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Biopharmaceutical Technology > Drug targeting and nanotechnology 2 + 3 > Flashcards

Drug targeting and nanotechnology 2 + 3 Flashcards

1
Q

What are micelles? How are drugs formulated as micelles?

A

Micelles are single-layer spheres made of amphiphilic polymers (both hydrophilic and hydrophobic)

  • Drug solubilised in hydrophobic micelle core
  • Drug covalently linked to hydrophobic portion of polymer chain
  • Polmeric micelle carrying antiboides attached to hydrophilic portion of polymer molecule
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2
Q

For micellar drug carriers;

A) What size are they? What may they penetrate?

B) What type of systems are they?

C) How can drugs enter and be released

A

A)

  • Polymeric micelles are commonly of the order of 50 - 150 nm
  • Therefore, may be able to penetrate the sinusoidal and fenestrated capillaries

B)

  • Polymeric micelles are self-assembled systems which are easy to prepare
  • Very versatile and allows for chemical modification of the surface.

C)

  • Drugs can be physically entrapped in the core or chemically bond to copolymer
  • Drug is released by diffusion or enzymatic cleavage

> Specific targeting ligands can be attached to the surface of polymeric micelles

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3
Q

For Dendrimers;

A) What are they?

B) What are they synthesised from? What can the terminal groups modified to?

C) What does every additional generation produce?

D) What is a positive aspect of them?

A

A)

  • Dendrimer are synthetic nanoscale polymer structures (1-100 nm) with regular and highly branched three dimensional architecture (quasispherical shape)

B)

  • Dendrimers are synthesised from core molecules with the branches similarly constructed from bi-functional molecules
  • The terminal groups can be modified chemically to achieve charged, hydrophilic, or hydrophobic surfaces

C)

  • Every additional generation produces a doubling in the number of surface groups, with accompanying potential for carrying drugs, antibodies or markers

D)

  • Dendrimers promise great versatility as drug delivery systems-as carriers and as agents themselves
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4
Q

What makes up the structure of dendrimers?

A
  • Core –> samll molecule, nanoparticles, polymer
  • Void space –> space for molecular cargo
  • Surface groups –> cationic, anionic, neutral
  • Branching –> robust covalent structure, connects core to the surface

generations: G0, G1, G2, G3, G4

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5
Q

What do dendrimers have the ability to form?

A

Dendrimers have the ability to form a variety of supramolecular arrays, some in response to external stimuli because of their unique features.

  • They can be used as building blocks for supermoleucular structures
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6
Q

What are the advantages of the dendrimer DEP docetaxel?

A
  1. Improved tumour targeting
  2. Significantly improved efficacy in a breast cancer model
  3. Extended half-life
  4. Water-soluble formulation (removing the need for certain toxic excipients).
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7
Q

What is the size of colloidal systems as drug carriers?

A

between 0.02 micron (um) to 100 micron (um)

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8
Q

What are colloidal carriers used for? Provide FOUR reasons.

A
  1. Protection of incorporated drug
  2. As a vehicle for drug with poor solubility, eg lipophilic drugs
  3. Drug targeting
  4. Altering pharmacokinetic profiles of drug in order to reduce toxicity and increase the therapeutic index of the drug
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9
Q

What are the types of colloidal carriers?

A
  • Liposomes

Stealth Liposome, Passive Targeting, Active Targeting

  • Nanoparticles
  • Microparticles
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10
Q

What is the structure of liposomes? Where are aqueous and lipid drugs carried?

A
  • Small vesicles (30nm-10μm) - bilayer of phospholipid surrounding aqueous compartment
  • Can be single or multi-layered

> Aqueous drugs may be carried in aqueous compartment

> Lipid drugs may be carried within the bilayer membrane

biodegradable and non-toxic

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11
Q

What is a typical phospholipid used in the preparation of liposomes? What is the structure?

A

distearoylphosphatidylcho line ( DSPC)

  • A: phosphatidylcholine, hydrophilic head group
  • B: glycerol bridge
  • C: steric acid chains, hydrophobic tail
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12
Q

What happens to liposomes in the blood circulation (in vivo)?

A
  • Liposomes become HDL then destroyed
  • Liposomes get opsonised (IgG) –> then uptaken by the mononuclear phagocyte system (MPS)
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13
Q

What are the interactions of liposomes with cells?

A
  1. fusion of liposomes with the cell membrane.
  2. endocytosis of liposomes by cells.
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14
Q

Provide an example of the concept of PEG-ylated/stealth liposomes.

A

Grafting hydrophilic flexible polymer such as polyethylene glycol (Mw 1000-5000) groups to the lipid bilayer of liposomes can prolong the circulation of liposomes in blood by reducing the ability of MPS to detect and clear the liposomes.

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15
Q

What is doxil?

A

Doxorubicin HCL –> pegylated stealth liposome

much longer half life than injection of the same form

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16
Q

What is passive targeting (liposome)

A

Passive targeting utilises the natural distribution pattern of a drug delivery system in vivo

17
Q

What is a example of passive targeting in antifungal therapy (liposome)

A

Uptake of liposomes by mononuclear phagocyte system (MPS) is used to selectively deliver amphotericin B to liver and spleen, the main sites of systemic fungal infection.

18
Q

Targeting of anticancer drug to tumour tissues is achieved by? (passive targeting in cancer chemotherapy –> liposomes) Provide THREE answers.

A
  1. enhanced permeability and retention ( EPR) effect
  2. phagocytosis of liposomes
  3. prolonged circulation time

examples: doxorubicin liposomes (Doxil®) and daunorubicin liposomes ( DaunoXome®)

19
Q

What is the extravasation of nanocarriers (eg 100 nm liposomes) from tumour vasculature affected by? What is the proposed mechanism?

A

Affected by hyperthermia (HT)

  • The effect is temperature dependent
  • The process is reversible
  • Reheating did not result in any increased extravasation of liposomes, suggesting thermotolerance can be developed

proposed mechaninsm: HT affects the endothelial cytoskeletal structure, leading to increased gaps between endothelia cells

20
Q

What are the different ways antibodies are located on the liposomes? (active targeting –> immunoliposomes)

A
  • Antibodies on surface –> PEG shielding
  • Antibodies on PEG chains
  • Antibodies on surface –> non-stealth
21
Q

What are the different pathways for immunoliposomes to the appropriate target cell? (active targeting)

A
  • Uptake in liver and spleen macrophages –> subsequent drug release
  • Release of drug close to the target cell
  • Release of drug close to target cell; external triggering of release
  • fusion with target cell; subsequent drug release
22
Q

What are the advantage of using liposome as a drug carrier?

A
  • Biodegradable
  • Biologically inert
  • Versatile: for both hydrophilic and hydrophobic drugs
  • Protecting entrapped drug
  • Reduce local & systemic toxicity.
  • Drug targeting by both passive and active methods
  • Prolonging biological half-life of encapsulated drug.
23
Q

What are the major disadvantages of liposomes as a drug carrier?

A
  • Stability problems ( in vitro and in vivo, lipid stability and drug leakage from vesicles)
  • Rapid clearance by MPS (mononuclear phagocyte system)
  • low drug loading
  • Relatively poorly controlled release of drug
24
Q

What are the examples of commercial liposome products?

A
  • AmBisome® ( Amphotericin B) –lyophilized powder
  • DepotCyte® (Cytarabine) –Multivesicular Lipid particles
  • DaunoXome® (Daunorubicin) Liposomal dispersion
  • Doxil® ( oxorubicin) - Pegylated stealth liposome product
25
Q

What are some precautions/notes on dispensing liposomes? Provide FOUR answers.

A
  1. Follow the instruction in product insert. eg Ambisome requires that the product is reconstituted with WFI prior to be diluted using 5% glucose
  2. Not to be admixed with NaCl or other electrolytes or any other diluent or preservative-containing solution unless it is specified OK in the product insert
  3. Store admixtures in a refrigerator (2-80C) and use within 24 hours. Do not freeze
  4. An in-line filter should NOT be used for the intravenous infusion
26
Q

What are nanoparticles and microparticles? What is their size? How are they formulated?

A

They are solid particles prepared from either natural or synthetic polymers

  • Size of nanoparticles: 10-1000nm
  • Size of microparticles: 0.5-1000µm diameter in size

> monolithic – micro/nanospheres (A) –> dispersed drug molecules in solution or solid form

> capsular – micro/nanocapsules (B) –> drug solution or suspension

27
Q

What are factors which can influence the performance of particulate drug delivery systems (in terms of properties of carriers)?

A
  • size of particles
  • surface characteristics of particles
  • biodegradability and biocompatibility
  • drug release profile and drug loading required
  • desirable interaction between matrix materials and drugs.
  • interaction between the carrier and targets
28
Q

What are the three factors which can influence the performance of particulate drug delivery systems? (in terms of pathological conditions and external stimuli) GIve examples.

A
  1. Pathological nature and conditions
    * eg, in cancer therapy, heterogeneous nature of tumours in vascularisation, blood flow & lymphatic drainage; not all tumour have EPR effect, bulk tumour has EPR effect but not metastasised/invasive cancer cells; brain tumours isolated and their access is restricted by the blood-brain barrier
  2. Active targeting with specific targeting ligands which can recognize and bind to the receptors that are upregulated in diseased conditions
  • peptide RGD binds integrin receptors upregulated in tumour neovasculature
  • RGD also has tumour penetrating properties after proteolytically cleaved in the tumour
  1. Influence of external stimuli
    * temperature (application of hyperthermia), magnetic field, ultrasound, light
29
Q

What is effect of particle size on passive targeting by nano and microparticles? What can a selective IA injection target?

A

Particle size is important determinant of disposition of particle in body

  • After IV injection the first capillary bed encountered is that of the lung
  • Selective IA injection can target a particular capillary bed

particle diameter greater than 12 um, for accumulation in the lung by capillary embolism

30
Q

Where do drugs get deposited for the following particle diameter after systemic administration (IV) by nano and microparticles? passive targeting

A) < 0.05 um

B) 0.1-2.0 um

C) 2.0-12 um

D) >12 um

A

A)

  • Liver, spleen, bone marrow and tumours in these organs

> extravasation via porous blood vessels

B)

  • Liver, spleen & bone marrow

> phagocytic uptake by MPS

C)

  • Lung ( >7µm), liver and spleen

> 7um capillary embolisation

D)

  • accumulation in lung

> capillary embolisation

31
Q

What are examples of embolisation?

A
  • Microparticle embolisation following intraarterial administration
  • Chemo-embolisation –> injection of drug bearing microparticles/microspherees (>10µm) for in situ release via selective arterial catheterisation
32
Q

Tumour blood vessels unresponsive to a vasoconstrictor. Normal blood vessels will constrict after IA administration and drug can be diverted to tumour. What is used?

A

Passive targeting of microparticles –> co-administration of microspheres (IA) after using angiotensin II –> just in the tumour sites

  • 2nd Order targeting to liver tumours.
33
Q

How is the active targeting of nano and microparticles achieved? Specify if microparticles or nanoparticles.

A
  1. attachment of antibodies or cell specific ligands on the surface of nanoparticles (NP)

> with or without steric stabilisation (eg stealth nanoparticle)

  1. Magnetically controlled drug targeting ( NP & MP)

> The movement of particles, which contain ferromagnetic materials such as Fe3O4, can be controlled by an external applied magnetic field to retain the carrier/particles at the target site.

> Only suitable for accessible tumours with well defined blood supply

34
Q

Nano- and Microparticles offer the potential of sustained release of drugs. Sustained drug release may reduce toxicity to normal tissue. What characteristics affect the sustained release system? What do the release mechanisms include?

A
  • Size
  • Type of Matrix material/wall
  • Stability of particles
  • drug loading
  • Drug binding mechanisms & localisation

Release mechanisms include

  • Dissolution, diffusion and de-sorption
  • Ion-exchange
  • Erosion or enzymatic degradation of matrix materials (dissolution and erosion)
35
Q

What is an example of the first commercial nanoparticle delivery system? What are the benefits?

A

Abraxane® for Breast cancer treatment

  • Abraxane™(paclitaxel protein-bound particles for injectable suspension) is an albumin bound form of paclitaxel nanoparticles with mean size of 130 nm
  • 50mL vial containing 100mg paclitaxel and 900mg of albumin
  • 1st –solvent free paclitaxel formulation

Benefits

  • Shortened infusion time (30 minutes).
  • No special IV equipment needed.
  • No need for premedication for hypersensitivity reactions.
36
Q

What are the features of micro and nano-particulate carriers?

A
  • In vivo distribution of the systems is non-uniform, size and targeting ligand-dependent.
  • extravasation of systems from the circulation is limited to particles with size < 150 nm
  • The systems, if no specific targeting ligands, can only be taken up by the phagocytic cells
  • Microparticle with size > 10 µm can be used for chemoembolisation
  • Systems can be prepared from a variety of materials however, their drug loading can be limited, better for potent drugs.
  • They can protect drugs from chemical and enzymatic degradation and systems can provide sustained-release of drug
  • Their potential toxicity must not be overlooked

Biopharmaceutical Technology (16 decks)

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