Tumour targeting and Brain specific drug delivery

Tumour targeting and Brain specific drug delivery

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  TUMOUR TARGETING &BRAIN SPECIFIC DRUG DELIVERY PRESENTED BY GUIDE MR. SHUBHAM GAJANAN WAGH PROF. DR.S.D.PANDE M.pharm (pharmaceutics) 1st year VIDYA BHARATI COLLEGE OF PHARMACY, AMRAVATI-444602 2021-22
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  INDEX Sr. No. ContentsPage No. 1 Introduction 3 2 Tumor targeting drug delivery 4 3 Strategies for tumor targeting 5-9 4 Brain specific drug delivery 10 5 Blood-brain barrier 11-12 6 Diseases related to brain 13 7 Factors affecting drug delivery to brain 14 8 Strategies for drug delivery to brain 15-24 9 Marketed formulations 25 10 References 26 2
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  INTRODUCTION Targeted drug delivery Itis a special form of drug delivery system where the pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells. It is also refers to predominant drug accumulation within a target zone that is independent of method and route of administration. The drug may be delivered: To the capillary bed of the active sites. To the specific type of cell (or) even an intracellular region. Ex- tumour cells but not to normal cells. To a specific organ (or) tissues by complexing with the carrier that recognizes the target. Targeted therapy It is type of medication that blocks the growth of cancer cells by interfering with specific targets which are needed for carcinogenesis and tumor growth 3
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  TUMOR TARGETING DRUGDELIVERY Tumor targeting drug delivery  A Specific interaction between drug and its receptor at the molecular level. A rapidly growing tumor requires various nutrients and vitamins. Therefore, tumor cells over express many tumor- specific receptors which can be used as targets to deliver cytotoxic agents into tumors  Targeted drug delivery system is achieved with the advantage of morphology and physiological differences between the normal cells and tumor cells. An ideal anticancer drug delivery system should fulfill the following requirements Effectively kill tumor cells Be non-toxic for healthy organs, tissues, and cells Not induce multidrug resistance Both physically and chemically stable in vivo and in vitro. Should have uniform capillary distribution. Controllable and predicate rate of drug release. Drug targeting to tumor is based on: 1) EPR effect(Enhanced Permeability and Retention) 2) Nanoparticle properties and design 3) Ligand-receptor interactions 4
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  STRATEGIES FOR TUMORTARGETING 5  Site specific drug delivery requires localization of drug and carrier within the desired target organ.  Selective accumulation of the drug at preferred site is also majorly affected by its physicochemical properties.  Most of the anticancer drugs fall in the category II/IV of Biopharmaceutical Classification Systems (BCS), thereby posing pharmaceutical problems while water soluble drugs pose problems related to permeability across various biological barriers. Major approaches could be employed which include  Subtle structural modifications for improving the physicochemical properties in accordance with structure– activity relationships (SAR),  Conjugating homing ligands for predetermined bio-distribution patterns, and  Involvement of carrier based approaches There are three main strategies for tumor targeting. A. Passive targeting B. Active targeting C. Triggered drug delivery
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  A. PASSIVE TARGETING Passive targeting is based on drug accumulation in the areas around the tumours with leaky vasculature; commonly referred to as the enhanced permeation and retention (EPR) effect  Passive targeting exploits the anatomical differences between normal and tumour tissue to deliver the drugs.  Passive targeting involves transport of nanocarriers through leaky tumour capillary fenestrations into the tumour interstitium and cells by convection or passive diffusion & selective accumulation of nanocarriers and drug then occur by the EPR effect. Enhanced Permeability & Retention Effect  The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors based on their anatomical and pathophysiological differences from normal tissues.  Macromolecular drugs could accumulate and retain in solid tumor tissues selectively but they will not distribute much in normal tissue.  EPR based chemotherapy is thus becoming an important strategy to improve the delivery of therapeutic agents to tumors for anticancer drug development. 6
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  7 Examples of passivetumor targeted drug delivery system Macromolecular conjugates 1. Polymer-drug conjugate 2. Protein- drug conjugate 3. Antibody-drug conjugate Particulate systems 1. Liposomes 2. PEGylated liposomes 3. Polymeric micelles
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   Active targetingis used to describe specific interactions between drug/drug carrier and the target cells, usually through specific ligand– receptor interactions.  Active targeting means a specific ligand–receptor type interaction for intracellular localization which occurs only after blood circulation and extravasation.  Active drug targeting is generally implemented to improve target cell recognition and target cell uptake, and not to improve overall tumor accumulation.  Ligand mediated targeting is the major approach that involves ligands developed against cell receptors or antigenic determinants expressed on tumor cells or vasculature. Examples of active targeting 1. Folate 2. Transferrin 3. Lectins 4.Galatosamine 8 B. ACTIVE TARGETING
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  C. TRIGGERED DRUGDELIVERY  The tumor microenvironment differs from that normal cells microenvironment.  Advantage of the difference in pH, temperature is used to release the drug in the tumor microenvironment.  It employs drug-carrier constructs that release drug only when exposed to specific microenvironments such as change in pH and temperature.  The drug release also triggered on subjecting to the external magnetic fields.  Thermosensitive liposomes – Destabilization of lipid membranes at mild hyperthermia 9
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  BRAIN SPECIFIC DRUGDELIVERY Introduction  Drug delivery to the brain is the process of passing therapeutically active molecules across the Blood-Brain Barrier for the purpose of treating brain maladies.  This is a complex process that must take into account the complex anatomy of the brain as well as the restrictions imposed by the special junctions of the Blood Brain Barrier.  In response to the insufficiency in conventional delivery mechanisms, aggressive research efforts have recently focused on the development of new strategies to more effectively deliver drug molecules to the CNS  Various routes of administration as well as conjugations of drugs. e.g. with liposomes and nanoparticles are considered.  Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. 10
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  BLOOD-BRAIN BARRIER  Theblood–brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS).  The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections.  The blood-brain barrier is composed of high density cells, restricting passage of substances from the bloodstream other than endothelial cells in capillarie. Anatomy of blood–brain barrier (BBB)  Basal membrane and brain cells, such as pericytes and astrocytes, surrounding the endothelial cells further form and maintain an enzymatic and physical barrier known as the blood–brain barrier (BBB).  BBB tight junctions are formed between endothelial cells in brain capillaries, thus preventing paracellular transport of molecules into the brain.  In brain capillaries, intercellular cleft, pinocytosis, and fenestrate are virtually non existent; exchange must pass trans-cellularly. Therefore, only lipid-soluble solutes that can freely diffuse through the capillary endothelial membrane may passively cross the BBB. 11
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  12 Physiology blood–brain barrier(BBB)  Small hydrophilic molecules such as amino acids, glucose, and other molecules necessary for the survival of brain cells use transporters expressed at the luminal (blood) and basolateral (brain) side of the endothelial cells.  Larger or hydrophilic essential molecules such as hormones, transferrin for iron, insulin, and lipoproteins use specific receptors that are highly expressed on the luminal side of the endothelial cells. These receptors function in the endocytosis and transcytosis of compounds across the BBB  The blood–brain barrier is protecting the brain from "foreign substances" (such as viruses and bacteria) in the blood that could injure the brain.  Shielding the brain from hormones and neurotransmitters in the rest of the body.  Maintaining a constant environment (homeostasis) for the brain.  Antibodies are too large to cross the blood–brain barrier, and only certain antibiotics are able to pass.  The blood–brain barrier becomes more permeable during inflammation.
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  DISEASES RELATED TOBRAIN 13 Diseases related to Blood Brain Barrier :-  Meningitis  Brain abscess  Epilepsy  Multiple sclerosis  Neuromyelitis optica  Late-stage neurological trypanosomiasis (sleeping sickness)  Progressive multifocal leukoencephalopathy (PML)  Alzheimer’s Disease  Cerebral oedema etc;
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  FACTORS AFFECTING DRUGDELIVERY TO BRAIN Factors affecting drug delivery to Brain are as follows : 1.Blood brain barrier(BBB) 2. Cerebrospinal fluid 3.Physico-chemical factors 1.Blood brain barrier(BBB)  It is present at level of brain capillaries  Different cell which are found in BBB are:- Endothelial cells ,pericytes ,astrocytes ,microglias ,  The wall of microcapillaries are madeup of Brain microvessel endothelial cells(BMEC)  P-glycoprotein(p-gp) are found at luminal membrane of BMEC 2.Cerebrospinal fluids Four types of fluids in entire brain :- Interstitial fluids, cerebrospinal fluids, intercellular fluids 3. Physico-chemical factors Molecular weight –limiting factor at >600 Dalton Lipid solubility Passive transport Active transport Concentration gradient of drug Affinity for receptors 14 Cerebral blood flow Systemic Absorption Decreases the clearance rate of drug Cellular enzymatic stability
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  STRATEGIES FOR DRUGDELIVERY TO BRAIN 1. INVASIVE TECHNIQUES a) Intra-cerebroventricular (ICV) infusion b) Convection-enhanced delivery (CED) c) Intra-cerebral injection or implants d) Disruption of the BBB. 2. NON INVASIVE TECHNIQUES a)Chemical techniques Prodrug Drug conjugates b) Colloidal Techniques Nanoparticles Liposomes c) Biological Techniques Receptor-mediated drug delivery 3. MISCELLANEOUS TECHNIQUES a) Intranasal delivery b) Iontophoretic delivery 15
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  1. INVASIVE TECHNIQUES Drugscan be delivered to the brain by first drilling the hole in the head, and then implant is placed by intra- cerebral (IC) or infusion is given by intra-cerebro-ventricular (ICV). a) Intra-cerebro-ventricular infusion (ICV)  Injection of intra-cerebro-ventricular infusion of drugs directly into the CSF.  Drugs can be infused intraventricularly using an Ommaya reservoir, a plastic reservoir implanted subcutaneously in the scalp and connected to the ventricles.  Drug solutions can be subcutaneously injected into the implanted reservoir and delivered to the ventricles by manual compression of the reservoir through the scalp.  Ex: Glycopeptide and an aminoglycoside antibiotics used in meningitis. b) Convection Enhanced Delivery (CED)  CED is a therapeutic strategy that was developed to facilitate targeted delivery of pharmaceuticals to the brain.  The CED procedure involves a minimally invasive surgical exposure of the brain, followed by placement of small diameter catheters directly into the brain tumour.  Subsequently, infusion of therapeutics into the tumour occurs over several hours to saturate the target tissue.  As this approach effectively bypasses the blood-brain-barrier, it allows for delivery of macromolecular drugs that would not normally enter the brain to effectively reach high concentrations within brain tumour tissue.  Ex : Brain tumours. 16
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  17 c) Intra -cerebral injection/implant  Placement of a biodegradable chemotherapeutic impregnated pellet/ wafer into a tumour resection area.  These are implanted intra cranially through which drug bypass the BBB and release drug molecules locally in the brain in a sustained fashion.  Both the bolus injection and implant rely on the principle of diffusion to drive the drug into the infiltrated brain.  Ex: Immunoglobulin-G injection for treatment of Neuromyelitis optica d) Disruption of Blood brain barrier(BBB)  This technique is used widely for CNS drug delivery and involves disruption of the BBB.  Exposure to X-irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol may disrupt BBB.  By inducing pathological conditions such as hypertension, hypoxia, or ischemia, BBB may also be disrupted.  Osmotic disruption: The osmotic shock causes endothelial cells to shrink, thereby disrupting the tight junctions.  Ex: Hypertonic mannitol Limitations of invasive approach  All these approaches are relatively costly, require anaesthesia and hospitalization.  These techniques may enhance tumour dissemination after successful disruption of the BBB.  Neurons may be damaged permanently from unwanted blood components entering the brain.
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  2. NON –INVASIVE TECHNIQUES  Non invasive approches make use of the brain blood vessel network for drug distribution.  These may be of a chemical or biological nature.  These methods usually relay upon drug manipulations which may include alterations as prodrugs, lipophilic analogues, chemical drug delivery, carrier mediated drug delivery, receptor-vector mediated drug delivery etc. a) Chemical Techniques  These are usually designed to improve some deficient physiological property such as membrane permeability or solubility.  Chemical methods involves the chemical transformation of drugs by changing the various functionalities. E.g.: esterification or amidation of hydroxy, amino, or carboxylic acid containing drugs.  These techniques are mainly of two types :  Prodrugs  Drug conjugates 18
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  19 Prodrugs  Prodrugs arepharmacologically inactive compounds that result from transient chemical modifications of biologically active species.  After administration, the prodrug, by virtue of its improved characteristics, is brought closer to the receptor site and is maintained there for longer periods of time.  It gets converted to the active form, usually via a single activating step(hydrolysis). Conversion to the active form is realized via an enzymatic cleavage.  Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. Drug conjugates  It involves caging compounds within glycosyl-, maltosyl and dimaltosly- derivatives of clyclodextrin.  The complexes are further covalently bonded with cationic carriers and permeabilizer peptides for delivery across the BBB and with the targeting moieties for uptake by brain cells.  The therapeutic complexes or conjugates comprise of an omega 3 fatty acid such as alpha-linolinic acid , or docosahexaenoic acid and their derivatives.
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  20 b) Colloidal Techniques Nanoparticles(NPs)  Nanoparticles (NPs) are solid colloidal particles made up of polymeric materials ranging in size from 1-1000 nm.  It includes both nano capsules, with a core-shell structure (a reservoir system), and nano spheres (a matrix system).  NPs are used as carrier systems in which the drug is dissolved, entrapped, encapsulated, adsorbed or chemically linked to the surface.  By using nanotechnology it is possible to deliver the drug to the targeted tissue across the BBB, release the drug at a controlled rate, and avoid degradation processes.  Reduction of toxicity to peripheral organs and biodegradability can also be achieved with these systems. Mechanism for transport  The mechanism for transport of lipoprotein to be endocytosis via the Low Density Lipoprotein (LDL) receptor of the endothelial cells after adsorption of lipoproteins form blood plasma to the nanoparticles.  It is suggested that the recognition and interaction with lipoprotein receptors on brain capillary endothelial cells is responsible for the brain uptake of the drug. Limitations of using nanoparticles  Their small size and large surface area can lead to particle-particle aggregation, making physical handling of nanoparticles difficult in liquid and dry forms.  In addition, small particles size and large surface area readily result in limited drug loading and burst release.
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  21 Liposomes  Liposomes orlipid based vesicles are microscopic vesicles that are formed as a result of self-assembly of phospholipids in an aqueous media resulting in closed bilayer structures.  Since lipid bilayered membrane encloses an aqueous core, both water and lipid soluble drugs can be successfully entrapped into the liposomes.  Lipid soluble or lipophilic drugs get entrapped within the bilayered membrane whereas water soluble or hydrophilic drugs get entrapped in the central aqueous core of the vesicles.  Liposomes are potential carrier for controlled drug release of tumours therapeutic agents and antibiotics.  Liposomes can be prepared with diameters ranging from 20 nm to 100 mm.
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  22 c) Biological Techniques Receptor-mediateddrug delivery  Receptor-mediated drug delivery to the brain employs chimeric peptide technology.  Peptide technology based on using the coupling of a non- transportable peptide pharmaceutical to a transportable peptide or protein, which undergo receptor-mediated transcytosis through the BBB.  Endocytosis can be triggered after binding of the vector to its receptor on the luminal surface of brain capillary endothelial cells.  Enzymatic cleavage may occur at the cleavage linkage between the vector and the drug to release the pharmacologically active moiety of the chimeric peptide.
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  3. MISCELLANEOUS TECHNIQUES a)Intranasal delivery  In nasal drug delivery system drug are deliver in nasal cavity.  The nasal mucosa used for delivering the drugs for CNS disorders and systemic administration of analgesics, sedatives, hormones, cardiovascular drugs, and vaccines, corticosteroid hormones.  The olfactory mucosa (smelling area in nose)is in direct contact with the brain and cerebrospinal fluid.  Medications absorbed across the olfactory mucosa directly enters the brain.  This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain. Mechanism for transport :- Two mechanisms underlying the direct nose to brain drug delivery: a.Intracellular transport mediated route b. Extracellular transport mediated routes. The intracellular transport mediated route is a relatively slow process, taking hours for intra nasally administered substances to reach the olfactory bulb. Extracellular transport mediated routes is rapid. 23
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  24 b) Iontophoretic delivery Ionophoretic is a method to deliver ionized molecules across the BBB by using an externally applied electric current.  In the body ,ions with a positive nature (+) are driven into the skin at the anode those with negative charge (-) at the cathode.  Iontophoresis is sometimes confused with electrophoresis.  Iontophoresis involving movement of the colloid (dispersed phase).  Electrophoresis involving the liquid (dispersed medium). Mechanism:  In Iontophoretic treatment electric potential may alter the molecular arrangement of the skin components hence change in skin permeability.  The flip-flop gating mechanism could be responsible for pore formation in the stratum corneum which is rich in keratin, an alpha –helical polypeptide.
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  MARKETED FORMULATIONS AVAILABLEAS A BRAIN TARGETED DRUG DELIVERY SYSTEM Sr. no. Brand name Active Pharmaceutical ingredient Role 1 AmBisome Amphotericin B Liposome for injection 2 Caelyx PEGylated liposomal doxorubicin hydrochloride Brain tumour 3 Aricept Donepezil Alzheimer's disease 4 Aurimmune Colloidal gold IV nanoparticles Solid tumors 5 AuroShell Gold-coated silica Nanoparticles IV (~150 nm) Solid tumors 25
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  REFERENCE  CNS drugdelivery systems : novel approaches. Shadab A.Pathan , Zeenat Iqbal .Recent patents on drug delivery & formulation 2009, 3, Pg.No:71-89.  Novel approaches for controlled drug delivery systems by N.K.jain Pg.No:23-46  CNS targeted drug delivery : current perspectives , arun rasheed , I Theja . JITPS 20120, vol. 1 (1) Pg.No:9-18.  Targeted nanoparticles for drug delivery through the blood-brain barrier for alzheimer’s disease. Celesete roney , padmakar kulkarni , journal of controlled release 108 (2005) Pg.No:193-214.  Nanoparticle drug delivery to the brain , K.Ringe , C. M. Walz , B. A. Sabel , encyclopedia of nano science and nanotechnology , edited by H.S. Nalwa volume 7: Pg.No : 91-104  https://www.slideshare.net/gipsmusta/brain-specific-drug-delivery-189768182  https://www.slideshare.net/PallaviKurra/brain-targeting-novel-approaches 26