Advanced drug delivery 4 - PDC Flashcards
General considerations for polymeric drugs
- Inert and non-toxic
- Polycations generally more haemolytic and cytotoxic than polyanions
- Polyanions generally less cytotoxic but can cause anticoagulant activity
- Toxicity is affected by MW
- Many polymers can be immunogenic
Effect of MW of polymeric drugs on elimination from body
Biodegradable polymer:
- Can get broken down in the body
- We can go above the renal threshold (~40k Da) for elimination
Non-biodegradable polymer:
- MW for renal threshold for elimination ~40K Da,
- Keep it below renal threshold be eliminated renally
- And to prevent accumulation of polymer in body
Ringsdorfs model of polymer drug conjugates is called
3(+1) model
What is a polymer drug conjugate
- Drug delivery which involves a polymer covalently conjugated to a drug
- API is low MWt
- Each polymeric chain carries several drug molecules
Discuss the Ringsdord model of PDC - 3(+1)
PDCs consist of 3(+1 optional)
Components
1. Hydrophilic polymeric backbone
2. Several low MW drug molecules
3. Biodegradable linker that joins these
(+1) Optional: targeting group
HPMA copolymer-DOX
- First synthetic PDC to undergo clinical evaluation
- Drug: doxorubicin, anthracycline
- The HPMA copolymer acts as a carrier for doxorubicin while reducing its toxicity
- Cardiac toxicity
What are angiogenic tumour vessels
Blood vessels formed in response to growth of a tumour
Tumour vessels <1-2mm
- No induction blood supply
- Obtains nutrients & O2 by diffusion
Tumour vessels >1-2mm
- Tumour grows
- Induction of angiogenesis
- Blood vessels formed in cancer are somewhat different to normal blood vessels: endothelium is disorganised and poorly formed
> 200 mm3
- Hypoxia and necrosis
- observed in ~ 20 % of tumour volume
What is angiogenesis
- Formation of new blood vessels
What is the Enhanced Permeability and Retention (EPR) Effect in tumour targeting?
- Enhanced permeability = accumulation of PDC in tumour tissue because of the leaky angiogenic tumour vessels
- There is enhanced retention due to less lympatic drainage
- Higher concentration of PDC in tumour which is the main rationale of suggesting PDC for cancer therapy
How can PDC be more selective for tumour cells than healthy cells/tissues
- Tumours have leaky angiogenic blood vessels due to the gaps
- This is not present in normal healthy tissue
- PDC are larger systems and have higher MW compared to low MW drugs
- They can permeate and accumulate causing retention in the tumour tissue at a much higher extent than healthy tissue because of their size
- Less off target binding and less SE
Dose thresholds and EPR effect
- EPR allows us to increase dose threshold compared to administering the free drug
- More drug reaches the tumour and the PDC is less toxic
EPR effect and dose thresholds for free dox and HMPA-copolymer-dox
Max tolerated dose for free toxicity: 60-80mg/m2
Max tolerates dose of HPMA-dox: 320mg/m2
Define lysosomotropic
Drug that is able to penetrate the lysosomes of particular cell types
PDC for lysosomotropic delivery
ICAETEULRC
- INJECTION: Inject PDC into the bloodstream (IV/SC)
- CIRCULATION: PDC circulates in the bloodstream and is extravasated through leaky blood vessels
- ACCUMULATION: PDC accumulates in tumour tissue via EPR effect
- Once in interstitial space, the polymer has to enter the cell
- TARGETING: A normal low MW free drug can cross the barrier through passive diffusion and act as its target, but polymer cannot
- It is internalised by endocytosis
- UPTAKE: Once PDC reaches cancer cells, it would be taken up by the cell and transported to intracellular compartments e.g. lysosomes
- Lysosomes are acidic (pH ~5.5) and breaks down internalised material via acidic pH and enzymes
- RELEASE: Once inside the lysosomes the PDC would release the drug
- CLEARANCE: the polymer is cleared: renal/hepatic
Why can a polymer not diffuse through the barrier in lysosomotropic delivery
Because of its size and physicochemical properties polymer cannot cross cell barrier
6 Advantages of PDC
- EPR effect
- Decreased toxicity so increased dose threshold
- Active tumour targeting if targeting moiety present
- Solubilisation of API (polymer helps solubilise)
- Prolonged circulation time because excretion is slowed down
- Overcomes some drug resistance mechanisms e.g. MDR because polymer masks drug
Requirements for PDC in relation to the drug
Needs to be potent in relation to polymer carrying capacity
Requirements for PDC in relation to linker
- Suitable functional group that is stable during transport
- Degradable within target environment to ensure minimal off target binding and ensure correct activity of drug
Requirements for PDC in relation to polymer
- TOXIC: Non toxic, non immunogenic
- SCALE: Suitable for industrial scale manufacture
- BIODEGRADABLE: Biodegradable or if not then below renal threshold for elimination
- CAPACITY: needs to be able to carry multiple drug molecules in single polymeric chain.
Requirements for PDC in relation to targeting group
Be specific for a target
General toxicity considerations for PDC
- Polymer has to be inert and non toxic
- Ensure polymer is not immunogenic
- Toxicity is affected by MW
- Toxicity of conjugate may be different from toxicity of polymer alone
