specific delivery of proteins and peptides. These targeting systems are equipped with carriers, polymers and homing devices of molecular specificity that could provide a direct approach to target site. Modification of proteins and peptides with natural polymers ,such as polysacchrides, or synthetic polymers, such as poly( ethylene glycol), may alter their physical characteristics and favour targeting the specific compartments , organs or their tissues within the vasculature. 45 Slide 46: Approaches used in Combination Targeting. Targeting can be achieved via physical (permeation enhancing), chemical (prodrug approach) or carrier encapsulation. Combination targeting using carrier approach can be signified when only carrier encapsulation (A) is accompanied by long circulatory attribute (B) , ligand component (C) and /or long circulatory carrier with anchored ligand (D) . 46 Problems associated with targeted delivery systems : Problems associated with targeted delivery systems Several problems have been identified which requires alterations in targeting strategies particularly, in vivo. These include : Rapid clearance of targeted systems specially antibody targeted carriers. Immune reactions against intravenous administered carrier systems. Target tissue heterogeneity. Problems of insufficient localization of targeted systems into tumour cells. 47 : Down regulation and sloughing of surface epitopes. Diffusion and redistribution of released drug leading to no-specific accumulation. 48 : 49 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.