12: Targeted Drug Delivery Systems and Biotech Products

Why is drug targeting used?

1. Increase drug concentration at disease site

2. Decrease side effects of drug on normal tissues

3. Reduce dose

What are three localized delivery strategies to apply a drug directly into an affected zone?

Implants, injectables, inserts

What are the four devices used as platforms for gastric retention (making sure drug stays in stomach region)

1. Low density systems (intragastric floating systems)

2. High density systems

3. Mucoadhesive systems

4. Unfordable, extensible, or swellable systems

What is the strategy used to target the small intestine?

enteric coating

How do oral vaccines work and what do they target?

1. Live attenuated vaccines mixed with excipients and put into gelatin capsules

2. Enteric coating layer added to make capsules resistant to stomach dissolution

3. In small intestine, vaccines colonized and elicit immune response similar to natural infection (M cells)

Why is targeting to the colon difficult?

• Hard to protect drug from GI tract degradation

• Colonic fluid is viscous and at natural pH (solubility issue)

What makes a drug candidate suitable for colon targeting?

Exhibits local effects in the colon to treat intestinal diseases

What are two design strategies that aid in targeting to the colon?

1. enteric coating

2. erodible barriers or cap release

When would you want a biodegradable localized delivery implant?

If you don’t want to keep the implant dosage form in the body (such as intracranial)

What are the three forms of drug targeting via parenteral routes / systemic administration

1. Passive (particle properties)

2. Physical (magnetic, ultrasonication, pH)

3. Active (use targeting ligand)

Biological/technical barrier to eye localized delivery

Accessing posterior segment of eye

Increasing intra-vitreal half-life

(local injection, topical delivery, implants, reservoirs)

Biological/technical barrier to brain localized drug delivery

non-uniform drug distribution, low diffusion

(biodegradable implants, intranasal)

Biological/technical barrier to ovarian localized drug delivery

Sustained release to prevent toxic effects while still maintaining therapeutic dose

(IP bolus injection, implants)

Biological/technical barrier to lung localized drug delivery

pulmonary compatibility of particles

(aerosols)

Biological/technical barrier to skin localized drug delivery

Minimizing systemic absorption through the skin

(topical gels/films/particles, microneedles, barrier disruption)

Biological/technical barrier to bladder localized drug delivery

Drug penetration for deeply embedded tumors

(intravesical delivery, indwelling devices)

What is passive targeting and what are the different forms of it?

Using the properties of particles to achieve delivery

• Controlling particle size

• Altering particle shape

• Particle surface properties

What is the ERP (enhanced permeability and retention) effect in solid tumor tissue, and how does this help with passive targeting?

Cancer cells grow fast so they need lots of nutrients; disrupt BV cells and build their own leaky/poorly formed vasculature

Smaller drug particles are able to passively slip through the gaps and enter the tumor; passive targeting to areas of leaky vasculature

What does altering particle shape affect how a drug interacts with the body?

Affects biodistribution of nanoparticles and interaction with cells

(ex: lung branches have various sizes; elongated particles can get sucked into narrow branches)

What is PEG and what does it do?

A polymer that prolongs nanoparticle and peptide circulation (tricks body into thinking drug is a water-like system so it’s not as immunogenic)

It is a form of passive targeting

What are the forms of physical targeting?

1. pH or temperature-sensitive drug release

2. pH sensitive drug targeting

3. Magnetic guided target delivery or drug release

Describe pH/temperature sensitive drug release

Form of physical targeting

Drug carrier is stable in blood circulation, but in the area with abnormal pH/temperature (likely more acidic in cancerous areas), the carrier disintegrates and releases free drug

Describe pH sensitive drug targeting

Form of physical targeting

1. At non-acidic pH, peptide is shaped normally and can’t enter cell membrane

2. When peptide enters acidic pH, its structure changes and directly interacts with the cell membrane and enters cell

(also a good diagnostic tool)

Describe magnetic guided targeted delivery/drug release

Drug carrier has magnetic core, magnet placed on body pulls drug carrier to blood vessel walls (not for full body treatment, used to guide delivery/distribution)

• Effective for specific targets/locations close to body’s surface

• Hyperthermia/ablation of tissue possible

Describe active targeting

Targeting over expressed receptors on target cells (GPS system)

Attach ligands of target cells to drug/polymer so they can be taken up by receptor (receptor-mediated endocytosis)

What determines the efficacy of drug targeting?

1. Target size

2. Blood flow through a target

3. Circulation duration

4. Number of binding sites in a target

5. Number and affinity of targeting moieties on a drug carrier (more ligands = better uptake)

6. Multipoint interaction of drug within a target

What are the different types of biologic drugs?

1. Proteins/peptides

2. Genes

3. Vaccines

4. Blood and blood components

5. Therapeutic cells

Why should protein solutions not be shaken?

Proteins irreversibly denature at interface, and shaking generates bubbles (large air/water interface)

Why do biologics need to have proper filters?

They tend to adsorb onto filters, resulting in loss and denaturation of protein

What happens when biologics are put under high shear for a long time?

They lose activity

How do repeated freeze-thaw cycles or repeated lyophilization impact biologics?

They denature proteins

What extremes should be avoided when handling biologics?

Extreme pH and extreme/high temperature

Proteins

> 50 amino acids (long-chain polypeptides)

Peptides

< 50 amino acids (short polypeptides)

What do monoclonal antibodies recognize and what are they used for?

They recognize the same specific epitope of an antigen, so they’re used for specific therapeutic outcome (mostly for cancer treatment)

What is Keytruda and what does it do?

lyophilized mAB powder (that gets reconstituted) against PD-1 (surface protein on T cell surface that suppresses T cell function); boosts body’s immune system to fight cancer

Gene

segment of nucleic acids that specifies a trait

DNA; definition and target

nucleic acid that stores genetic info long-term

target: nucleus

RNA

central to protein synthesis

target: cytoplasm

transcription

DNA → RNA

translation

RNA → proteins

How are genes delivered into cells?

in vivo using viral genomes (immunogenic, may revert back to pathogenic form) or bacterial plasmids (recombinant DNA technology)

What are some major barriers in gene delivery?

DNA nucleases in biological fluids

low uptake across plasma membrane

Slow release of the DNA with limited stability

Lack of nuclear targeting

Was happens if the endosome doesn’t release DNA vectors for gene therapy?

Morphs into lysosome and contents get degraded in acidic environments

What are the most widely used non-viral systems for gene therapy, but why is this unsafe?

Cationic liposomes/lipids and polymers (easily binds with negatively charged RNA/DNA and use charge-charge interaction to get into cell), they show high cytotoxicity

How does the immune system respond when the body is faced with a pathogen for the second time and why?

Responds to a larger degree and for a longer period of time (fast and efficient) due to immune “memory system”

Live attenuated vaccines

living virus/bacterium is given and can replicate itself (may revert to virulent form), strong response

Inactivated/killed vaccines

exposed to chemicals/heat/radiation; less potent and may need multiple boosters

Subunit/conjugate vaccines

Essential antigens (best stimulate immune system) administered; weak response & needs adjuvants

mRNA vaccines

mRNA injected into body → body self-produces antibody;

no virulence, but has the weakest response and needs adjuvants

Recombinant vector vaccines

Use of attenuated varus/bacterium to introduce microbial DNA

How do adjuvants modify the immune response?

Administered with antigens to enhance and potentiate the immune system

• Slow release to prolong antigen stimulus

• Attract macrophages

• Increase phagocytosis

• Stimulate lymphocytes

What are oil-in-water emulsions and what is their external phase?

a type of adjuvant; water is the external phase (meaning it interacts with the body)

How does aluminum act as an adjuvant?

Forms aluminum-vaccine complexes that slow down the escape of the antigen from the IM/SC depot → prolongs antigen stimulus (creates effect of multiple micro booster exposures)

What is the formulation of a vaccine?

1. Active components

2. Adjuvants

3. Antibiotics

4. Stabilizers

5. Preservatives

6. Trace components

What are the administration routes of vaccines?

1. SC/IM injection (adjuvants needed for slow release)

2. Intradermal injection

3. Nasal

4. Oral administration

What is in a quadrivalent vaccine?

1. 4 different viral strains

2. Isotonic solution

3. Trace amounts of formaldehyde (inactivating agent) and Triton X-100 (disrupting agent)

4. Thimerosal preservative

Protein drug admin route

Parenteral

Protein drug plasma protein binding

negligible importance

Protein drug Vd

mainly limited to blood volume

Protein drug half life

long (days, weeks)

Protein drug cell-surface receptor interactions

plays a significant role

Protein drug elimination

phagocytosis, endocytosis, proteolysis, renal