Targeted drug delivery systems, tdds, biological processes involved in targeted drug delivery system, brain targeted drug delivery system, tumour targeted drug delivery system.

1. TARGETED
DRUG
DELIVERY
SYSTEMS
Presented by:
Pallerla Naveen Reddy,
M.pharm(pharmaceutics),
Central University of South
Bihar,

2. 1) Concepts
2) Biological process involved in targeted drug
delivery systems
3) Tumour targeted drug delivery system
4) Brain Specific Drug Delivery system
CONTENT
S:

3. Targeted drug delivery:
It is a special form of drug delivery system where the phamacologically 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.

4. Biological process and events involved in drug
targeting
Drug targeting has been classified into three types:
a) first-order targeting-this describes delivery to a discrete organ or tissue;
b) second-order targeting -this represents targeting to a specific cell type(s)
within a tissue or organ (e.g., tumor cells versus normal cells and hepatocytic
cells versus HupRer cells); and
c)third-order targeting-this implies delivery to a specific intracellular
compartment in the target cells (e.g, lysosomes)
Basically, there are three approaches for drug targeting. The first
approach involves the use of biologically active agents that are both potent and
selective to a particular site in the body (magic bullet approach of Ehrlich). The
second approach involves the preparation

5. or pharmacologically inert forms of active drugs, which upon reaching the
active sites become activated by a chemical or enzymatic reaction (prodrug
approach). The third approach utilizes a biologically inert macromolecular
carrier system that directs a drug to a specific site in the body where it is
accumulated and affects it's response.
Various biological process and drug targeting events that govern drug
targeting are discussed below:
 Cellular uptake and processing,
 Transport across epithelial barrier,
 Extravasation,
 Lymphatic uptake.

6. Following administration low molar mass drugs can enter into or pass
through various cells by simple diffusion process.Targeted drug delivery
usually have macro molecular assemblies hence cannot enter by such
simple process. Hence take up by a process called ENDOCYTOSIS.Steps
involved:
*Internalization of the plasma membrane.
*Concomitant with engulfment of extracellular material.
Other methods of gaining access to cells include passive diffusion,
membrane fusion, and binding to either specific or nonspecific regions of
the cell. Endocytosis is divided into two types:
(a) phagocytosis and (b) pinocytosis.
Phagocytosis is carried out by specialized cells of the
Cellular uptake and
processing:

7. mononuclear phagocyte system (MPS), called phagocytes. It is mediated by
the adsorption of specific blood components. (eg: immunoglobulin dg) G,
complement C3b, and fibronectin), called opsonins, and relevant receptors
located on macrophages.
Compared with phagocytosis, pinocytosis is a universal phenomenon in all
the cells pinocytosis does not require any external stimulus.
Pinocytosis is divided into two types:
1. Fluid phases pinocytosis
2. Adsorptive pinocytosis
Compared with phagocytosis fluid phase pinocytic capture of
molecules is relatively slower being directly proportional to the concentration
and size dependant.

9. Transport across the epithelial barrier:
The oral buccal nasal vaginal and rectal cavities are internally lined with
one or more layers of epithelial cells.Depending on the position and
function in the body epithelial cells can be varied forms: Three layer
physiology:
1)Epithelial.
2)Lamia propria.
3)Basal lamina.
*Low molar mass drugs cross the above by passive diffusion carrier
mediated systems and selective and non-selective endocytosis.
*The polar materials diffuse through tight junctions of epithelial cells
*Passive transport is usually higher in damaged mucosa where as active
transport depends on structural integrity of epithelial cells.

10. *Positively charged particles showed increased uptake than negatively charged
counterparts.
*Absoption of drugs from buccal via transcellular and paracellular later being
dominant.
Some proposals:
*Ex-vaginal cavity could be an effective delivery site for certain
pharmaceuticals.
*Such as calcitonin for the treatment of postmenopausal osteoporosis.
*It was demonstrated that when delivered vaginally first undergo uterine pass
effect suggesting that the vaginal route can be useed to target to the uterus.
Extravasation:
Many diseases result from the dysfunction of cells located outside the
cardiovascular system thus for a drug to exert its therapeutic effects it must
exit from the central circulation this process of trans vascular exchange is
called Extravasation, which is governed by blood capillary walls.
Factors that control permeability of capillaries:

11. a) Structure of the capillary wall.
b) Pathological condition.
c) Rate of blood and lymph supply.
d) Physicochemical factors of drug.
The structure of the blood capillary varies in different organs tissues. It
consists of a single layer of endothelial cells joined together by intercellular
junctions.
 Depending on the morphology and continuity of the endothelial layer and the
basement membrane blood capillaries are divided into
*Continuous,
*Fenestraded,
*Sinusoidal.
 Continuous capillaries are common and distributed in the body exhibit
tight inter endothelial junctions and an uninterrupted basement
membrane.
 Fenestrated capillaries shows inter endothelial gaps of 20-80nm.

12.  Depending on the tissue or organ the basal membrane is either absent ex-
liver. (or) present in discontinuous example-spleen and bone marrow.

13.  Macromolecules can transverse the normal endothelium by passive process such as
nonspecific fluid phase trans capillary pinocytosis and passage through inter endothelial
junctions gaps or fenestrate or by receptor-mediated transport systems.
 Organs such as the lung with very large surface areas have a proportionately large total
permeability and consequently a high extravasation.
 Depends on charge shape, size, HLB, characteristics of macromolecules.
 The endothelium of brain is the strongest of endothelia formed by continonus endothelial
cells which show no pinocytic activity.
 Soluble macromolecules permeate the barrier more readily than particulate macromolecules
the rate of movement of fluid across the endothelium all non fenestrated endothelial appears
to be directly related to the difference between the hydrostatic and osmotic forces.
Lymphatic Uptake:
*Following extravasation drug molecules can either reabsorb into the blood stream directly or
enter into the lymphatic system and return with the lymph to the blood circulation.
Also drugs administered by subcutaneous intracellular transdermal peritoneal routes can reach
the systemic circulation by lymphatic system.

14. Factors know to influence the clearance of drugs from interstitial sites:
 Route of administration,
 Size and surface characteristics of particles,
 Formulation medium,
 The composition,
 pH of the interstitial fluid,
 Disease within the interstitium.
The direct delivery of drugs into lymphatics has been proposed as a potential
approach to kill malignant lymphoid cells located in lymph nodes.

16.  Tumour targeting drug delivery:
A Specific interaction between drug and its receptor at the molecular level. A rapidly
growing tumour requires various nutrients and vitamins. Therefore, tumour cells over
express many tumour- specific receptors which can be used as targets to deliver cytotoxic
agents into tumours.
Targeted drug delivery system is achieved with the advantage of morphology and
physiological differences between the normal cells and tumour cells.
An ideal anticancer drug delivery system should full fill the following requirements:
Effectively kill tumour 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 tumour is based on:
1) EPR effect(Enhanced Permeability and Retention).
2) Nanoparticle properties and design.
3) Ligand-receptor interactions

17. Strategies for Tumour 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 I/IV of Biopharmaceutical
Classification Systems (BCS), there by 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,
*Involvement of carrier based approaches

18. There are three main strategies for tumor targeting.
A. Passive targeting
B. Active targeting
C. Triggered drug delivery
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 tumours
based on their anatomical and pathophysiological differences from normal tissues.
*Macromolecular drugs could accumulate and retain in solid tumour tissues selectively but they
will not distribute much in normal tissue.

19. EPR based chemotherapy is thus becoming an important strategy
Examples:
Macromolecular conjugates:
1. Polymer-drug conjugate
2. Protein- drug conjugate
3. Antibody-drug conjugate
Particulate systems:
1. Liposomes
2. PEGylated liposomes
3. Polymeric micelles
B) 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.

20. *Active drug targeting is generally implemented to improve target cell
recognition and target cell uptake, and not to improve overall tumour
accumulation.
*Ligand mediated targeting is the major approach that involves ligands
developed against cell receptors or antigenic determinants expressed on
tumour cells or vasculature.
Examples of active
targeting:
1. Folate.
2. Transferrin.
3. Lectins.
4.Galatosamine.

21. c) Triggered drug delivery:
*The tumour microenvironment differs from that normal cells
microenvironment.
*Advantage of the difference in pH, temperature is used to release the
in the tumour microenvironment.
*It employs drug-carrier constructs that release drug only when exposed
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.

23. MARKETED FORMULATIONS FOR TUMOURS:
Brand name API Role
Lipodox Doxorubicin Breast cancer receptor
targeted drugs delivery
Myocet Doxorubicin Breast cancer
Caelyx Doxorubicin Liposomal nanoparticles

24. Brain Specific Drug Delivery:
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.
*The blood-brain barrier acts very effectively to protect the brain from many
common bacterial infections

25. *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 is composed of high density cells, restricting
passage of substances from the bloodstream other than endothelial cells in
capillary.
DISEASES RELATED TO BRAIN:
Diseases related to Blood Brain Barrier:
*Meningitis.
*Brain abscess.
*Epilepsy.
*Multiple sclerosis.
*Neuromyelitis optica.
*Late-stage neurological trypanosomiasis (sleeping sickness).
*Progressive multifocal leukoencephalopathy (PMIL).
*Alzheimer's Disease.
*Cerebral oedema, etc

26. FACTORS AFFECTING DRUG DELIYERY 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 cells 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(p-gp) are found at luminal membrane of BMEC
2.Cerebrospinal fluids:
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..
*Cerebral blood flow.*Systemic Absorption.
*Decreases the clearance rate of drug.

27. STRATEGIES FOR DRUG DELIVERY TO BRAIN:
1. INVASIVE TECHNIQUES:
a) Intra-cerebroventricular (1CV) 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.

28. 3. MISCELLANEOUS TECHNIQUES.
a) Intranasal delivery.
b) lontophoretic delivery.
1.INVASIVE TECHNIQUES:
Drugs can be delivered to the brain by first drilling the hole in the head, and then implant is
placed by intra-cerebral or infusion is given by intra-cerebro-ventricular.
a) Intra-cerebro-ventricular infusion:
*Injection of intra-cerebro-ventricular infusion of drugs directly into the CSE.
*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 is a therapeutic strategy that was developed to facilitate targeted delivery of
pharmaceuticals to the brain.

29. *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.
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

30. 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.

31. 2. 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.
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.

32. Prodrugs:
Prodrugs are pharmacologically 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.

33. 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

34. 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.
Liposomes:
*Liposomes or lipid 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.

35. *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.(Diameter-20nm to100mm)

36. Receptor mediated

37. 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 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.
3.MISCELLANIOUS TECHNIQUES
a) Intranasal delivery:
*In nasal drug delivery system drugs are delivered 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.

38. *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:
The intracellular transport mediated
route is a relatively slow process, taking
hours for intra nasally administered
substances to reach the olfactory bulb.
b. Extracellular transport mediated
route:
Extracellular transport mediated routes
is rapid.

39. b) Iontophoretic delivery:
*lontophoretic 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.
*lontophoresis 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.

41. Brand name API Role
Ambisome Amphotericin B Liposome for injection
Aurimmune Colloidal gold IV
nanoparticles
Solid tumors
Aricept Donepezil Alzheimer’s disease
Marketed formulations of brain targeted drugs:

42. References:
*CNS drug delivery systems: novel approaches. Shadab A.Pathan , Zeenat
.Recent patents on drug delivery& formulation 2009, Pg.No:71-89.
*Novel approaches for controlled drug delivery systems by N.K.jain Pg.No:23-
*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.
*To exploit the tumor microenvironment: Passive and active tumor targeting of
nanocarriers for anti-cancer drug delivery- Author Fabienne Danhiera,Olivier
Feronb, Véronique Préata, Journal of controlled release volume 148, issue 2, 1
December 2010, page:135-146.
*PEGylation and its alternatives Srinivas Abbina, Anilkumar Parambath, in
Engineering of Biomaterials for Drug Delivery Systems, 2018.
review of intranasal formulations for the treatment of seizure
emergenciesMamta Kapoor , James , Cloyd , Ronald A. Siegel journal of
controlled disease -2016.

43. *“Multifunctional Self-stratified Polyurethane-polyurea Nanosystems for
Smart Drug Delivery - Scientific Figure on ResearchGate.[accessed 14 May,
2022].
*Lu, Cui-Tao, et al. “Current approaches to enhance CNS delivery of drugs
across the brain barriers.” International Journal of Nanomedicine, vol. 9,
annual 2014,

44. Thank
you