Delivery of therapeutic macromolecules Flashcards
What is a therapeutic macromolecule?
The term therapeutic macromolecules refer to
• Large molecules…by definition these are polymeric drugs
• High molecular weight
• Complex structure
• Difficult to characterise – average MW rather than specific, will have an idea of the composition, sometimes with proteins
• Often hydrophilic/water-soluble – cylcosporin (a peptide) is an exception which is poorly water-soluble due to its composition – amino acids. Improving water solubility is important.
- Obtained through a complex production process
- Biotechnology
- You might see drugs in this class referred to as
- Biological drugs – process through which they are obtained
- Biopharmaceuticals
- Biologics
What can be used as therapeutic macromolecules?
Amino acid based therapeutics:
Peptides (<50 amino acids) - insulin and cyclosporin
Proteins: Erythropoeitin, vaccines, antibodies, growth factors
Polysaccharide therapeutics: Heparin
Nucleic acid-based therapeutics: siRNA, Plasmid DNA
What are the advantages of therpeutic macromolecules?
No barriers to cross which would be a problem because they are big and hydrophilic
Wont cross membranes that easily
Issues with degradation - difficult to administer through oral route
Increased stability
Increased internalisation
Tailored and targeted drug delivery
Effective at low dose
What are the disadvantages of therapeutic macromolecules?
Issues with stability – enzymes which degrade macromolecules.
Issues with immunogenicity – Problematic because there are proteins also if they are quite big can trigger an immune response (if they don’t look like the human form as much)
How can you improve cellular uptake with a macromolecule?
- Increase the hydrophobicity of the macromolecule – chemically link fatty chains (CH2) to make molecule more hydrophobic (could attach phospholipid). BUT need to balance so don’t want it too hydrophobic as solublilty will become an issue and therefore can cause precipitation in blood
- Improved interaction with cell membrane
- Lipidisation of peptides or oligonucleotides
• Add permeation enhancers to the formulation – strategy will work if you are disrupting the membrane or tight junctions.
Consequence of using long term – increase chance of infection, longer permeability of membrane
Permeating enhancers used:
• Surfactants
• Cationic polymers
• Calcium chelators (e.g. EDTA) – need calcium to maintain the tightness of tight junctions
What is a solution for enzymatic degradation?
Peptides are shorter so they have fewer points which can be recognized by enzymes where it can be cut.
• RNAse/DNAse
• Polysaccharidases
How can you limit degradation of biologics?
- Chemically modify the macromolecule
- Phosphorothioate
- Pegylation
- Anti-PEG antibodies - PEGylation – attaching chain of PEG, makes macromolecule chunkier, so limits the accessibility of the enzyme to cutting site of action.
Goal is to prevent enzyme from recognizing the site where would normally cut.
- Co-administer with inhibitors – prevents activity of enzyme
- Risk of long term toxicity as preventing enzyme from degrading infectious molecules.
• Encapsulate the macromolecule in nanomedicines
What does the immunogenicity of biologics depend on?
- Size and source – the bigger the antibody, the worse – will likely to trigger immune reaction
- Route of administration
- SC, IM > IV
SC and IM have the machinery to trigger immune response so immunogenicity is more of an issue if the therapeutic agents is administered through these routes.
How close the antibody resembles the human antibody, changes the immunogenicity. Injecting something that is very different is very likely to cause an immune reaction
How can the risks of immunogenicity be mitigated?
The risk can be mitigated by
• Using fragments (e.g. antibody) – decreasing the size, decrease immunogenicity.
• Adjusting the production process – favoring something that will look like the human version
• PEGylation – masking the protein / antibody do body won’t recognise as foreign
• Encapsulating the biologics in nanomedicines
