Introduction:-

• Novel drug delivery systems are designed

for targeting the biologically active

molecules to its site of action.

• They also control the delivery of drug over

an extended period of time.

• Vascular targeting of drugs provide more

concentration of drug to the target site.

What is vascular targeting?

• The targeting of the drug to a specific target site

through the endothelium of blood vessels is

called as vascular targeting.

• The drug reaches the target site through blood.

• The drug is introduced into blood stream by

using various catheters.

Barriers for drug targeting:-

Current Nanoscience, 2005, Vol. 1, No. 1

Approaches to drug targeting:-

PASSIVE TARGETING

1.Pathophysiological factors:

.Inflammation

.EPR effect

ACTIVE TARGETING

1.Biochemical targets:

.organs .cellular

.organelles .intracellular

2.Physicochemical factors:

.Size

.Molecular weight

2.External stimuli:

.ultra sound

.magnetic field

3.Anatomical opportunities:

.Catherization

.Direct injection

3.Sandwich targeting

4.Chemical approaches:

.Prodrugs

.Chemical delivery

systems

4.Transcriptional targeting

Reference:Nanosystems in Drug Targeting: Opportunities and Challenges

• 1.Receptors:

Folic acid

LDL

Peptide

• 2.Lipid components of cell

membranes

• 3.Surface antigens or proteins

Reference:Nanosystems in Drug Targeting: Opportunities and Challenges

Targeting Ligands for vascular

endothelium:-

• Folic acid

• Sugars

• Lectins

• Modified Albumins

• Peptides

• Antibodies

Reference:Nanosystems in Drug Targeting: Opportunities and Challenges

Advantages of Vascular

targeting:1.Increased regional drug concentration.

2.Decreased systemic toxicity.

3.Enhanced activity of some drugs.

Reference:Advances in controlled & novel drug delivery system by N.K.Jain,

page no.167

Applications of Vascular targeting:

1.Regional therapy via capillary filtration.

2.Acts as a circulating depot of drug.

3.Diagnostic imaging.

4.Prevention of Restenosis.

Reference:Advances in controlled & novel drug delivery system by N.K.Jain,

Page no.168

Criteria that define a good target:

• 1.It must be expressed on endothelial cells.

• 2.Surface density of the target must be sufficient

to promote the binding of drugs.

• 3.Binding site must be accessible to blood.

• 4.Consequences of DDS binding to a target

determinant must meet therapeutic goals.

Advanced Drug Delivery Systems That Target The Vascular Endothelium

Affinity Moiety Selection:

• Affinity ligands for endothelial cell targeting

are

1)Natural ligands-

Transferrin and

Vascular endothelial growth factor

2)Immunoglobulin G

>These are well suited for conjugation with

drugs and drug carriers.

Advanced Drug Delivery Systems That Target The Vascular Endothelium

Drug delivery vehicles for vascular

targeting:-

• Polymeric Nanoparticles

• Liposomes

• Micelles

• Microcapsules

• Microspheres

• Microemulsions

Davies, P.F. Mechanisms involved in endothelial responses to hemody-namic forces.

Liposome Ingredients

45% DPPC dipalmitoylphosphatidylcholine

45% Cholesterol

5% DPPG dipalmitoylphosphatidylglycerol

5% DPPE dipalmitolyphosphatidylanolamine

Liposome Preparation

http://www.avantilipids.com

Liposome Preparation

http://www.avantilipids.com

• Niosomes are non-ionic surfactant vesicles. The

success achieved with Liposomal systems

stimulated the search for other vesicles forming

amphiphiles.

• Non-ionic surfactants were among the first

alternative materials studied. A large number of

surfactants have been found to self assemble into

bilayer vehicles which can be used as drug delivery.

Liposome Preparation

http://www.avantilipids.com

Lipid Hydration method

Most widly used method for the preparation

of MLV

Involves: drying a solution of lipids – thin film

at the bottom of rbf

Hydrating the film by adding aqueous buffer

and vortexing the dispersion for some

time.

Hydration above the Tc of lipids.

Lipid Hydration method

The compond to be encapsulated is either

added in the lipid solution or aqueous

buffer.

Disad.:low internal vol

low encalsulation efficiency

heterogeneous size distribution

Hydration

MLV with high encapsulation – prepared by

hydrating the lipids in presence of an

immiscible organic solvent (petroleum

ether).

Content emulsified by sonication or vortexing.

Organic liquid is removed by passing stream

of nitrogen over mixture.

Disad.:exposure to organic solvent and

sonication

Solvent spherule method

Dispersing in aqueous solution the small

spherule of volatile hydrophobic solvent in

which lipid has been dissolved.

Then controlled evaporation of organic

solvent in a water bath

Small unilamellar liposomes

MLV are sonicated either with bath type or

probe sonicator under an inert

atmosphere.

Disadv.:low encapsulation, low internal vol.

degradation of phospolipids and

drug

Metal contamination from tip of probe and

Presence of MLV .

SUV by french pressure cell

methodInvolves the extrusion of MLV at 20,000 psi

at 40C through a small orifice.

Adv.:simple, rapid, reproducible

Disadv.:Temp. Difficult to achieve, working

vol. Is small(50 ml max.)

LUV( large unilamellar

liposomes)They have high encapsulation efficiency.

Solvent injection method:

- Ether infusion method

- Ethanol injection method

Ether infusion :A solution of lipid dissolved in

diethyl ether or ether/methanol mix. Is

slowly injected to an aqueous solution of

the drugat 55-65oC or under reduced

pressure.Subsiquent removal of

ether(vacuum)

Ether injection

Disadv.:size heterogenous(70-190 nm)

drug exposure to organic solvent

and temp.

Ethanol injection

Lipid solution of ethanol is rapidly injected to

a vast excess of buffer.

Disad:- size 30-110 nm

- liposomes are dilute

-removal of all ethanol difficult(azeotrope)

drug degradation in ethanol

LUV, detergent removal method

The detergents at their CMC are used to

solubilize lipids.As the detergent is

removed,the micelle becomes richer in

phospholipid and finely combined to form

LUV.

Detergent removed by dialysis.

Adv.- reproducible, uniform size.

Disadv: presence of trace detergent.

LUV, reserves phase

evaporationFirst w/o emulsion is formed by brief

sonication of two phases;phospholipid in

organic solvent (diethyl ether or isopropyle

ether or mix. Of isopropyl ether and

chloroform) and aqueous buffer.

The organic solvent is removed under

reduced pressure.

Disadv.-exposure to organic solvent

-sonication

LUV, Calcium-induced fusion

method Used to prepare luv from acidic

phospholipid.

When calcium is added to suv it induces

fusion of suv and results in formation of

multilamellar structure in spiral

configuration.

Addition of EDTA to this results in formation

of luv.

Adv:-gentle condition

Disad; only from acidic phospholipid

Luv, microfludization method

Liposome Preparation

http://www.avantilipids.com

Liposome Preparation

http://www.avantilipids.com

Liposome Preparation

http://www.avantilipids.com

Liposome encapsulation

• Reverse-phase evaporation method

Lipid in organic solvent solution

Add nanoparticles in buffer under

sonicationEvaporation

Extrusion

Liposomes and unencapsulated nanoparticles

Size exclusion

chromatographyPurified liposomes

Liposome Preparation

Lipid in organic solvent solution

Evaporation

Extrusion (or sonication)

Liposomes and unencapsulated SRB

Lipid film

Freeze/thaw cycles

Gel filtration

Purified liposomes

Hydrate with sulforhodamine B (SRB) solution