Drug Targeting 1 Flashcards
What are the three types of endothelial cell structures recognised?
- Continuous
- Fenestrated pancreas (gaps are 20-80 nm)
- Sinusoidal (liver) (gaps are up to 150nm)
Describe sinusoidal endothelial cell structure
Gaps between cells are up to 150nm
The basement membrane is discontinuous (spleen, bone marrow) or absent (liver)
What cells are involved in MPS?
Macrophages in blood circulation and Kupffer cells in the liver
What size particle tends to be cleared by MPS?
0.1-7micrometres
What charge particle is cleared by MPS?
negative
Are hydrophilic or hydrophobic particles cleared by MPS?
Hydrophobic
What is one of the pathological changes to tissue due to some diseases?
Increased endothelial fenestration size up to 20nm
What is important if you are using a non-degradable polymer for a polymer-drug conjugate?
Molecular mass - ensure it is <40kDa to ensure renal excretion
What kind of functional groups are used for linkers in polymer-drug conjugates?
Amine
Carbamate
Esters
Name the drug, linker and polymer in Oncaspar
Drug: L-asparaginase (enzyme)
Linker: amide
Polymer: m-PEG (5kDa)
Name the drug, linker and polymer in PEG-Asys
Drug: Interferon alfa-2a
Linker: amide
Polymer: branched m-PEG (40 kDa)
Name the drug, linker and polymer in Neulasta (pegfilgrastim)
Drug: g-CSF
Linker: amide
Polymer: m-PEG (20kDa)
Name the drug, linker and polymer in PEG-intron
Drug: interferon alfa-2b
Linker: carbamate
Polymer: m-PEG
Name the drug and polymer in Adagen
Drug: adenosine deaminase
Polymer: PEG
Indication of Pegasys
Hepatitis C
Indication of Neulasta
Neutropenia
Indication of Adagen
Immunodeficiency disease
Indication of Oncaspar
Acute Lymphoblastic Leukemia
What is Neulasta the biosimilar of?
Fulphila
What is the drug in Cimzia?
Certolizumab pegol
Indication of Cimzia
Arthritis
How does Cyclophosphamide work?
There is increased enzyme activity in tumour cells - cyclophosphamide is given in active/ prodrug form and is only converted to active form in tumour cells
How does Misonidazole work?
Takes advantage of the fact that tumour cells are often hypoxic which means that reductases are more active - Misonidazole is only toxic in hypoxic cells
What is ADEPT?
Antibody-directed enzyme prodrug therapy
Give an example of 2 systems which use ADEPT
5- Fluorocytosine is broken down by cytosine deaminase into 5-fluorouracil
Protax is broken down by B-lactamase into Taxol
Give 4 targeting moieties commonly used
- Folate
- Aptamers
- Oligopeptides
- MABs - whole monoclonal antibodies or Fab fragments
What is an RGD sequence?
Arginine-Glycine-Aspartic acid sequence found in ECM proteins and integrins which helps cells to stick to their surroundings. However, this can be non-specific and may stick to more cells than intended
What is Cilengitide?
A cyclic RGD peptide
Targets αvβ3 and αvβ5 integrins → blocks angiogenesis (blood vessel growth to tumors)
Tested in glioblastoma, lung, and pancreatic cancers
Discontinued in EU due to limited success in trials
Give an example of a humanised MAb
Trastuzumab
Give an example of a chimeric MAb
Rituximab
Give an example of a human MAb
Adalimumab
