Fundaments Of Targeted drug delivery

1. Prepared By : Mayur Pandya
14mph114
3rd Sem
Guided by : Dr. Tejal Mehta
HOD
Pharmaceutics

2.  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.
 Targeted drug delivery implies for selective and effective
localization of pharmacologically active moiety at pre
identified (preselected) target in therapeutic concentration,
while restricting its access to non-target normal cellular
linings, thus minimizing toxic effects and maximizing
therapeutic index.

3.  Drug administration protocols may be simplified
 Drug quantity may be greatly reduced as well as the cost of
therapy
 Drug concentration in the required sites can be sharply
increased without negative effects on non-target
compartments.

4.  Rapid clearance of targeted systems.
 Immune reactions against intravenous administered carrier
systems.
 Problems of Insufficient localization of targeted systems into
tumour cells.
 Diffusion and redistribution of released drugs.
 Target tissue heterogeneity.
 Down Regulation and Sloughing Of Surface Epitodes.

5.  Targeted drug delivery system should be- biochemically inert
(non-toxic), non-immunogenic.
 Both physically and chemically stable in vivo and in vitro.
 Restrict drug distribution to target cells or tissues or organs and
should have uniform capillary distribution.
 Controllable and predictable rate of drug release.

6.  Drug release should not affect the drug action
 Therapeutic amount of drug release Minimal drug leakage
during transit.
 Carriers used must be bio-degradable or readily eliminated
from the body without any problem.
 The preparation of the delivery system should be easy or
reasonably simple,reproductive and cost effective.

7.  Most important entity required for successful transportation of
the loaded drug.
 Drug vectors which, retain and transport drug; deliver it within
or in the vicinity of target.
 Do so through an inherent characteristic or acquired through
structural modification.

8.  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 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

9.  After recognition and internalization, the carrier system
should release the drug moiety inside the target organs,
tissues or cells.

10.  Based on the nature of their origin
 Endogenous - LDL , HDL Chylomicrons, Serum albumin,
Erythrocytes.
 Exogenous - Microparticulates, Soluble polymeric and
Biodegradable polymeric drug carriers.

11.  Polymers
 Microcapsules
 Microparticles
 Lipoproteins
 Liposomes
 Micelles

12.  Antibodies
 Lectins and other proteins
 Lipoproteins
 Hormones
 Charged molecules
 Polysaccharides
 Low-molecular-weight ligands

13.  Colloidal carriers
 Cellular carriers
 Supramolecular delivery systems
 Polymer based systems
 Macromolecular carriers

14.  Vesicular systems- Liposomes, Niosomes,
Pharmacosomes, Virosomes, Immunoliposomes
 Microparticulate systems- Microparticles,
Nanoparticles, Magnetic microspheres, Albumin
microspheres, Nanocapsules.

15.  Erythrocytes, Serum albumin, Antibodies, Platelets,
Leucocytes.

16.  Micelles ( Reverse, mixed, polymeric) liquid crystals,
lipoproteins (chylomicrons, VLDL,LDL )

17.  Signal sensitive, Muco-adhesive, Biodegradable,
Bioerodible, Soluble synthetic polymeric carriers.

18.  Proteins, glycoproteins, Neo glycoproteins and artificial
viral envelopes (AVE).
 Glycosylated water soluble polymers (poly-L-lysine).
 Mabs, Immunological fragments, antibody enzyme
complex and bispecific Abs.
 Toxins, immunotoxin .
 Lectins and polysaccharides.

19. 1. Passive targeting
2. Inverse targeting
3. Active targeting
(a) Ligand mediated targeting
(b) Physical targeting

20. 4. Dual targeting
5. Double targeting
6. Combination targeting

21.  Systems that target the systemic circulation.
 Devices include- drug bearing bilayer vesicular systems
as well as cellular carriers of micron or submicron size
range.

22.  Based on attempts to circumvent and avoid passive
uptake of colloidal carriers by RES, leading to reversion
of bio distribution trend of the carrier.

23.  The function of RES is suppressed by a pre-injection of
colloidal carriers or macromolecules like dextran sulphate
leading to RES blockade and resulting in impairment of host
defense system.
 Alternative strategies include: modification of the size,
surface charge,composition, surface rigidity & hydrophilicity
of carriers for desirable biofate.

24.  The facilitation of the binding of the drug carrier to
target cells by the use of ligands to increase receptor
mediated localization of the drug and target specific
delivery of drug is referred to as active targeting.

25.  First order targeting(organ compartmentalization).
 Second order targeting (cellular targeting).
 Third order targeting (intracellular targeting).

26.  Restricted distribution of the drug carrier system to
the capillary bed of the predetermined target site,
organ or tissue.
 Compartmental targeting in lymphatics, peritoneal
cavity, plural cavity, cerebral ventricles, lungs, joints,
eyes, etc.

27.  The selective delivery of drugs to a specific cell type
such as tumour cells (and not to the normal cells) is
referred to as second order targeting.

28.  Drug delivery specifically to the intracellular site of
target cells.
 e.g., 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.

29.  Achieved using specific mechanisms such as receptor
dependent uptake of natural LDL particles and
synthetic lipid microemulsions of partially reconstituted
LDL particles coated with the apoproteins.

30.  The drug delivery programmed and monitored at the
external level (ex vivo) with the help of physical means.
 Temperature sensitive liposomes.

31.  Drug targeting using carrier molecules, having 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.

32.  The virus replication process can be attacked at
multiple points, excluding the possibilities of resistant
viral strain development.

33.  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.

34.  Combination Targeting for 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.

35. 1. Physical or Mechanical Approach.
2. Biological Approach.
3. Chemical Approach.

36.  Involves formulation of drug using particulate delivery
device  physical localization  differential release
of drug.
 Site specificity is due to higher drug concentrations at
the site.
 E.g. microspheres, nanoparticles or liposomes.

37.  IV administered liposomes—localize within MPS.
 MPS consists of connective tissues of mesenchymal
origin.
 Functions of MPS
› Clearance of large variety of harmful substances from
plasma.
› Catabolism of macromolecules.
› Participation in immune response.
› Synthesis and secretion of various effector molecules.

38. EXAMPLES:
 Targeting of azidothymidine (AZT) to macrophages as
nanoparticle carriers by iv & oral routes.
 Liposomal delivery of certain compounds may provide
extended retention.
 Liposomal delivery of drugs systemically enhances drug
concentration of antimicrobials.

39. Targeting to the Pulmonary Region
• Liposomes 50 nm in size—retained for many hrs.
• iv administered microspheres of certain drugs tend to
localize in lungs—diagnostic purposes.
Extravascular Delivery
• Solid lipid nanoparticles on iv administration accumulate
in the brain.
• E.g.: anticancer drug camptothecin loaded in
nanoparticles  increase avg residence time.

40.  Mucosal surface—main site for pathogenic entry.
 Production of IgA provide immunity for mucosal
surface against many pathogens.
 Microspheres protect vaccine from acid pH of stomach.
 Cause induction of IgA Ab in gut mucosa as well as
other mucosal surfaces like respiratory &
genitourinary tracts.
 E.g. microspheres of Staphylococcal enterotoxin B
toxoid

41.  Involves delivery of the drug using carrier system with
targeting moiety either in-built (by virtue of the structure of
the carrier) or is chemically coupled.

42.  4 approaches
1. Antibodies directed against specific cell surface
antigens,
2. Endogenous carbohydrate-binding proteins
(lectins),
3. Glycoconjugates functioning as specific ligands
for receptors on specific cells that recognize
particular sugar residues, and
4. Hormones functioning as specific ligands for
receptors on specific targets.

43.  Higher immune response—when antigens are directed to
antigen presenting cells (APCs) & lymphocytes.
 Done by coupling antigen with a ligand of strong binding
affinity for molecules of MHC.
 E.g. coupling of viral antigens to monoclonal antibodies
against a mouse Class II MHC.
 Advantage
› Preparation of safer vaccines.
› Targeting without use of carriers.
› Targeted antigen required only in 1st injection.
› Upto 1,000 fold increase in efficiency achieved.

44.  Endogenous carbohydrate-binding proteins of tumours
are known as lectins.
 Glycoproteins or neoglycoproteins act as carriers 
drug incorporated in glycoproteins  carbohydrate on
glycoprotein cause its uptake by lectin  drug
released intracellularly during proteolysis of carrier.

45.  EXAMPLE
 Targeting of naproxen using lysozyme as carrier since it is
taken up & catabolized in proximal tubules of kidney—Showed
70 fold increase in retention in kidneys compared to free
naproxen.
 Captopril conjugated with lysozymes—6 times more retention
in kidneys observed.
 Polysaccharides such as dextran also show high potential as
oral drug carriers.

46.  Insulin used as enzyme carrier for correcting enzyme
deficiency disease in fibroblasts from patients with
cholesterol storage disease.

47.  Incorporates targeting consideration into the drug
design process—for design of safe, localized delivery.
 Targeting to active biological molecules based on
predictable enzymatic activation.
 Allow sustained release of drugs also.

48. Drug Targeting to Lungs
• E.g. ester derivatives of chlorambucil and cromolyn  hydrolyze in
lungs rapidly into active parent drugs  enhance delivery and retention
time to lung tissue.
Drug Targeting to Brain
• Blood-brain barrier (BBB)  obstruct free flow of blood b/w brain
and rest of the body.
• BBB is impermeable to hydrophilic substances  prevent loss of
neurotransmitters to the plasma after synthesis in brain  hence
chemical methods are used.

49.  E.g. bisphosphonic (BP) prodrug for 17 β-estradiol
(E2)  estrogen replacement therapy in patients of
post menopausal oesteoporosis.
 In rats showed rapid uptake and enhanced halflife of
estradiol as compared to free estradiol.

50.  In the Future, targeted drug delivery systems may also prove
particularly valuable to enable the use of a drug seems to be
ineffective or toxic, if delivered systemically
E.g. Neural growth factor which need to cross BBB or Vaccines
which need to taken up by antigen presenting cells
 At the Current pace of Gene Cloning and Recombinant-Protein
Production within biopharmaceutical industry, many more site
specific drug delivery products will be clinically investigated and
implemented in near future.

51.  Targeted and Controlled drug delivery (Novel carrier
systems), S P Vyas and R K Khar, CBS publishers, page
no: 38-61.
 Progress in Controlled and Novel drug delivery
systems by N K Jain, CBS publishers, page no: 362-
366.
 Drug Targeting Organ-Specific Strategies Edited by
Grietje Molema and Dirk K. F. Meijer, page no:1-16.