Drug Delivery/Formulation Flashcards
1
Q
What is tumour-associated hypoxia? (2)
A
- A condition in which the body or a region of the body is deprived of adequate oxygen supply at tissue level
- Hypoxia as a major component of the tumour microenvironment shapes stroma reactivity and tumour heterogeneity
2
Q
What is the signalling pathway involved with tumour-associated hypoxia? (5)
A
- HIF-1α doesn’t undergo proline hydroxylation and therefore doesn’t undergo VHL mediated degradation
- Causes build up of HIF-1α, which is then translocated to the nucleus
- HSP90 interacts with α subunit’s PAS domain, thus has a role in stabilisation and nuclear translocation
- HIF-1β and transcription factor ARNT bind to it through dimerization
- Activates transcription of genes through activating hypoxia responsive element (HRE)
3
Q
What factors in the tumour microenvironment can affect the uptake/effectiveness of drugs? (5)
A
- Sprouting angiogenesis
- Oxygen and nutrition
- Heterogeneity of tumour
- Cell proliferation rate
- Interstitial fluid pressure
4
Q
Sprouting angiogenesis (1)
A
- Referring to de novo formation of new vessels via local proliferation and extension of endothelial cells from the wall of an existing vessel
5
Q
Oxygen and nutrition (2)
A
- Oxygen: HIF-1 is induced in low O2. HIF-1 confers resistance to conventional therapies through a number of signalling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux
- Nutrition: tumours rely on glycolysis for energy supply, resulting in excessive lactate production (tumour acidity). Chemotherapeutic drugs that are basic (e.g., doxorubicin) are protonated thereby decreasing cellular uptake
6
Q
Heterogeneity of tumour (1)
A
- Tumours are composed of clones with different drug sensitivity
7
Q
Cell proliferation rate (1)
A
- Quiescent tumour cells are considered significantly less drug sensitive with a greater repair capacity than cycling cells
8
Q
Interstitial fluid pressure (2)
A
- Most solid tumours have increased IFP.
- Reasons include blood-vessel leakiness, lymph-vessel abnormalities, interstitial fibrosis and a contraction of the interstitial matrix mediated by stromal fibroblasts
9
Q
What is a bioreductive drug? (2)
A
- Inactive prodrugs that are converted into potent cytotoxins under conditions of either low oxygen tension or in the presence of high levels of specific reductases
- Rationale – “Exploit the reductive environment of tumours by developing drugs that are reduced preferentially to cytotoxic species in the hypoxic regions of tumours”
10
Q
Three main classes of bioreductive drugs (3)
A
- Quinone antibiotics e.g., mitomycin C
- Nitroaromatics e.g., RSU1069 (normal tissue cytotoxicity prevented clinical usage)
- Di-N-oxides e.g., tirapazamine (currently in Phase III clinical trials), AQ4N (currently in Phase I/II clinical trials)
11
Q
What is the function of carbonic anhydrases and which ones are linked to cancer? (2)
A
- Catalyse a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO2) and water (H2O) into bicarbonate (HCO3-) and protons (H+)
- Carbonic anhydrases IX / XII
12
Q
Carbonic anhydrases IX/XII (4)
A
- Selectively expressed by tumour cells
- Increased expression is linked with tumour progression
- Regulated by hypoxia (oxygen-deprived microenvironment in tumour)
- Increased expression linked to more aggressive phenotype and to poor prognosis
13
Q
What are active and passive delivery of liposome-loaded drugs? (2)
A
- Active: functionalising the nanoparticles
- Passive: extravasation of nanoparticles
14
Q
Factors contributing to passive uptake of nanoparticles (6)
A
- Size of the nanoparticle
- Physicochemical properties of nanoparticles (e.g., charge)
- Tumour vascular permeability
- Lymphatic drainage
- Level of angiogenesis
- Interstitial fluid pressure (intratumoral pressure)
15
Q
What does active cellular targeting increase? (3)
A
- Liposome/drug accumulation
- Liposome/drug specificity
- Liposome/drug uptake by endothelial cells and target cells
