This document provides an overview of targeted drug delivery systems. It discusses how targeted delivery aims to increase drug concentration in specific tissues while reducing it in others, improving efficacy and safety. Key concepts covered include active targeting using ligands and receptors for cellular uptake, and passive targeting exploiting pathological leakiness. Examples of active targeting moieties like antibodies and transferrin are given. Challenges of the brain barrier and approaches like prodrugs and nanocarriers to cross it are summarized. Advantages of targeting include reduced toxicity and dosing, while disadvantages include immune reactions and high technology requirements.

1. Prepared by :- Arjun S.Dhawale
MPharm 2 SEM
Pharmaceutics,
Kamla Nehru
College of Pharmacy,
Butibori , Nagpur.

2. Content :-
• Introduction .
• Concepts .
• Biological process involved in drug targeting .
• Tumor targeting .
• Brain specific delivery .
• Advantages .
• Disadvantages .
• Reference .

3. Introduction :-
Targeted drug delivery system is a special form of delivery
where the medication is selectively targeted delivered only
to its site of action and not to the non targeted organ or
tissue or cell .
Increase the concentration in specific site of the body part .
Concentration the medication in the tissue of interest while
reducing the relative concentration of the medication in
remaining tissues .
Increase efficacy and reduce adverse effect .

4. Concept :-
The concept is to prolong , localize , target and have a
protected drug interaction with the diseased tissue .
The conventional drug delivery system is the absorpting of
the drug across a biological membrane , whereas the
targeted release system release the drug is a dosage form
to specific site .

5. Biological process involved in drug targeting :-
• Cellular uptake .
• Transport across epithelial barrier .
• Extravasating .
• Lymphatic uptake .
• Function of RES .

6. Cellular uptake :-
• After administraion of the drug , the drug frequently
passes through various cell membranes and reach its
target site .
• Low molecular weight drugs enter or pass through cells
by simple diffusion .
• TDDS comprising of macromolecules are unable to enter
the cells by simple processes .

7. • However , large particles are able to enter cell by active
transport process such as :-
1] Endocytosis - i ] Phagocytosis .
ii ] Pinocytosis .
2]Exocytosis .

8. 1] Endocytosis :-
• Endocytsis is a process in
which a cell absorbs
extracellular material by
engulfing it with their cell
membrane to form a
vesicle which is then
pinched off intracellularly .

9. i] Phagocytosis :-
Phagocytosis is a cellular
process for ingesting and
eliminating particles larger than
0.5 micrometer in diameter ,
including microorganism ,
foreign substances .

10. ii] Pinocytosis :-
Pinocytosis is a process by
which the cell takes in the
fluids along with dissolved
small molecules. In this
process, the cell membrane
folds and creates small
pockets and captures the
cellular fluid and dissolved
substances.

11. 2] Exocytosis :-
Exocytosis is the last step of
the secretory pathway and it
involves the fusion of
vesicles with the plasma
membrane a process that,
ensures the delivery of cell
wall-synthesizing enzymes,
membrane proteins, and
lipids in areas of active
growth.

12. Transport across epithelial barriers :-
In the epithelial cells that line the
intestine, for example, that
portion of the plasma membrane
facing the intestine, the apical
surface, is specialized for
absorption; the rest of the
plasma membrane, the lateral
and basal surfaces, often
referred to as the basolateral
surface, mediates transport of
nutrients , drugs .

13. Extravasating :-
For a drug to exert its therapeutic effects , it must move from the
central circulation and interact with its extra vascular - extracellular
or extra vascular - intracellular target this process of transvascular
exchange is called Extravasation .
Extravasation is governed by :-
1] Permeability through blood capillary walls .
2] Rate of blood .
3] Molecular shape , size and charge of drug .

14. Factors control permeability of capillaries :-
• Pathological condition and physiological factors of drug .
• Rate of blood and lymph supply .
• Structure of the cappilary wall .
• Structure of the blood capillary varies indifferent organs
tissues .
• Change shape , size , characteristics of macromolecules .

15. Lymphatic uptake :-
• After the process of extravasation ,the drug molecules
can either reabsorb into the blood stream directly by the
enlarged post capillary interendothelial cell pores found in
most tissues or enter into the lymphatic system and then
return with the lymph to the blood circulation .
• Drug administration through subcutaneous,intramuscular,
transdermal and peritoneal routes reach the systemic
circulation by lymphatic system .

16. Lymphatic circulation is a
path of minor importance
in drug absorption into
systemic circulation for
two reasons :-
1] The lymph vessels are
less accessible that the
capillaries .
2] The Lymph flow is
exceptionally slow .

17. Factors know to influence the clearance :-
• Formulation medium and its composition .
• Size and surface characteristics of particle .
• Routes of administration .
• pH of the intestinal fluid and disease within the interstitium
.

18. Function of RES :-
• Reticuloendothelial System comprised of a set of
mononuclear phagocytic cells which originate from
precursors in bone marrow , enter blood stream as
monocytes and pass into various tissues where they
differentiate into macrophages .
• Macrophages are essential part of defense function .
• RES is also involved in formation of new R.B.C & W.B.C
by destruction of older ones .
• Since macrophages are conc. at site of inflammation such
as tumors , drug targeting is thus achievable .

19. Tumor :-
A tumor is when this uncontrolled growth occurs in solid
tissue such as an organ, muscle, or bone.
There are two types of Tumor :-
1} Malignant [Cancerous] .
2} Benign [Non - Cancerous] .

20. Cancer Development :-

21. Types of Tumor targeting :-
• Active Targeting .
• Passive Targeting .

22. Active Targeting :-
• Active targeting means specific interactions between drug ,drug
carrier and the target cells,commonly through specific ligand-
receptor interactions .
• The ligand and receptor interactions are possible only when these
components are in adjacent proximity (<0.5 nm).
• Specific ligand-receptor interaction for intracellular localization
occurs after extravasations and blood circulation.
Eg:-
1] Folate .
2] Transferrin .
3] Lectins .

23. Classification of active targeting :-
1] First order targeting :-
Drug carrier system goes to predetermined target sited like
organ and tissue including compartments like lymphatics ,
eyes , joints .
2] Second order targeting :-
Selective targeting to the tumor cells , kupffer cells .
3] Third order targeting :-
Selective targeting intracellular sites , using ligand mediated
enter by endocytosis .

24. The main mechanism behind active targeting is to recognition of ligand by its
target substrate. Representative ligand includes antibodies, protein peptide,
nucleic acids sugars and small molecules such as vitamins. Receptor includes
epidermal growth factors; vascular epithelial growth factors and transferrin are
used in targeted drug delivery in cancer cells.
Active targeting moieties :-
Monoclonal antibodies recognize the protein or antigen on the surface of the
cancer cell and lock into it. Some most exploited targets for antibody targeting
are :-
1] Transferrin receptors :- High level of transferring receptor on Malignant
glioma cells.
2] Fibronectin :- Expressed in the around neoplastic blood vessels during
angiogenesis.
3] Epidermal growth factors receptor :- Over expressed in the portion of breast
cancers and other solid tumors.
4] Vascular endothelial growth factor :- Expressed in neoplastic blood vessels.

25. Passive Targeting :-
• Passive targeting refers to the accumulation of a drug-carrier
system or drug targeting at a precise site; it may be attributed to
chemical, physical, pharmacological, and biological aspects of the
disease.
• The nanoparticle size and surface properties of the drug targeted
system must be specially controlled to evade uptake by the
reticulo-endothelial system to maximize the targeting capability
and increase its circulation.
• Rapid vascularization assists fast-growing tumor tissue, imparting
itself to a defective or leaky architecture enhancing the
permeability of toxic chemotherapeutic drugs.

26. Drug Carriers

28. Eg:-
1]Carrier :- Nano particles
Drug :- Paclitaxel
Brand :- Nanoxel
Used :- Breast Cancer
2]Carrier :- Liposomes
Drug :- Vincristine
Brand :- Marqibo
Used :- Leukemia

29. Brain specific delivery :-
• Brain specific delivery is the process of passing
therapeutically active molecules across the Blood Brain
Barrier [BBB] to the Cerebrospinal fluid [CSF] .
• The Blood Brain Barrier [BBB] is a highly selective
permeability barrier that separates the circulation blood
from the brain extracellular fluid [BECF] in the central
nervous system [CNS] .

30. Factors affecting drug transport across the BBB :-
• Metabolism by other tissues .
• Pathological condition .
• Lipophilicity of drug .
• Cellular enzymatic stability .
• Systemic enzymatic stability .
• Cerebral blood flow .
• Concentration gradient of drug .

31. Approaches to CNS drug delivery :-
1] Invasive approaches .
i] Intra - cerebro ventricular [ICV] infusion .
ii] Convection - enhanced delivery [CED] .
iii] Disruption of BBB .
2] Non - invasive approach .
i] Chemical techniques .
a] Prodrug .

32. b] Drug conjugate .
ii] Colloidal Techniques .
a] Nano particles .
b] Liposomes .

33. 1] Invasive approaches :-
It involves placement of a biodegradable chemotherapeutic impregnated pellets
into tumor restriction area. Drug added to polymer and compressed to form
pellets. These are implanted intra-cranially through which drug bypass the BBB
and release drug molecule locally to the brain in the sustained fashion.
i] Intra-cerebroventricular (ICV) infusion :-
Intra cerebro ventricular infusion one strategy for bypassing BBB intra-
ventricular infusion of drug directly into the CSF. Drug solution can be
subcutaneously injected into the implanted reservoir and delivered to the
ventricles manual compression of the reservoir through the scalp.
ii] Convention enhanced delivery :-
It involves insertion of a small caliber catheter into the brain parenchyma.
Through this catheter, infusate is actively pumped into the brain parenchyma
and penetrates in the interstitial space.

34. iii] Disruption of BBB : -
Disruption makes tight junction between the endothelial cells of the brain
capillaries leaky. The BBB can be transiently disrupted by a variety of
techniques such as osmotic disruption technique.
2] Non-invasive techniques:-
This technique usually interrelated to drug manipulation which may include
alternation as prodrugs, lipophilic analogues, chemical drug delivery, carrier
mediated drug delivery, receptor mediated drug delivery .
i] Chemical techniques: -
It improves some deficient physiological property such as membrane
permeability. Chemical methods involve the chemical transformation of drugs by
changing the various functionalities.

35. a] Prodrug :-
Prodrug which is lipid soluble and can cross the BBB. Prodrug is
pharmacologically inactive compounds that results from transient chemical
modification of biologically active species. It is metabolized within the brain and
converted to the parent drug.
Examples :-
Levodopa, GABA, Niflumic acid, valproate.
b] Drug conjugates :-
It involves caging of compounds within glycosyl, maltosyl, diglucosyl and
dimaltosly derivatives of cyclodextrin. The therapeutic complexes comprise of
an omega 3-fatty acid such as alpha linolinic acid, eicosapentaeoic acid and
their derivatives.

36. ii] Colloidal Techniques :-
a] Nano particles: -
Nano particles are micronized solid colloidal particles prepared of polymeric
materials ranging in size from 1-1000 nm. It is used as carrier systems in which
the drug is dissolved, entrapped, encapsulated, adsorbed or chemically linked
to the surface. Systems in CNS targeted drug therapy supply better penetration
of therapeutic and diagnostic agents, and a reduced risk in comparison to
conventional treatments. Nano particles are used to deliver drugs through oral,
nasal, parenteral, intra - ocular .
b] Liposome: -
Liposomes are colloidal, vesicular structures composed of one or more lipid
bilayer surrounding an equal number of aqueous compartments. A free drug
injected in blood stream typically achieves therapeutic level for short duration
due to metabolism and excretion. Drug encapsulated liposome achieves
therapeutic level for long duration. Liposomes are biodegradable and
essentially non toxic vesicles can encapsulate both hydrophilic and hydrophobic
materials and are utilized as drug carrier in drug delivery system.

37. Advantages :-
• Drug administration protocols may be simplified .
• Toxicity is reduced by delivering a drug to its target site , there by
reducing harmful effects .
• Drug can be administration in a smaller dose to produce the
desire effects .
• Avoidance of hepatic first pass metabolism .
• Enhanced the absorption of target molecules such as peptides .
• Selective targeting to infections cells that compare to normal cells
.

38. Disadvantages :-
• Rapid clearance of targeted system .
• Immune reactions against intervenous administration
carrier system .
• Insufficient localization of targeted system into tumors .
• Diffusion and redistribution of released drugs .
• Requires highly sophisticated technology for the
formulation .
• Requires skill for manufacturing , storage , administration
.
• Difficulty to maintain stability of dosage form .

39. Reference :-
• Scholarly articles .
Research Gate .
American Journal of pharmtech research .
• Smart Drug Delivery System by Ali Sezer .

40. Thank you