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SR PM4B > Advanced drug delivery 3 - PPC and PEGylated Proteins > Flashcards

Advanced drug delivery 3 - PPC and PEGylated Proteins Flashcards

1
Q

What is a polymer protein conjugate? (PPC)

A

Drug delivery system where there is a polymer covalently conjugated to a protein
- The protein is the API
- Single protein has one or more polymeric chains attached (usually multiple).

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2
Q

Polymer drug conjugate (PDC)

A

Drug delivery system where there is a polymer covalent conjugated to the drug
- The drug is the API
- API is typically low MW molecules like traditional anticancer drugs e.g. dox, paclitaxel
- Each polymeric chain carries several drug molecules

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3
Q

Similarity between PDC and PPC

A

Both have covalent conjugation between API and polymer

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4
Q

Problems with using proteins as therapeutic agents

A
  • Rapid renal excretion
  • Proteolytic degradation
  • Immunogenicity
  • Aggregation
  • Solubility
  • Difficulty in formulation
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5
Q

Rapid renal excretion

A
  • Smaller proteins are rapidly excreted
  • Too quick = insufficient therapeutic action
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6
Q

Aggregation

A

Occurs before or after administration

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7
Q

Solubility

A

Needs to be soluble in blood - some proteins arent.

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8
Q

Advantages of PPC

A
  • Protection
  • Increased hydrodynamic volume, therefore reduced renal clearance.
  • Reduced protein aggregation
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9
Q

PPC: Protection

A
  • Polymeric chains protect proteins from proteolytic degradation
  • Also protects the body from unwanted characteristics of the protein e.g. immunogeneicity
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10
Q

Increased hydrodynamic volume and reduced renal clearance

A

Conjugated protein vs Native protein:
Conjugated protein = increased hydrodyanmic volume = slower renal excretion because of the larger size

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11
Q

Reduced protein aggregation

A
  • Attaching polymeric chains prevents protein aggregation
  • Because of steric hindrence.
  • Conjugate polymer in areas that are not key to the binding site to prevent interaction with molecular target
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12
Q

General structure of protein

A
  • Amine group
  • Alpha carbon
  • Variable R group (side chain)
  • Carboxylic acid
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13
Q

What does the polymer bind to in a protien

A
  • The side chain: either C terminus or N terminius
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14
Q

Lysine

A
  • Use lysine with a polymer with an activate carboxyl group
  • Side chain of lysine has an amino group that the polymer can bind to
  • Available in 2 forms: NH2, NH3+
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15
Q

Lysine group

A
  • Use lysine with a polymer with an activated carboxyl group
  • Side chain of lysine has an amino group that the polymer can bind to
  • Available in 2 forms: NH2, NH3+
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16
Q

pH when conjugating lysine

A
  • Must be used at a pH above pKa (>9.3-9.5) so that it is in the unprotonated form
  • The unprotonated (NH2) form is suitable for conjugation
  • Participates in a nucleophilic attack reaction, lone pair reacts with COOH
  • pH ~10, not too high to denature protein
17
Q

Monofunctional polymer

A

Polymer with only one reactive group per monomer unit

18
Q

Polyfunctional polymer

A

More than one reactive group in side chain. So it has multiple sites for reaction

19
Q

Which type of polymer is best for PPC

A
  • Monofunctional
  • Polyfunctional can end up cross-linking with several proteins and form a very heterogeneous mixture
20
Q

Which type of polymer is best for PDC

A
  • Polyfunctional
21
Q

Why multifunctional polymers are not used in PPC

A
  • High variability
  • Too large conjugates form cross linking with several proteins
  • Difficult characterisation
22
Q

What enzyme is ideal for protein conjugation

A
  • PEG, in its methoxy form (mPEG)
23
Q

Why should PEG be in its methoxy form?

A
  • Only one reactive group (OH) - monofunctional
  • Water soluble
  • Soluble in some organic solvents
  • Non-toxic
  • Broadly non-immunogenic (although research is now indicating some immunogenecity)
24
Q

Which enzyme is most stable

A
  1. mPEG2-trypsin
    - It is PEGylated with branched PEG
  2. mPEG-trypsin
  3. Native trypsin
    - Not stable
    - Very fast degdradation
25
Q

Example of PEGylated protein for cancer

A

Pegaspargase (Oncospar)
- Acute lymphoblastic leukemia
- Increases half life of L-Asparginase in body

26
Q

3 catgeories of proteins used for therapeutic applications

A
  • Enzymes
  • Singalling proteins
  • Antibodies
27
Q

What is the advantage of using branched PEG compared to linear PEG?

A

More protection of the protein from enzyme degradation

28
Q

Mention one point in the protein where you can have polymer-conjugation

A

Amino terminus, carboxylic acid terminus

29
Q

What is pKa

A

Shows the strength of an acid

SR PM4B (41 decks)

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