Targeted Drug Delivery to brain and tumor Systems

Targeted Drug Delivery Systems: Concepts, Events and biological process
involved in drug targeting. Tumor targeting and Brain specific delivery.

Targeted drug delivery systems (TDDS) are advanced methods of delivering drugs to patients in a sequence that increases the concentration of the drug at the targeted body part of interest (organs, tissues, or cells). This approach improves the efficacy of treatment by reducing side effects associated with drug administration. TDDS utilizes drug carriers such as liposomes, nanoparticles, and monoclonal antibodies to transport drugs to their intended sites. These carriers can actively or passively target drugs to specific organs, tissues, or cells.

targeted drug delivery systems offer a promising approach to improving the efficacy and safety of drug treatments by selectively delivering drugs to their intended sites of action. By understanding the concepts, events, and biological processes involved in drug targeting, researchers can develop more effective TDDS for various diseases, including cancer and neurological disorders.

Brain-Specific Delivery:
Brain-specific delivery is a particularly challenging task due to the blood-brain barrier, which restricts the entry of many drugs into the brain. Targeted drug delivery systems can be designed to overcome this barrier by utilizing ligands that bind to receptors on the brain endothelial cells or by using nanoparticles that can cross the blood-brain barrier.

Tumor Targeting:
Tumor targeting involves the use of drug delivery systems that specifically target tumor cells while sparing healthy cells. This can be achieved through the use of tumor-specific ligands, such as antibodies or peptides, which bind to receptors or antigens on the surface of tumor cells.

1. Department of Pharmaceutics B. K. ModY Government Pharmacy College, Rajkot Prepared by – Chintan S Kalsariya M.pharm ( sem - II ) Drug delivery to brain Drug delivery to tumor

2. INDEX BRAIN DRUG DELIVERY SYSTEM 2 No Contents 1 Introduction 2 Brain specific drug delivery 3 Blood Brain Barrier 4 Blood cerebrospinal fluid barrier 5 Disease related to brain 6 Factor affecting drug delivery to brain 7 Tumor targeting drug delivery system 8 Marketed formulation 9. Refrances

3. Introduction Drug delivery to brain drug delivery to tumor 3 Drugs that act on the CNS include those used for the treatment of psychosis, affective (mood) disorders, such as depression and mania, anxieties and related disorders, seizure disorders (epilepsies), Parkinson’s disease, Alzheimer’s disease, pain (opioid analgesics) and brain tumors.

4. 4 Drug delivery to brain drug delivery to tumor Ideally, drugs used in the treatment of diseases affecting the CNS would be delivered directly to the site of action. However, drugs generally do not readily enter the brain from the circulating blood. Access to the brain is particularly difficult for the “ new biotherapeutics ” such as peptide, protein and nucleic-acid based biopharmaceuticals. Entry of molecules to the brain is regulated by a selective barrier that exists between the brain and the blood , known as the blood-brain barrier (BBB). This chapter reviews the structure and physiology of this barrier and the new and emerging technologies to overcome this barrier and achieve drug delivery to the CNS.

5. 5 presentation title 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- tumor cells but not to normal cells. To a specific organ (or) tissues by complexing with the carrier that recognizes the target.

6. Targeted therapy 6 BDDS 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

7. BRAIN SPECIFIC DRUG DELIVERY 7 BDDS 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.

8. 8 BDDS 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.

9. 9 presentation title • BBB & BCF C ontrol the entry of compounds into the brain and R egulate brain homeostasis. R estricts access to brain cells of blood–borne compounds and F acilitates nutrients essential for normal metabolism to reach brain cells.

10. 10 BDDS It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB.

11. Blood Brain barrier (BBB) 11 BDDS Blood capillaries in the brain are structurally different from the blood capillaries in other tissues; T hese structural differences result in a permeability barrier between the blood within brain capillaries and the extracellular fluid in brain tissue.

12. 12 BDDS This permeability barrier, comprising the brain capillary endothelium, is known as the Blood-Brain Barrier (BBB) The blood-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 capillaries.

13. 13 presentation title Blood-Brain barrier

14. 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. 14 BDDS

15. 15 BDDS 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.

16. 16 BDDS DISEASES RELATED TO BRAIN Diseases related to Blood Brain Barrier : Meningitis – inflammation of brain and spinal cord Brain abscess – Bacteria and fungi enter in brain tissue Epilepsy – Seizures which are brief episode in Voluntary moments Multiple sclerosis – Damages of protecting covering of never Neuromyelitis optica – Inflammation in nerve of eye & spinal cord Late-stage neurological trypanosomiasis (sleeping sickness) – neurological disorder cause sleep disturbance Progressive multifocal leukoencephalopathy (PML) – a rare viral infection that damages white matter of brain & cause inflammation Alzheimer's Disease – short term memory loses

17. 17 BDDS DRUG TRANSPORTS ACROS THE BBB BIG MOLECULES HIGHLY CHARGED MOLECULES TOXIC SUBSTANCES SMALL MOLECULES GLUCOSE

18. ii. Blood cerebrospinal fluid barrier 18 presentation title Fenestrated Endothelial cells Modified Ependymal cells (Choroidal cells) . TIGHT JUNCTIONS ENDOTHELIAL CELLS CHOROIDAL CELLS BASAL MEMBRANE

19. 19 BDDS SCHEMATIC REPRESENTATION OF BCSF

20. 20 presentation title Sr No Transports Mechanism Description 1 PASSIVE TRANSPORTS 1. Molecular weight (>600 Dalton is limiting factor) Inversely related to passive transport 2. Lipophilicity is directly related to passive transport log P values (- 0.2 to 1.3) is responsible for optimal cerebral transport 3. Protein binding : Protein drug complex size is responsible for transport (Free fraction of drug is transported.) 2. ADSORPTIVE MEDIATED TRANSCYTOSIS/ ENDOCYTOSIS 1. Adsorptive-mediated transcytosis Macro molecules like cationic Macro molecules e.g. histone, Avidin and Cationized albumin 2.Brain targeting using adsorptive mediated endocytosis Cationized human serum albumin (cHSA) as a transport vector coupled to 3H-biotin is able to cross the BBB in significant Amounts 3 ACTIVE TRANSPORT requires energy

21. 21 BDDS

22. 22 BDDS BBB TRANSPORTS MECHANISM

23. 23 presentation title Receptor-mediated transport Active efflux-mediated transport Transporter(Carrier) - mediated transport Transferrin receptor ( TfR ) Adenosine triphosphate-binding cassette (ABC) transporter subfamily B, member 1 (P-glycoprotein) Glucose transporter(Glut1) Insulin receptor(IR) MRPs(1&5) Large neutral amino acid transporter (LAT1) Nicotinic acetylcholine receptor Organic anion transporting peptide Cationic amino acid transporter (CAT1) Low-density lipoprotein receptor Glutamic acid amino acid transporter Monocarboxylic acid transporter (MCT1) Insulin-like growth factor receptor(IGF-R) Taurine transporter Choline transporter Diphtheria toxin receptor Organic anion transporter (oatp2) Nucleobase transporter Leptin receptor(OB-R) BBB-specific anion transporter type 1 (BSAT1) CNT2 adenosine transporter TRANSPORTER

24. 24 BDDS FACTORS AFFECTING DRUG DELIVERY TO BRAIN Factors affecting drug delivery to Brain are as follows: Blood brain barrier (BBB) Cerebrospinal fluid Physico-chemical factors

25. 25 BDDS Blood brain barrier (BBB) It is present at level of brain capillaries Different cell which are found in BBB are:- Endothelial cells pericytes astrocytes, microglia. The wall of microcapillaries are made-up of Brain micro vessel endothelial cells(BMEC) P- glycoprotein are found at luminal membrane of BMEC

26. 26 BDDS B. Cerebrospinal fluid Three types of fluids in entire brain- Interstitial fluids – fluid outside of body Cell & outside the blood vessels cerebrospinal fluids intercellular fluids C. Physico-chemical factors Molecular weight-limiting factor at 600 Dalton Lipid solubility Passive transport Active transport Concentration gradient of drug Decreases the clearance rate of drug Cellular enzymatic stability Affinity for receptors Cerebral Blood Flow Systemic Absorption

27. 27 BDDS

28. 28 BDDS STRATEGIES FOR DRUG DELIVERY TO BRAIN INVASIVE TECHNIQUES NON INVASIVE TECHNIQUES MISCELLANEOUS TECHNIQUES

29. 29 BDDS INVASIVE TECHNIQUES Intra-cerebroventricular (ICV) infusion Convection-enhanced delivery (CED) Intra-cerebral injection or implants Disruption of the BBB

30. 30 BDDS Intra-cerebroventricular (ICV) infusion 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: Glycopeptid e and an aminoglycoside antibiotics used in meningitis.

31. 31 BDDS 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 tumor Subsequently, Infineon of therapeutics into the tumor 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 tumor tissue Ex: Brain tumors

32. 32 BDDS c) Intra-cerebral injection or implants Placement of a biodegradable chemotherapeutic impregnated pellet wafer into a tumor 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 bruin. Ex: Immunoglobulin-G injection for treatment of Neuromyelitis Optica

33. 33 BDDS d) Disruption of the 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 i schemia , BBB may also be disrupted Osmotic disruption: The osmotic shock causes endothelial cells to shrink, thereby disrupting the tight junctions. Ex: Hypertonic mannitol

34. 34 BDDS Limitations of invasive approach : All these approaches are relatively costly , require an aesthesia and hospitalization These techniques may enhance tumor dissemination after successful disruption of the BBB Neurons may be damaged permanently from unwanted blood components entering the brain.

35. 35 BDDS II. NON INVASIVE TECHNIQUES Non invasive approaches 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.

36. 36 BDDS Chemical techniques Pro drug Drug Conjugates B) Colloidal Techniques Nanoparticles Liposomes C) Biological Techniques Receptor-mediated drug delivery

37. 37 BDDS 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 . Eg. . esterification or amidation of hydroxy, amino, or carboxylic acid containing drugs These techniques are mainly of two types: Prodrugs Drug conjugates

38. 38 BDDS Prodrugs Prodrugs are pharmacologically inactive compounds that result from transient chemical modification 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

39. 39 BDDS ii. Drug conjugates It involves caging compounds within glycosyl -, maltosyl and dimaltosly -derivatives of cyclodextrin, 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.

40. 40 BDDS B) Colloidal Techniques Nanoparticles (NPs) Nanoparticles (NPs) are solid colloidal particles made up of polymeric materials ranging in sire from 1-1000 nm. It includes both nano capsules, with a core-shelf 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.

41. 41 BDDS 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.

42. 42 BDDS 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.

43. 43 BDDS Liposomes : Liposomes or lipid based vesicles are microscopic vesicles that are formed as a result of self-assert phospholipids in an aqueous media resulting in closed bilayer structures. Since lipid bilayer membrane encloses an aqueous core, both water and lipid soluble drugs can be successfully entrapped into the liposomes.

44. 44 BDDS C) Biological Techniques : Receptor-mediated drug 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 capillaryendothelial 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.

45. 45 BDDS

46. 46 BDDS III. MISCELLANEOUS TECHNIQUES Intranasal delivery Iontophoretic delivery 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 offactory macosa (smelling area in noselis in direct contact with the brain and cerebrospinal fluid.

47. 47 BDDS Medications absorbed across the olfactory mucosa directly enters the brain. This area is termed the nose brain pathway and offers a rupid , direct route for drug delivery to the brain. Mechanism for transport: - Two mechanisms underlying the direct nose to brain drug delivery: Intracellular transport mediated route Extracellular transport mediated routes.

48. 48 presentation title The intracellular transport mediated route is a relatively słow process, taking hours for intra nasally administered substances to reach the of factory bulb. Extracellular transport mediated routes is rapid. b) Iontophoretic delivery : Iontophoretic is a method to deliver ionized molecules across the BBB by using an externally applied elecucurrent. invasomes are effective carriers for transdermal delivery of finasteride through the application of iontophoretic techniques

49. 49 BDDS 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 : 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.

50. Tumor targeting drug delivery It is 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. 50 BDDS

51. 51 BDDS A Specific interaction between drag 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

52. 52 BDDS 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: EPR effect Enhanced Permeability and Retention Nanoparticle properties and design Ligand-receptor interactions

53. 53 BDDS STRATEGIES FOR TUMOR TARGETING 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.

54. 54 BDDS 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 Involvement of carrier based approaches There are three main strategies for tumor targeting. Passive targeting Active targeting Triggered drug delivery

55. 55 BDDS 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.

56. 56 BDDS 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.

57. 57 BDDS

58. 58 BDDS Examples of passive tumor targeted drug delivery system Macromolecular conjugates : Polymer-drug conjugate Protein- drug conjugate Antibody-drug conjugate Particulate systems : Liposomes PEGylated liposomes Polymeric micelles

59. 59 BDDS ii. Active targeting Active targeting is 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.

60. 60 BDDS Examples of active targeting ; Folate Transferrin Lectins Galactosamine

61. 61 BDDS Active targeting drug delivery in tumor tissue and schematic representation of the receptor-mediated endocytosis process: (a) NP (NANOPARTICLE) modified with ligand; (b) NP recognition and binding to the cell membrane receptor; NP entrapped in the endosome; endosomal escape; and drug release into the cell cytoplasm.

62. 62 BDDS iii. Triggered drug delivery 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

63. According to who…. 63 BDDS Lancet Neurology study, with WHO collaboration, reports over 3 billion individuals worldwide lived with neurological conditions in 2021. Neurological disorders are now the primary cause of ill health and disability globally. Disability-adjusted life years (DALYs) attributable to neurological conditions rose by 18% since 1990. Over 80% of neurological deaths and health loss occur in low- and middle-income countries. Access to treatment significantly varies, with high-income countries having up to 70 times more neurological professionals per 100,000 people compared to low- and middle-income countries.

64. References: 64 BDDS Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists  [ Page no 319-333] Potential of solid lipid nanoparticles in brain targeting by Indu Pal Kaur a, Rohit Bhandari b, Swati Bhandari b, Vandita Kakkar a Challenges in drug delivery to tumors of the central nervous system: An overview of pharmacological and surgical considerations By Laura P. Serwer , C. David James https://www.who.int/news/item/14-03-2024-over-1-in-3-people-affected-by-neurological-conditions--the-leading-cause-of-illness-and-disability-worldwide Transferrin Receptor-Targeted Nanocarriers: Overcoming Barriers to Treat Glioblastoma by Maria Ramalho , Joana Loureiro , Manuel A N Coelho Maria Carmo Pereira

65. Thank you