Targeted Drug

Delivery
An Insight into the Recent Trends
in Drug Delivery Systems
Targeting
 Objective

 Provide therapeutic
concentrations of drugs
at the site of action

 Reduce systemic
toxicity

 Increase patient
compliance
Types of Targeting

 Active & Passive

 Organ, Cellular & Sub-

cellular

 Site directed & Site

avoidance targeting
Other Types of Targeting

 Biochemical
 Carrier Dependent
 Biomechanical

 Biophysical  Carrier Independent

 Bioadhesive
Approaches to Targeting

 Retrometabolic Systems:
 Individual drug molecules chemically modified to
target particularly to the disease site.
 Carrier – Based Systems:
 Drug is first packaged non-covalently into a synthetic
Carrier that is then targeted to the disease site.
Carrier Types

 Microspheres

 Monoclonal
Antibodies

 Nanoparticles

 Liposomes
 Specifically
Bind binding to
chromosomal tumor cell
DNA in target
tumor cell

Two-Step
Targeting
Reverse Targeting
Prodrugs
Targeting specific organs
 Prodrugs

 Compounds that undergo biotransformation

prior to exhibiting pharmacological effect
 Need for prodrugs

 Organic drugs elicit response by interacting

with receptors at the site of action.
 Barriers for the drug
Overcoming Barriers
Chemically linking pro-moiety to form prodrug
↓
Biotransformation
↓
Release of parent drug
↓
Barrier is circumvented
Classification
Based on organ or Based on administration
system route

 Brain  Nasal
 Liver  Ocular
 Kidney  Parenteral
 Lymphatics  Transdermal
 Buccal
 Targeting
the Brain

Delivery of drugs
to brain is limited
by BBB
Eg. L-dopa
Targeting the Liver
Site selective transport
pathways
 Bile acid transport
system
eg: chlorambucil
 Hepatic receptor
mediated endocytosis
eg: acyclovir
Targeting the Kidney
 Selective accumulation
of dopamine in kidney
 IP administration of
prodrug
 Prodrug→ Drug
 by catalytic action of
enzymes that posses
high activity in the
kidney
eg: sulphamethaxazole
Lymphatic Targeting
 Oral drug enters systemic circulation through portal
blood or intestinal lymphatics
 Properties of drug and formulation
 Portal blood → first pass metabolism
 Intestinal lymphatics → only for highly lipophillic
compounds

So, prodrugs used for

 drugs that undergo extensive first pass
metabolism
 for local lymphatic delivery
Disease State
Cancer
 In diseased state elevated level of specific
enzyme can be associated with cancer cells
than normal cells
 Selective activation of prodrugs through
metabolism at desired site of action
eg: Breast cancer
 Magnetic Drug
Targeting
The Biophysical Targeting
Technique
Magnetic Drug Targeting
 using magnetic nanoparticles (ferrofluids)

 enhancingefficacy
 minimum side effects

 ferromagneticelement (e.g. an implant) is

placed in a magnetic field, it becomes
magnetically energized
 Magnetic implants – Transdermal Injection
 Optimization of intratumoral magnetic particle
concentration
Factors:
 particle size

 magnetic field strength

 delivery capability of FF complex

 method of injection
 Studies conducted - squamous cell
carcinoma
 Experimental animal used – Rabbits

 Treated with FFs bound to mitoxantrone (FF-

MTX)
 FF – MTX injected – i.a, i.v

 Result: No signs of toxicity

Advantages
 Magnetic drug targeting is used to treat
malignant tumors loco-regionally without
systemic toxicity.

 Magnetic particles used as “carrier system”

for a variety of anticancer agents, e.g.
radionuclides, cancer – specific antibodies,
and genes
 LIPOSOMES
Successful carrier systems in drug targeting
 A brief introduction…
•What are Liposomes?
•Why do we need Liposomes?
Why Liposomes?

•Solubilization
•Protection
•Duration of action
•Directing potential
•Internalization
•Amplification
 TYPES
1. CONVENTIONAL
2. STEALTH LIPOSOMES
DRUG INCORPORATION
 Encapsulation

 Partitioning

 Reverse loading
OBSTACLES

 Non-specific clearance

 Cross endothelium and basement membrane

 Low endocytic capacity

Antibody- Directed
Drugs
Emerging Cancer Therapeutics
 Cancer treatment- Double-edged sword

 Earlier- surgery, radiation and chemotherapy

 Approaches- target proteins or deliver drugs

 Use of ANTIBODIES as ‘magic bullets’

Antibodies & Antigens

 Antibodies are proteins

used by the immune
system against foreign
molecules called
antigens
Antibody- Antigen Interaction
 Antibody- Antigen
binding forms the basis
for such methods

 Binding is based on
affinity between them

 Specificity
Types of antibodies
 Polyclonal antibodies

 Monoclonal antibodies

 Naked or Un-conjugated

 Conjugated
 Monoclonal Antibody
Technology

 Hybridoma technology

 Murine monoclonals
 Chimeric - ‘humanized’
murine monoclonals

 Phage - display library

technology
Un-conjugated Antibodies
 Mechanisms of action

 Antibody-dependent cellular cytotoxicity (ADCC)

 Complement-mediated cytotoxicity (CMC)
 Apoptosis or Programmed cell-death
 Prevent formation of new blood vessels
 Block cytotoxicity - inhibiting antigens
 Prevent cell adhesion and metastasis
 Conjugated Monoclonal
Antibodies
 Conjugation with

 Drugs
 Toxins
 Enzymes
 Radio-isotopes
 Proteins
 Killer Cells
 Liposomes
 Various functions of
therapeutic monoclonals
Antibody- Drug Conjugates
 Cytotoxic drugs
e.g antifolates,vinca alkaloids,anthracyclines
 not tumour - specific
 go to rapidly proliferating cells
 increased toxicity against normal cells
 given in sub - optimal doses

SOLUTION : Antibody- drug conjugates

 Action of drug
immunoconjugates
 Monoclonal antibodies
as delivery vehicles
 Conjugate is inactive
 Selectivity towards cells
with respective
antigens
 Internalized by cell via
receptor-mediated
endocytosis
 Parent (active) drug is
released into the cell
 Improving drug
immunoconjugates
 Use of ‘ linkers’

 Increased drug loading

 Highly cytotoxic drugs

 Chemical conjugation
Toxins
• From bacterial origin
e.g. Pseudomonas exotoxin, Staphylococcal
enterotoxin A, Ricin toxin A
• Enzymes
• Highly cytotoxtic agents
• Single molecule sufficient
• Need modifications
• Remove normal cells binding sites
• Avoid rapid clearance
Immunotoxins
 For solid and
hematological tumours
e.g. cutaneous T-cell
lymphoma
 Toxin immunogenicity,
vascular leak syndrome
and hepatocyte injury
 Improvements via
 PEG - ylation
 Humanized toxins -
RNase
Antibody-directed enzyme
prodrug therapy (ADEPT)
 Two step approach

 Antibody- enzyme
conjugate attached to cell
 Weakly toxic prodrug
converted to active agent by
the enzyme

 Three classes of enzymes-

I, II and III
Proteins- Cytokines
Cytokines are
 immunoregulatory molecules
 activate immune responses by increasing tumour
immunogenicity
 act locally or to some distance
 effect: damage tumour vasculature

e.g. Interleukine-2 (IL-2)

Tumour necrosis factor- α (TNF- α )
Antibody- Cytokine fusion
proteins
 Earlier- direct injection into tumour
 But neither localized nor
accessible

 Need to fuse them with tumour-

specific Abs

 Does not impair binding and

response
 Stimulates innate and adaptive
immunity (B cells and nature
killer cells),
 Increases antigen
immunogenicity

 Combinations used to prevent side

effects
Radio- Immunoconjugates
 Radio-isotopes coupled to antibodies
 Uptake- less than 0.01% per g of tumour

 Continuously present

 Choice of radionuclide
 α emitters - Bismuth
 β emitters
 Medium energy - Iodine
 High energy - Yttrium
 Challenges with use of radio-
immunoconjugates
 Problem:
 Radiation exposure to bone marrow due to
residence in blood stream
 Radio-resistance of solid tumours
 Solution:
 Engineered antibody fragments
 Multi-step pre-targeting using bi-specific
antibodies or diabodies
 Un-labeled diabody sent in
 Hapten (small drug) enclosed in labeled peptide
Bi-specific antibody therapy
Evolving New Approaches

 Induce tumour cell death- apoptosis

 Block protein expression at RNA level- siRNA

 Target co-stimulatory molecules

 Enrich immunomodulatory molecules

Conclusions
 Immunogenicity, selectivity and penetration

 Fully human antibodies

 Characterization of antigens and their antibodies

 Solid tumour targets

 Target tumour vasculature

 ISSUES IN DRUG TARGETING

 Protein folding and amino acid sequencing

 Loss of antigen from target cell

 Immunological response to targeting agent

 Oral administration not feasible

 Less number of available target cells

 CHALLENGES …
 Avoiding liver uptake

 Tumour cells create physical barrier

 Pharmacokinetic parameters of the drug

preparations

 Validation of targeting concept

CONCLUSION
Drug targeting should be incorporated in the earliest stages of drug
development… it is rational, selective and wave of the future.

One can continue to expect for the future, a series of new drugs
 that are conveniently delivered

 that is given by mouth

 that have very modest side effect profiles

 that control the disease by novel mechanisms, and

 that will, for the first time, control a series of diseases that were
once thought as incurable...
 Our Team
 Divya. M
 Geetha. D

 Kavita Sree. S

 Ramya Gopal

 Saranya. J

 Shanmuga Priya. R