Drug targeting and nanotechnology 1 Flashcards
What are the two types of controlled drug delivery?
Controlled release and Site-specific drug delivery
Why is site-specific delivery systems desirable?
some drugs never reach the target site
- Because of short half life
> rapid elimination
> inactivation by metabolic action or degradation
- Undesirable distribution of drug, too little at the target, too much at the non-target organs
- Poor transport of drug across biological membrane
> poses a problem if the target is intracellular
> caused by physical-chemical properties of drug such as size, hydrophilicity etc
Presence of drug at non-target sites may cause unacceptable side effects
- Low therapeutic index
What are EIGHT requirements for an ideal drug targeting system?
- Control drug release to achieve the desired therapeutic effects.
- Prevent degradation or inactivation of drug during transit to the target sites.
- Maintain the drug-carrier integrity until the target is reached.
- Target recognition and association.
- Enhance therapeutic index of drug.
- Biocompatible
- Biodegradable
- Simple, reproducible and cost effective
What are the 1st,2nd and 3rd order targetting of site-specific delivery systems?
- 1st Order Targeting (vascular compartment) – delivery to a discrete organ or tissue
- 2nd Order Targeting (cellular) –targeting to a specific cell type(s) within a tissue or organ (eg tumour cells versus normal cells)
- 3rd Order Targeting (intracellular) – this implies delivery to a specific intracellular compartment in the target cells (eg lysosomes )
What is the difference between active and passive targeting for site-specific delivery systems?
Passive: use the natural disposition (set-up) of the carrier in the body
Active: uses some type of “homing” device or principle to change the natural disposition pattern of the carrier to selectively target a particular tissue or cell type
What does the success of drug delivery depend on for site-specific drug delivery systems? Provide THREE different reasons.
- access to the target site
- retention at the target site
- timing of drug release at the target site
The therapeutic efficacy of targeted drug delivery systems depends on the timely availability of the drug in active form at the target site and its intrinsic pharmacological activity
What are THREE factors influencing drug targeting?
- Drug properties - less important if drug is carried by a delivery system
- Properties of delivery system: eg size, charge, surface ligands
- in vivo condition/environment: pH, blood flow; enzyme; vasculature; temperature
What are THREE key biological processes for drug delivery?
- Vascular release (extravasation)
- Cellular uptake
- Lymphatic uptake
What is Vascular release (extravasation)? Describe the process.
Drug or drug delivery system –> blood circulation —> extravasation –> target site (extravascular)
- Most drug/carrier systems need to leave the blood vessels and act on or in cells of target area
- The way drug/carrier leaves vessel depends on:
> permeability of vessel wall
> drug/carrier compound itself
Blood vessel structure varies in different body areas
What are the THREE types of capillaries (blood vessels) which impacts extravasation?
Continuous
- tight interendothelial junctions
- uninterrupted basal lamina
Fenestrated
- 20-80nm gaps in endothelium
- gaps have a thin membrane
Sinusoidal
- ≤150nm interendothelial gaps
- basal membrane discontinuous or absent
fenestrated and sinusoidal present in liver, spleen and bone marrow
For extravasation;
A) What is it governed by?
B) What is extravasation of drug molecules affected by?
C) What is extravasation of drug molecules in drug delivery systems are influenced?
A)
- Extravasation is governed by permeability of blood capillary walls
B)
- Extravasation of drug molecules is also affected by the physicochemical properties of drug such as molecular size, shape, charge & lipophilicity.
C)
- Extravasation of drug molecules in drug delivery systems are influenced by the physicochemical properties of drug delivery systems, not drug molecules.
- Different types of delivery system, their extravasation pathway can be different.
What are the two ways substance pass out of blood vessels (extravasation)
Passively
- Via gaps
- Non-specific phagocytosis
dependent on: molecular size and blood vessel structure
Actively
- receptor-mediated transport
Compare extravasation of soluble macromolecules vs colloidal particles. Include MW in answer.
Macromolecules (soluble)
- (1) by non-specific fluid phase pinocytosis
- (2) passage through inter-endothelia junctions and gaps in the capillary structure
- (3) by receptor-mediated transport systems
If Mw>70kDa, retained in the circulation
Colloidal particles
Escape vasculature through
- (1) the gaps in fenestrated and sinuosoidal regions
- (2) by phagocytes transporting it out of blood
- (3) also via receptor-mediated transport systems.
In certain pathological conditions, more extravasation occurs (eg MW ≤300kDa may escape in tumour tissues.)
For cellular uptake;
A) What is endocytosis?
B) What are the two types of endoyctosis?
A)
- Internalisation of plasma membrane engulfing some extracellular material (fluid or particle)
B)
- Phagocytosis – particle “cell eating”
- Pinocytosis – fluid “cell drinking” –> small particles suspended in the extracellular fluid are moved into the cell
What are the steps involved in phagocytosis (cellular uptake)?
Phagocytes belong to mononuclear phagocyte system (MPS)
- Recognition (opsonisation/complement activation)
> Foreign particle is “opsonised” (IgG, complement C3b and fibronectin adsorb onto particle and phagocyte recognises it)
- Adhesion
- Internalisation and Digestion –> Phagocyte cell engulfs particle and phagosome fuses with lysosome inside cell
