Pharmaceutics 3 - Pharmaceutics of Anticancer Drugs

Question 1

What are the problems associated with injected doxorubicin?

Answer 1

Consider cardiotoxicity;
Drug injected into the vein passes to the heart
Passes through pulmonary circulation and heart then pumps it around tissues.
Doxorubicin is also rapidly cleared from blood post injection and is distributed to tissues (lung, liver, heart, spleen and kidneys).

Question 2

Where is doxorubicin metabolised into its active metabolite?

Answer 2

Liver
Metabolism to active metabolite Doxorubicinol
50% excreted in bile after 7 days, the rest remain unchanged

Question 3

Does Doxorubicin cross the BBB?

Answer 3

No but can potentially cross placenta

Question 4

What is the dose limiting factor for Doxorubicin?

Answer 4

Cardiotoxicity

Question 5

What is a risk with Doxorubicin in terms of administration and subsequent adverse events?

Answer 5

Is a severe irritant; can cause thrombophlebitis
Extravasation after the injection is serious and can lead to local necrosis and ulceration
Increased leakage into tissue at multiple injection sites.

Question 6

What are three processes by which we can avoid systemic toxicity?

Answer 6

Combine cancer and biology therapeutics
Exploit the Enhanced Permeation and Retention effect
Encapsulate doxorubicin into virus-sized carrier (carriers around the body and protects healthy tissue from exposure)

Question 7

What is the Enhanced Permeation and Retention effect?

Answer 7

Relates to the ability of drugs to permeate vasculature and then also residence time in the tumour

Question 8

What are the factors effecting the EPR?

Answer 8

Vehicle: plasma residence time, particle size, carrier vehicle, polymer architecture

Tumour: tumour type, microenvironment

External mediators: radiation, bradykinin antagonist, cyclooxygenase inhibitor, nitric oxide scavengers.

Question 9

What does increased plasma residence time mean?

Answer 9

It means beneficial exposure and longer residence at target tumour site

Question 10

How does prolonged blood circulation of drug carrier affect passive targeting?

Answer 10

Drug carriers are transported through blood stream to target tissue; extravasation into tumour considered to be a slow and passive process and so prolonged circulation is beneficial

Question 11

What obstacles are faced by particulate or macromolecular carriers of drugs?

Answer 11

Glomerular excretion by the kidneys

Recognition by the Reticuloendothelial System (RES) in the lungs, spleen and liver.

Question 12

How can drug carriers avoid renal excretion?

Answer 12

Increasing particle size to 42-50kDa so that they are not excreted.

Question 13

How can detection by the RES system be avoided?

Answer 13

Carriers <200nm that do not activate complement cascade

Question 14

Aside from the size of a carrier for drug delivery, shape plays a role also. How do the different shapes and surfaces of carriers compare?

Answer 14

Neutrally charged carriers are most neutral/passive

Pill shaped carriers are detected most by the RES system (spherical shapes are the best).

Question 15

What are the three layers to liposomal doxorubicin?

Answer 15

Doxorubicin hydrochloride (loaded by pH gradient)
Liposomal phospholipid bilayer encapsulates drug
Poly(ethyleneglycol)PEG) corona - steric shield

Question 16

What size are liposomal doxorubicin molecules?

Answer 16

90-100nm diameter
Virus size; deliberate to evade defense mechanisms such as RES.
Good size for transport in the body; limiting factor for drug loading.

Question 17

What is the role of the PEG (Poly(ethyleneglycol) corona) layer in liposomal doxorubicin formulation?

Answer 17

Prevents attachment of plasma proteins - entropic stabilisation and prevents aggregation.

Question 18

Why are liposomes described as a ‘balanced leaky box’?

Answer 18

Balance between containing and carrying the drug but also allowing its release. Some drug leaks out during transportation.

Question 19

How does changing the pH and counter-ion in liposomal doxorubicin help formulation assembly?

Answer 19

Allows high loading of drug and self assembly.

Question 20

Within the liposome, a high concentration of Dox gel is possible - why is this not a formulation option for non-encapsulated drugs?

Answer 20

It would result in aggregation

Question 21

How does the pH affect the efficacy of liposomal doxorubicin?

Answer 21

Reduced pH in solid tumours means that liposome are retained and increases efficacy.

Question 22

What are the disadvantages of EPR?

Answer 22

Unwanted accumulation at sites with poor circulation

Question 23

What is Palmar-plantar syndrome?

Answer 23

Damage to peripheral sites such as fingers and toes

Question 24

How can individual cancer cells contribute to the removal of small molecules from a tumour site?

Answer 24

Efflux transporters

Question 25

What does release of doxorubicin intracellularly avoid?

Answer 25

Efflux pumps

Question 26

What is the problem with paclitaxel formulation?

Answer 26

Paclitaxel is almost insoluble in water

Question 27

Hypersensitivity is common in paclitaxel administration - what is the likely cause?

Answer 27

Surfactant excipient - polyoxyl castor oil

Question 28

How are liposomes taken into a cell?

Answer 28

Endocytosis

Question 29

How can biochemistry be applied to avoid the solubility problem facing paclitaxel?

Answer 29

Albumin in blood transports hydrophobic molecules so we can use albumin to transport paclitaxel as a carrier.

Question 30

How is albumin used in paclitaxel bridge?

Answer 30

Exploits albumin receptor gp60-mediated transcytosis across endothelial cells.
This helps to concentrate drug in tumours due to binding of albumin to Secreted Protein, Acidic and Rich in Cysteine (SPARC) receptor. (SPARC induces apoptosis).

Question 31

What is the paclitaxel formulation mode of action?

Answer 31

1. Administration followed by rapid dissolution
2. Binding to albumin specific receptors on endothelial cells leads to activation of transcylosis
3. Release of vesicle contents into the subendothelial space and tumour interstitium.
4. Tumour uptake and tumour cell death

Question 32

What is transcylosis?

Answer 32

Transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side.

Question 33

When is endocrine therapy used?

Answer 33

To treat cancer growth in hormone-related tumours.

Question 34

Is Tamoxifen acidic or basic?

Answer 34

A weak base (pKa 8.8)

Low aqueous solubility

Question 35

How does tamoxifen work?

Answer 35

Antagonist of ER in breast via active metabolite 4-hydroxytamoxifen

Question 36

What enzymes are responsible for tamoxifen metabolism?

Answer 36

CYP3A4, CYP2C9, CYP2D6

Question 37

What are the roles of tamoxifen metabolites?

Answer 37

Bind to ER but do not activate it e.g. endoxifen and afimoxifene both have greater affinity for ER than tamoxifen itself.