Future Anti-Cancer Systems

Question 1

What does using a carrier avoid?

Answer 1

Plasma bindings, resistance by using a different pathway and efflux pumps.

But it could cause a reaction or immune response

Question 2

Why are drugs difficult to get out of tumours?

Answer 2

Different vasculature; not homogenous

Question 3

How do adenovirus virions work?

Answer 3

a) Adenovirus virions binds to the coxsackie adenovirus receptor (CAR) and integrins on plasma membrane; virions enter by cell-mediated endocytosis, as endosome acidifies the capsid breaks and double stranded viral DNA is released.

Question 4

How does the Anthrax toxic get into cells?

Answer 4

b) Anthrax toxic assembly and entry into cells:
- Binding of protective antigen to its receptor
- Proteolytic activation of PA and dissociation of PA20
- Self-association of monomeric PA63 to form heptameric prepore
- Binding of Edema factor (EF) to prepore
- Endocytosis of receptor-PA63-ligand complex
- pH dependent insertion of PA63 and translocation of the ligand.

Question 5

What does a multifunctional Envelope-type nano device?

Answer 5

Draw Diagram

Question 6

What is the role of the lipid membrane in the MEND?

Answer 6

• Lipid membrane means it can fuse to cell and enter.

Question 7

What does the cationic polymer bind to?

Answer 7

The nucleotides in the core

Question 8

What is the reality of nano devices?

Answer 8

• Not a huge amount of drugs, but billions are being spent on it.
• In a Wilhelm paper 2016, it states that only 0.7% is reaching the target; you couldn’t have this rate of failure in any other industry.
• However, having 1% in target site is better than many drugs injected systemically.
• You need to have a HIGH loading dose to be effective, to get dose into tumour sight.

Question 9

What is DTXL-TNPS, and the advantages?

Answer 9

• DTXL-TNPS; polymer micelle formulation, prostate specific antigen
• Polymer formulation stays in the blood stream a lot longer
• You can predict the dosing and circulation time.
• The PK profile didn’t differ between animal models
• Signs of tumour shrinkage

Question 10

What are the advantages of siRNA?

Answer 10

New treatment
Long-lasting effect
Picomolar efficacy
Cheaper therapy
Less ADRs
Quick and easy synthesis

Question 11

What are the disadvantages of siRNA?

Answer 11

Toxicity
Short half-life
Lack of tissue targeting
Effective cellular uptake
Chemical stability
Formulation-related difficulties

Question 12

What are the biological barriers and challenges to SiRNA

Answer 12

• Rapidly degraded by nucleases.
• Size allows glomerular filtration in kidneys.
• Hydrophilic; low binding to plasma proteins, not directed to sink compartments.

Mustn’t go into wrong site/incorrect RNA: toxicity and off-target effects

Question 13

What is the mechanism of action of SiRNA?

Answer 13

• After internalization into the cell, siRNA duplex is recognised and unfolded by RNA-induced silencing complex (RISC)
• RISC then catalyzes cleavage of messenger RNA (mRNA) of specific sequence and prevents it from being transcribed into a protein
• If longer than 23bp, dsRNA reaches cytosol, initial processing by endonuclease Dicer occurs.

Question 14

What physical processes does siRNA exploit?

Answer 14

chemoembolization, lymphatic uptake, RES uptake

Question 15

How is siRNA accumulated in disease site?

Answer 15

• Accumulation of drug in disease site through prolonged circulation coupled with reduced excretion due to change in biological state in site

Question 16

Does siRNA have the EPR effect?

Answer 16

Yes

Question 17

What are the future needs of cancer that need addressing?

Answer 17

1) New potent cytotoxics
2) New anti-cancer mechanisms
3) Better-delivery systems; bottom-up approach; top-down approach.