Targeted Drug Delivery

What are the 3 types of targeting systems?

1) Passive Targeting: deliver therapeutics via EPR effect where leaky vessels deliver drugs at the tumor

2) Negative Targeting: avoids the site where it wants to go

3) Active Targeting: receptor-ligand interaction

When designing PDC (polymer drug conjugates) what are 4 design criteria for designing one ?

1) HPL Polymer backbone: vehicle that carries drug through the bloodstream (synthetic vs natural) dissolves easily and circulates long

• polysaccharides

• proteins

• HPMA (synthetic)

2) Linker: attaches drug to the polymer and cleaves at the target becoming active thus preventing systemic toxicity

3) Targeting Agent: ligand binds to receptor

4) Drug

What was an in class example of a polymer backbone?

HPMA

• HPL (provide water solubility and stable circulation)

• biocompatible

• stable

What are the three different types of linkers for designing PDC?

1) pH- induced linkage: cleave at C=N → aldehyde + NH2-NH-Drug

2) reducing linker: disulfides Antibody- (S-S)-Drug → SH + SH-Drug

3) peptide linkers: cleaved by cathepsin B//1,6, elimination

4) nondegradable: thioether

What is a liposome, and what size range (~100 nm) do your notes indicate?

lipid vesicles that are 100nm big and encapsulate either HPB or HPL drugs

What is the structure of a lipid bilayer?

HPB drugs: drugs are in the core while lipid bilayer surrounds the core

HPL drugs: drugs are embedded into the lipid bilayer and core is water

How do you engineer liposomes w/ HPB drugs ?

1) Lipids + Org. solvent (DCM) + HPB drug

2) Rotated and vacuumed which leaves lipid coating

3) Hydrated with aq solution (H20) and sonicated to form lipid vesicles

4) Filtered through syringe into uniform sizes

How do you engineer liposomes with HPL drugs?

1) Lipids + org solvent (DCM)

2) Vacuumed to form lipid coating

3) Hydrated with water and HPL drug

4) Forms particles with drug embedded

5) Filtered through syringe into uniform sizes

What is the difference between unilamellar and multilamellar vesicles? (types of liposome structures)

Unilamellar: one bilayrer

• perfect for HPL drugs

Multilamellar: multiple layers

• slower diffusion

• larger particle size

• more space for HPB drugs

What is an ADC? (Antibody drug conjugate)

Antibody + Drug + Linker: links a drug to an antibody

What are the 3 types of ADC’s?

Monoclonal: binds to one target

Bispecific: binds to two targets

Polyclonal: binds to all sorts of things

What are the four mechanisms for antibody killing?

1) Apoptosis: triggers cell death

2) Antibody directed cellular cytotoxicity: signals immune system (NK cells) to kill cancer cells

3) Antibody directed phagocytosis: antibodies recruit macrophages to engulf and digest cancer cells

4) Activation of complement cascade: forms pores which leaks contents and leads to cell death

What are two design criteria when adding your drug to your conjugate?

1) Linker(drugs linked by different types of linkers to PDC)

2) Optimization (4 drugs per antibody to optimize design to avoid it from aggregating and lower the targeting capacity)

Draw pH induced linker

Draw it

Draw disulfide linker

S-S → SH + SH-Drug

Draw Peptide linker

1) cleavage by Cathepsin B

2) 1,6 elimination

Draw nondegradable linker

thioether