Drug targeting Flashcards
There are a number of problems associated with conventional therapy that lead to sub-optimal treatment.
• Non-specific distribution of drug throughout body
• Lack of drug selectivity for a particular pathological site
• Large total dose of drug required but low dose at site required
• Non-specific toxicity and other adverse effects
Drug targeting is the ability of the drug to accumulate in the target organ or tissue selectively independent of the site or method of administration.
Passive targeting
Nanoscale drug delivery systems can increase the concentration of drug at site of action through passive or active targeting. In addition, they can decrease drug concentration in normal (non-diseased tissue) to reduce toxic side effects and they improve pharmaco-kinetic/dynamic profiles.
To achieve this, minimum amounts of drug should be released during transit, and as much as possible should be released at targeted site.
• Nanoparticles
o Solid, spherical ~100 nm in size with drug in polymer matrix
• Nano-capsules
o Drug entrapped in a cavity surrounded by a polymer membrane
• Polymeric micelles
o Spheroidal structure with hydrophobic core which increases solubility of poorly-water soluble drugs, and hydrophilic corona which allows a long circulation time and prevents interactions between core and blood. Dynamic structures ~50 nm.
• Liposomes
o Closed spherical vesicles formed by one or more phospholipid bilayers around an aqueous core in which drug can be entrapped.
As with any foreign particle that enters the body, liposomes encounter multiple defence systems aimed at recognition, neutralization, and elimination of invading substances.
The Reticuloendothelial system (RES)
is an important component of the immune system. This comprises phagocyte cells found in various organs of the human body. They are located in reticular connective tissues. Upon leaving the circulatory system, phagocytes become macrophages. Macrophages will readily take up and phagocytose liposomes.
Doxorubicin can be given using stealth liposomes (>90% of doxorubicin is encapsulated).
Stealth liposomes are protected from detection by the mononuclear phagocyte system because they are coated using surface-bound methoxy PEG. This increases blood circulation time and increases the chance of being taken up by tumour cells. In addition, doxorubicin is less cardiotoxic, myelotoxic and nephrotoxic in this formulation because distribution is altered.
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. This occurs when a tumour exceeds 2mm. Defective blood vessels have sac-like formations and fenestrations, which have enhanced permeability & retention. There is enhanced permeability for drugs/carriers to move from microcapillaries to interstitium surrounding tumour cells and a lack of lack of lymphatic drainage, so drugs will be retained in the tumour interstitium. Drugs should be >10 nm to avoid filtration by kidneys and <100 nm to avoid capture by liver and should be neutral or anionic to avoid renal elimination.
