Drug_Carriers_and_Targeting_One

Drug Carriers and Drug Targeting1N.RAJU : 

Drug Carriers and Drug Targeting1N.RAJU

Outline : 

Outline Terminology of drug delivery and targeting Drug targeting systems Polymer-drug conjugates (Directed Study) Poly(N-(2-hydroxypropyl)methacrylamide) (HPMA) Particulate carrier systems Liposomes Polymeric micelles Protein nanoparticles Lipoprotein carriers

Terminology of drug delivery and targeting : 

Terminology of drug delivery and targeting Modified release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time Zero-order release: the drug release does not vary with time. The delivery system maintains a relatively constant & effective drug level in the body for prolonged periods, e.g. Zoladex®. Targeted drug delivery: the system achieves site specific drug delivery. Controls the fate of the drug.

Targeted drug delivery : 

Drug targeting systems are used to achieve site- specific drug delivery Targeted drug delivery Tumour Tumour Conventional formulation Targeted drug delivery

Targeted drug delivery : 

Targeted drug delivery Site-specific drug delivery is desirable in therapeutics, in order to improve: - drug safety => reduce side effects - drug efficacy => improved effect with lower dose - patient compliance. Conventional dosage forms – achieve site specific delivery by the local administration of the therapeutic compounds, i.e. topical creams. However this can still lead to systemic uptake => side effects. Sophisticated oral drug targeting systems – achieve site specific delivery within GI tract, e.g. gastro-resistant tablets or prodrugs M/R local delivery, e.g. Gliadel® – biodegradable wafers implanted in brain Most advanced drug targeting systems – parenteral route => target site in body and accumulate there via circulation.

The 3 levels of drug targeting : 

The 3 levels of drug targeting First level to the organ, e.g. liver. Second level to the particular type of tissue within the organ, tumour. Third level selective uptake by the diseased cell, e.g. specific tumour cells. Also target invading organism/foreign body, e.g. HIV The higher the level the more efficacious, however more complicated to achieve. 1st level - Liver

Targeting : 

Targeting Two main types: Active and Passive Passive targeting – where physicochemical properties determine the fate, e.g. trapping of ‘large’ particles in lung capillaries (5-6 μm), Enhanced Permeability and Retention (EPR) effect for passive tumour targeting. Likely to only be level one or two.

EPR Effect : 

EPR Effect

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Active targeting – where receptor interactions are involved in the targeting, i.e. ligand or antibody directed drug targeting, e.g. use over expression of folate receptors on tumour cells to facilitate specific uptake. Level three targeting However more difficult to achieve due to additional synthesis and purification due to attachment of ligands.

Active Targeting : 

Active Targeting

Active and Passive : 

Active and Passive

Characteristics of an ideal drug targeting system (DTS) : 

Characteristics of an ideal drug targeting system (DTS) Able to protect the drug and does not release the drug before reaching the target site. No non-specific biological interactions. Restricts biodistribution of the drug to the desired target tissue. Restricts the drug’s activity to the target site over a controlled period. Has high drug loading capacity. Biocompatible. Capable of pharmaceutical production.

General Advantages and Limitations and Considerations for DTS : 

General Advantages and Limitations and Considerations for DTS Advantages: Use of DTS increases drug MWt => reduces first pass and kidney clearance => increased circulation time => longer acting more effective treatment.

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Limitations: DTS may not be able to partition across endothelium of vascular system as easily as drug alone due to large MWt. Difficult to get DTS into target site cf drug which can partition across cell layers passively/actively. Therefore most suitable for sites with gaps in endothelium, e.g. liver, inflamed/tumour sites. Also more likely to be detected by immune system than drug alone => eliminated as foreign body. Therefore produced so that surface hydrophilic and < 100 nm size. However immune system uptake can be used to facilitate drug delivery (later).

DTS : 

DTS Prodrugs – chemically modify drug (covered elsewhere) Carrier systems: alter drug biodistribution (uptake and elimination) Polymer-drug conjugates (Directed Study) Drug encapsulated within particulate carrier

Particulate Carriers : 

Particulate Carriers 1pm (picometre) = 1x10-12 m (metre) 1nm (nanometre) = 1x10-9 m (metre) 1 µm (micrometre) = 1x10-6 m (metre)

Particulate Carrier Systems : 

Liposomes Conventional ‘Stealth’ Polymeric Micelles Protein Nanoparticles Lipoproteins Particulate Carrier Systems

1A. Conventional Liposomes : 

Passive targeting possible. However drug release may be more likely due to interaction with immune system, i.e. may not target release at all, but may produce controlled release (later). Vesicular structures based on one (unilamellar) or more (multilamellar) lipid bilayers encapsulating an aqueous core. Lipid molecules are usually phospholipids (which are amphiphilic - a hydrophilic head group and two hydrophobic chains). Diameter of the vesicles can vary between 10 nm - 3 µm. 1A. Conventional Liposomes

Conventional Liposome : 

Conventional Liposome

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Depending on the physicochemical properties of the drug, it can either be: Encapsulated in the aqueous phase (hydrophilic drugs). Interact with the bilayer (electrostatic interaction – DNA/peptide/protein). Taken up in the bilayer structure (lipophilic drugs). Serve as carriers for a wide variety of drugs including antitumour and antimicrobial agents, peptides, proteins & DNA. About 8 commercially available including: AmBisome® (hydrophobic - amphotericin B), DaunoXome® (hydrophilic - doxorubicin)

Advantages & Disadvantages of Conventional Liposomes vs. Traditional I/V drug treatments : 

Advantages & Disadvantages of Conventional Liposomes vs. Traditional I/V drug treatments

1B. ‘Stealth’ Liposome : 

1B. ‘Stealth’ Liposome

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Two types: 1. Long circulating liposomes Covalently attach the hydrophilic polymer (polyethylene glycol (PEG)) to the liposome bilayers. Highly hydrated PEG groups create a steric barrier against interaction with molecular and cellular components, i.e. prevent immune system uptake. Therefore much more likely to achieve passive targeting compared to conventional. 2. Immunoliposomes Specific antibodies or antibody fragments on the surface of liposomes enhance target site binding. Active targeting of anticancer agents.

Conventional vs ‘Stealth’Doxorubicin in breast cancer : 

Conventional vs ‘Stealth’Doxorubicin in breast cancer Conventional: Myocet® (Liposomes with size ~180 nm) MOA – Rapidly taken up by immune system: Taken up by macrophages which then fuse with lysosomes – liposomes broken down by enzymes – C/R of Doxorubicin similar to I/V infusion. Dosing of 60-75 mg/m2 every 3 weeks (First line in metastatic breast cancer). Stealth: Caelyx®/Doxil® (PEGylated liposomes of < 100 nm) MOA – Tumour accumulation due to EPR effect Dosing of 20-50 mg/m2 every 3-4 weeks (Advanced breast cancer).