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ESC > Site specific delivery > Flashcards

Site specific delivery Flashcards

1
Q

What are the benefits of site specific delivery?

A
  • Optimises interaction of drug with its site of action at the right rate and frequency
  • Reduces s/e of drug used by restricting distribution to target sites
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2
Q

What is the magic bullet concept?

A
  • The idea that a compound could selectively raget a disease-causing organism
  • Agent for selectivity along with the toxin would be delivered to kill only the organism
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3
Q

What are the pharmacokinetic considerations for drug targeting?

A
  • Drugs with high total clearance
  • For response sites with a small blood flow - carrier mediated transport is suitable
  • If a drug is highly eliminated around the body, there is a greater need for targeted drug delivery so a good amount stays in target
  • Drug from the carrier should be restricted to response compartment to maximise targeting effect
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4
Q

What is chronopharmacology and its associated general pathway?

A
  • Target cell responsiveness and influence of polymediator cascades
  1. Precursor cell (partially differentiated)
  2. Primed cell via Mediator 1 (more differentiated)
  3. Effector cell via Mediator 2 (responses to stimulus and effects change)
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5
Q

What is the role of a carrier system in drug delivery?

A
  • To effect a favourable distribution of the drug
  • To protect the drug from metabolism
  • To protect the drug from early clearance
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6
Q

Give an example of a soluble macromolecular carrier

A

Antibodies or ligands with polymers such as Polyethylene glycol (PEG)

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7
Q

Give examples of particle carriers

A
  • Liposomes
  • Micelles
  • Nanoparticles
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8
Q

Factors affecting drug delivery targeted system

A
  • Endothelial lining if the blood circulation
  • Anatomical location of the target (accessibility, blood supply, barriers
  • Macrophages (MPS) mononuclear phagocytic system or Reticuloendothelial system (RES)
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9
Q

What are the types of blood capillaries?

A
  • Continuous capillary as found in general circulation with tight junctions. Subendothelial basement membrane is also continuous
  • Fenestrated capillary (exocrine glands and pancreas). Subendothelial basement membrane is continuous
  • Sinusoid capillary (discontinuous) as found in liver spleen, bone marrow. The endothelium contains various gaps of varying size. The subendothelial basement membrane is absent
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10
Q

Outline the Mononuclear Phagocytic system (also known as the reticuloendothelial system)

A
  • Fixed cells : macrophages in the liver (Kuppfer cells), spleen lung bone marrow and lymph nodes
  • Mobile cells : blood monocytes and tissue macrophages

MPS functions include:

  1. The removal and destruction of bacteria
  2. The removal and destruction of denaturated proteins
  3. Antigen processing and presentation
  4. Storage of inert colloids
  5. Assisting in cellular toxicity
  • Particle size : 0.1-7 µm are cleared by the Kuppfer cells in the liver
  • Particle charge: for liposomes, negative and positive charged vesicles are rapidly cleared. Neutral vesicles remain longer
  • Surface hydrophobicity: Hydrophobic particles are covered by blood proteins opsonins which help phagocytosis
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11
Q

What if the difference between healthy and tumour cells in terms of permeation and retention?

A

Normal blood vessels: tight contacts
between pericytes (P) and
endothelial cells (EC)
P/EC ratio ~ 1/1

Pericytes wrap around endothelial cells that line the capillaries

Tumor blood vessels: loose contacts
between pericytes (P) and
endothelial cells (EC)
P/EC ratio &laquo_space;1/1.

In tumour cells, there is also leaky vasculature resulting in nanoparticle accumulation in interstitial space. In healthy cells, they are retained in the bloodstream.

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12
Q

Outline the Enhanced Permeation and Retention Effect (EPR)

passive targeting

A
  • Rapid vascularization in fast-growing cancerous tissues is known to result in leaky, defective architecture and impaired lymphatic drainage. This structure allows an EPR effect resulting in the accumulation of nanoparticles at the tumor site
  • For such a passive targeting mechanism to work, the size and surface properties of drug delivery nanoparticles must be controlled to avoid uptake by the reticuloendothelial system (RES) (<100 nm).
  • To maximize circulation times and targeting ability, the optimal size should be less than 100 nm in diameter
  • The surface should be hydrophilic to circumvent clearance by macrophages. A hydrophilic surface of the nanoparticles safeguards against plasma protein adsorption and can be achieved through hydrophilic polymer coatings such as PEG.
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13
Q

What is active targeting? Give examples

A

– Surface chemistry allows
functionalization with targeting molecules. Examples include:

  • Antibodies, Herceptin attached to nanoparticles.
  • Folic acid attached to dendrimers
  • Carbohydrates attached to gold nanoparticles.
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14
Q

What do monoclonal antibodies target in cancer treatment and what is its MOA?

A

Targeting:

  • Tumour associated antigens
  • Angiogenic vessel antigens

MOA:

  • induce apoptosis
  • induce cytolysis (disruption of cell)
  • carry a toxic payload of drug/toxin
  • inhibit angiogenesis
  • cause blood coagulation in the angiogenic vessels
  • enhance natural immune responses - cancer vaccine
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15
Q

What is the most common antibody used for antibody-based drugs and drug carriers?

A

IgG

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16
Q

How does BR96- Doxorubicin work?

A
  • Soluble macromolecular Antibody-Drug conjugate
  • Doxorubicin (anthracycline) + BR96 (monoclonal antibody) via hydrazone linker which is pH sensitive
  • conjugate is taken up by
    endocytosis and drug released
    intracellularly
  • Targets carcinoembryonic antigen (Anti-CEA) present on solid tumours
  • Antigen may also be present in the bloodstream so could target y EPR effect
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17
Q

What was the issue with BR96-Doxorubicin?

A
  • Maximum tolerated Dose = 27 mg/m2
  • Poor tumour targeting - dose limiting toxicity was GI tox

• Drug was not released fast enough as the receptor
recycles

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18
Q

What are polymers used for in pharmaceuticals?

A
  • Biomedical materials (safe as implantable material)
  • Pharmaceutical excipients in oral formulations
  • Components of devices
  • In controlled release products
  • Solubilisers in parenteral formulations
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19
Q

Outline a polymer drug conjugate.

Give some examples of drugs that would be good for this delivery

A
  • Natural/synthetic macromolecule attached to a drug via a biodegradeable link, such as amino acid sequence
  • Drug is in a lysosomal enzyme then drug exits lysosome to then act
  • Drugs such as doxorubicin and cistplatin are good as they are low molecular weight and can readily diffuse into cells
  • Cleaved inside the cell via Cathespin B (lysosomal protease)
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20
Q

What is HPMA copolymer-doxorubicin?

A
  • Large molecular weight
  • Doxorubicin content ~ 8%
  • Max dose tolerated is higher than the BR96-doxorubicin
  • Passive targeting
  • Via Gamma camera imaging, it was found that poylmer drug had longer circulation time and doesn’t localise in lung/liver/spleen
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21
Q

Outline the opsonisation of tumour targeting by EPR effect with polymer conjugates

A

I. Selective uptake of the polymer
conjugate by the EPR effect

II. Uptake of polymer conjugates by endocytosis (release of drug intracellularly)

22
Q

How can active targeting be applied to liver cancer?

A

The use of galactose promotes
targeting to the
asialoglycoprotein
receptor in the liver.

It is a target for hepatocytes and hepatoma.

23
Q

What clinically viable targets can you use for tumour targeting?

A
  • The membrane = liposomes
  • The matrix = GRAS polymers, lipids, proteins
  • The solid core = Metals
24
Q

What are the different types of nanoparticles that can be used for drug delivery?

A
  • Biodegradeable polymers
  • Ceramic
  • Polymeric micelles
  • Metals
  • Dendrimers
  • Liposome
  • PRINT (particle replication in non-wetting template)
  • Calcium phosphosilicate
25
Q

What are liposomes used for in nanoparticle drug delivery?

What are the advantages and disadvantages?

A
  • 50-100 nm
  • Carries Chemotherapeutic agents, proteins, DNA
  • Advantages = reduced systemic toxicity and increased circulation time
  • Disadvantages = Leakage of encapsulated product, has a fixed functionality after synthesis
26
Q

What are biodegradeable polymers used for in nanoparticle drug delivery?

What are the advantages and disadvantages?

A
  • 10-100nm
  • Carries Plasmid DNA, proteins, low MW organic compounds
  • Advantages = sustained localised delivery for weeks
  • Disadvantages = Exocytosis of undissolved particles. It has a fixed functionality after synthesis
27
Q

What are polymeric micelles good for in drug delivery?

A

Suitable for water-insoluble drugs due to hydrophobic core

28
Q

What are PRINT nanoparticles?

A
  • Hydrophobic core and hydrophilic outer chains forming coronas
  • Some can be pH and temperature responsive to form an aggregate
  • Its porosity is important as it allows diffusion of particles
  • Size needs to be controlled in order to achieve predictable PK, so that more particles reach tumour
29
Q

All nanoparticles tend to aggregate. What keeps the particles apart?

A

PEG

30
Q

Outline the mechanism of action of Paclitaxel (Taxol), a targeted chemotherapy for metastatic breast cancer

A
  • Taxol has low solubility and Cremaphor can be added as a solvent to help this however this induced toxic side effects
  • Taxol + albumin creates another formulation that is more soluble. It is lipophilic and an aggregate forms and swells from 50-130nm to induce cytotoxicity. Complex is more able to enter into the cell
  • When in the albumin particle, Taxol is a non-crystalline amorphous state
  • Will dissociate into Taxol (concentration dependent)
31
Q

What are liposomes?

A

Double phospholipid membrane, can be filled with drugs

32
Q

What are the 3 main liposomal drug delivery methods?

A
  1. Large multilamellar vesicle:
    - High uptake in liver
    - Poor stability as they are large and will aggregate
    - Vaccines
    - 0.5-10 microns
  2. Small unilamellar vesicles:
    - Sonication (sound frequencies) to make smaller
    - Improved stability but less liver uptake
    - Hydrophilic core
  3. Polymer-coated vesicles (PEGylated)
    - Much more stable and long circulating
    - Stealth liposomes
33
Q

What is an antibody-targeted immunliposome?

A

Antibody covalently coupled to phospholipids or hydrophobically anchored

34
Q

How do you make a liposome long-circulating?

A

Graft it with a protective polymer such as PEG which shields the liposome surface from interaction with opsonin

For a long-circulating immunoliposome, antibody should be attached to the distal end of the grafted polymeric chain

35
Q

What are some new generation liposome compartments?

A
  • Attachment of stimuli-sensitive polymer
  • Incorporation of positively charged lipids allowing for complexation with DNA
  • Attachment of cell-penetrating peptide
36
Q

You can edit ligands for active targeting and take fragments away.

What is an affibody?

A
  • Type of ligand for active targeting

- Alpha helix bundle with binding surfaces

37
Q

Name some examples of nanocarriers employing active targeting strategy

A
  • PEGylated liposomes such as anti-HER2 monocloncal antibody fragments. Targeted liposome will contain doxorubicin
  • Thiolated herceptin liposome containing paclitaxel
  • PEGylated liposomes targeting EGFR with doxorubicin
38
Q

What are the therapeutic benefits of nanoparticles?

A 
• Solubility
– Carrier for hydrophobic entities
• Multifunctional capability
• Active and passive targeting
– Ligands; size exclusion
• Reduced toxicity
39
Q

How can nanoshells treat cancer?

A

Absorbs heat and are taken up by tumour cells

Heat is later emitted (Near-infrared) in the form of hyperthermia which will kill cancer cells and does not harm healthy cells

40
Q

What is the process of nanoparticle cancer treatment with heat?

A
  1. Nanoparticle containing anticancer drug/photosensitiser/imaging agent
  2. Nanoparticles are injected IV. Porous blood vessels at the tumour enhance nanoparticle extravasation into the tumour interstitial space
  3. Hyperthermia is induced through microwaves which facilitates drug release from nanoparticles and facilitates destruction of cancer cells.

Near-infrared light activates photosensitisers producing singlet oxygen which can diffuse into the tumour space

  1. Pores generated in the nanoparticles allow drug to diffuse out of the particle and into the tumour. Photosensitisers can diffuse out of the nanoparticles or a singlet oxygen can be generated within the nanoparticle
  2. Apoptosis and necrosis occur from heat/anticancer drug/generation of reactive oxygen species
41
Q

What is rheumatoid arthritis?

A
  • Rheumatoid Arthritis is a chronic autoimmune disease
  • Joint synovial inflammation
  • Progressive cartilage & bone destruction
  • Activated synovial fibroblast, macrophages and T cells play a major role in RA
  • significant difference between the superficial synovial fibroblast lining and deeper synovial fibroblast lining.
42
Q
  1. What transcription factor seems to be the most important for progression of RA disease and mediating inflammation?
  2. What are its targets?
A
  1. NF-kB

2. Cytokines, IL-1, TNF-a

43
Q

What happens in RA in regards to inflammation?

A
  • TNFa and interleukins provoke inflammation
  • inflammation -> the synovium thickens ->the cartilage and the underlying bone begin to disintegrate and evidence of joint destruction occurs.
44
Q

How do you diagnose RA?

A

Any 4 of these must be present:

Morning stiffness ≥ 1h

Three or more joints involved

Arthritis of hand joints

Symmetric arthritis

Rheumatoid nodules

Radiographic changes (must show erosion/decalcification)

45
Q

What are the treatments for RA?

A
  1. NSAIDs
    Volterol, Vioxx, Celebrex
    (GI ulceration & Bleeding. Not DMARD)
  2. DMARDs
    Methotrexate, Leflunamide, Hydroxychloroquine
    Efficacy (refractory), Safety – Myelosuppression, Hepatic toxicity
  3. BIOLOGICALS
    Infliximab, Adalimumab, (IL-1r)
    Expensive, inconvenient Admin, Partial/Non-responders?,
    Safety – TB, Opportunistic infection
46
Q

What is important in DMARD therapy?

A
  • Must change course of RA over 1 year to decrease inflammation, prevent structural joint damage
47
Q

What DMARDs do you use in early mild RA?

A
  • Hydroxychloroquine which decreases protease function

- Sulfasalazine

48
Q

What DMARDs do you use in moderate-severe RA?

A

Methotrexate which is an antimetabolite and antifolate drug

Combination DMARD therapy is also used e.g. DMARD + Biological

49
Q

What are some biological drugs used in RA?

A
  • TNFa inhibitors
    Infliximab
    Etanercept
    Adalimumab
50
Q

Why is it important to block TNFa in RA?

A
  • Gatekeeper of inflammatory cascade
51
Q

What are side effects of TNF inhibitors?

A
  • TB- TNF is essential for formation of granuloma which sequesters mycobacteria and prevents their spread
  • Skin and soft tissue infections

?malignancy- solid tumours

52
Q

What is the potential for selective drug delivery for RA?

A
  • Glucocorticoids with long-circulating liposomes
  • Prednisolosone and lipsome
  • HPMA dexamethasone
  • EPR effect of inflammed tissues
  • Synovial tissue-specific antigens that could facilitate direction of delivery vehicles to the inflamed joints
  • Albumin coupling with methotrexate

ESC (6 decks)

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