Monoclonal antibodies Flashcards
What is chemotherapy?
the use of synthetic and natural chemicals to inhibit the growth of malignant or cancerous cells
What is the magic bullet concept?
the idea that a compound can selectively target disease-causing organisms with a toxin for that specific organism (without harming the host/body)
- maximises therapeutic index
What are examples of different magic bullets?
anti-bacterial
- penicillin
= inhibits the formation of peptidoglycan crosslinks in the bacterial cell wall
anti-viral
- aciclovir
= converted into acyclo-GMP which is incorporated into viral DNA resulting in chain termination
anti-protozoal
- quinine
= inhibits hemozoin biocrystallisation causing toxin free heme accumulation (causes parasite to starve and die)
What are types of cancer chemotherapy?
alkylating agents including platinum compounds
- form covalent bonds with DNA and inhibit DNA replication
cytotoxic antibodies
- substances which prevent mammalian cell division
anti-metabolites
- block or subvert one or more of the metabolic pathways involved in DNA synthesis
What is the mechanism of action of cisplatin?
alkylating agent
- diamine-platinum complex reacts with water and covalently binds with DNA (via purine A and G bases)
- covalent binding leads to intra-strand and inter-strand crosslinks causing subsequent strand breaks (via H bond breakage)
- blocks DNA synthesis and cell growth
What is the mechanism of action of doxorubicin and daunorubicin?
anthracycline antibiotics
- intercalates into DNA between base pairs and inhibits progression of topoisomerase II (stabilises the topoisomerase II complex preventing DNA release)
- blocks DNA and RNA synthesis
= prevents DNA double helix from being resealed and stops DNA replication
What are the side effects of chemotherapeutics?
bone marrow toxicity
impaired wound healing
depression of growth
- in children
sterility
teratogenicity
alopecia
damage to gastrointestinal epithelium
How do anticancer nanomedicines work?
embed a small active molecules into a larger system
- attach a chemotherapeutic agent to a polymer via a degradable linker
- formulate a liposome/micelle containing the active
- produce a nanoparticle that will release the active
is able to enter tumour tissue due to leaky vasculature but unlikely to be able to enter health tissues
What do tumours consists of?
blood vessels
- due to vascular endothelial growth factors (VEGF) and angiogenesis
= creates leaky vasculature (gaps of 200-800nm)
lymph vessels
- absence of lymph causing build up of blood/plasma/fluid (no exit route)
What is the ideal system for nano-medicine delivery to tumour?
stable during transport to tumour
able to release drug at optimal rate
- peptidyl linkages
- pH dependent release
What are the disadvantages of nano medicines?
accumulation in liver
- due to rejection
must ensure degradation take place in the correct place
- not prior to ingestion or at tumour site
levels of free drug are difficult to estimate
regulatory hurdles
What is the difference between passive and active targeting in chemotherapy?
Passive targeting allows for the efficient localization of nanoparticles within the tumor microenvironment
Active targeting facilitates the active uptake of nanoparticles by the tumor cells themselves
What is Rindorf’s model?
is a delivery system
the proposed model consists mainly of five components:
- the polymeric backbone
- the drug
- the spacer
- the targeting group = provide transport to a desired physiological destination or bind to a particular biological target (Man or ligand)
- the solubilising agent = imparts hydrophilicity and ensures water solubility,
What are the disadvantages of monoclonal antibodies?
immunogenicity
- can be avoided with chimeric (mouse) and humanised (mouse parts attached to human) monoclonal antibodies
loading
- may affect antibody binding
polymer
- may add excessive weight
regulatory hurdles
What is ADEPT?
antibody directed enzyme prodrug therapy
- monoclonal antibody has an enzyme attached which performs a non-endogenous function
inactive prodrug is attached to the mAb and enzyme
prodrug is cleaved to provide active drug
Examples include paclitaxel and the anthracyclines
