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
- Renal threshold of MW for elimination = ~40K Da
Biodegradable polymer:
- Can get broken down in the body so we can go above the renal threshold.
Non-biodegradable polymer:
- MW must be below renal threshold so that it can be excreted.
- Prevent accumulation of polymer in body
Ringsdorfs model
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
- Hydrophilic polymeric backbone
- Several low MW drug molecules
- Biodegradable linker that joins these
- Optional: targeting group
HPMA copolymer-DOX
- First synthetic PDC to undergo clinical evaluation
- Drug: doxorubicin, anthracycline
- Drug delivery system designed to improve efficiency of doxorubicin while reducing toxicity to healthy cells
- 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 dox: 60-80mg/m2
Max tolerates dose of HMA-dox: 320mg/m2
Define lysosomotropic
Drug that is able to penetrate the lysosomes of particular cell types
PDC for lysosomotropic delivery
- INJECTION: Inject PDC into the bloodstream (IV/SC)
- CIRCULATION: PDC circulates in the bloodstream and is extravasated through leaky blood vessels
- 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 drug
Needs to be potent in relation to polymer carrying capacity
Requirements for biodegradable 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 of polymer
- Non toxic, non immunogenic
- Suitable for industrial scale manufacture
- Biodegradable or if not then below renal threshold for elimination
- Carrying capacity: needs to be able to carry multi drug molecules in single polymeric chain.
Requirements for 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
Movantik
- Only PDC on market
- Contains PEGylated naloxone
- Oral opioid antagonist derivative
- Approved for treatment of opioid induced constipation
Why does Movantik violate the rules for PDC
Violates general rules for PDC
- Has a non-biodegradable linker
- Oral whereas PDC normally given IV
What is the dose of Movantik?
OD
Movantik MoA
Antagonises morphine induced peripheral effects in GIT without affecting CNS effects
Dextrin-2 sulphate
- Polymeric drug
- MW 25kg/mol
- Tested intraperitoneally in AIDS patients
What is Capaxone
- Polymeric drug
- Random copolymer of 4 amino acids
- MW 5-11kg/mol
- Administered s/c
- Used for treatment of MS
Capaxone MoA
Mimics myelin to slow down disease progression
Passive tumour targeting
Responsible for the accumulation of polymer-drug conjugates in the tumour tissue
Active tumour targeting
Responsible for accumulation of PDSC in tumour tissue due to:
- Polymer
- Drug
- Linker
- Targeting moiety
