Site Specific Delivery

What are the issues for drug delivery?

Drug not delivered to target, drug may decompose. Need to change route of administration, change physicochemical properties of the drug molecule (modify chemical structure), change formulation

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Why is site specific drug delivery? (1)

To transfer the therapeutic at the right site. To minimise the dose. To minimise unwanted effects by exposure of the therapeutic to healthy tissues

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Why is site specific drug delivery? (2)

Ensure delivery to diseased tissue (or healthy tissue). Need to manufacture therapeutics to reach target more efficiently. Minimise dose (due to dose being related to toxicity)

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What are the benefits of selective drug delivery? (1)

Optimise interaction of drug with its site of action at the right rate and frequency. Reduce S/E of drug used by restricting distribution to the target sites

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What are the benefits of selective drug delivery? (2)

Anti-cancer agents – cardiotoxicity (drug interacts with receptors in the heart), not well tolerated by cancer patients. Improve therapeutic index – reduce S/E, restrict distribution to target site (disease tissue, healthy tissue not exposed)

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State features of the magic bullet

Concept comes from selectively stained tissues for histology for Gram staining bacteria (kill the organism target/disease causing organism)

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Why is there no selected drug targeting for paracetamol?

Goes everywhere in the body, pain can be located anywhere in the body

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What are the PK considerations related to drug targeting? (1)

Drugs with high total clearance are good candidates (drugs remaining in the body for a long period of time – not good candidates, small molecules). Carrier-mediated transport is suitable for response sites with a relatively small blood flow

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What are the PK considerations related to drug targeting? (2)

Tissue – no methods to provide drug via passive diffusion, change molecule to be able to bind to carrier to allow carried mediated transport into cells

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What are the PK considerations related to drug targeting? (3)

The higher rate of elimination of free drug from either central or response compartments the greater the need for targeted drug delivery

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What are the PK considerations related to drug targeting? (4)

If molecule leaves the body via kidneys or blood/metabolised extensively in the liver rapidly – need drug delivery system

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What are the PK considerations related to drug targeting? (5)

To maximise targeting effect, release of the drug from the carrier should be restricted to the response. Selective drug delivery for specific drugs e.g. mAbs for specific receptors, carry drug to correct target/cells

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What are the requirements for specific site delivery? (1)

Understand the biology involved in the disease process. Utilise these processes to obtain selective drug delivery, taking into account the pathophysiology, biochemistry and chronicity (time period) of the disease

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What are the requirements for specific site delivery? (2)

Biology involved in disease process – different stages in disease, expresses different biomarkers/molecules e.g. cancer starts from very few cells, certain profile, cancer develops, start to have a different molecular profile

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What are the requirements for specific site delivery? (3)

Promotion of cancer cells and metastasis, need to know biomarkers at every stage of disease process, use process to determine selective drug delivery

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Improved accessibility is required for which conditions? (1)

Diseases of the CNS, diseases of the immune system, cancerous states, some CVD, arthritic disease

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Improved accessibility is required for which conditions? (2)

Improved accessibility required for particular diseases – e.g. CNS, CVD (atherosclerotic plaque), change in physiology (drugs don’t approach tissue to greater extent), understand and overcome transport mechanism at stages of disease

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What is retention? (1)

If drug delivered intracellularly but has high cellular permeability it can diffuse rapidly away from the site of action

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What is retention? (2)

Retention – intracellular receptors, rapid diffusion but drug moves away from site of action (need to drug to be at site of action for the time period required for effect)

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What are the components of the drug delivery and targeting systems? (1)

The active (therapeutic effect). The carrier system, soluble or particle (to effect a favourable distribution of the drug, protection drug from metabolism/early clearance)

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What are the components of the drug delivery and targeting systems? (2)

Homing mechanism or a homing device (passive/active to specifically target the cells or tissue)

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What are the components of the drug delivery and targeting systems? (3)

E.g. toxic anti-cancer drug, introduce drug in carrier system which would take drug to target, favour cancer drug, protection anti-cancer drug from degradation, protect drug from early clearance e.g. liver and kidneys

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What is the clearance in the kidneys based on?

Clearance in kidneys – via filtration based on size (increase molecular size to prevent excretion, use large/inert functional/hydrophilic group – PEG, conjugation)

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What would happen if a lipophilic drug was used?

Lipophilic group – if used, drug remains in body for a very long time

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What is an alternative method which would avoid the use of a pro-drug/conjugation?

Encapsulate drug, circulate in the body, reach correct target site, nanoparticles, prevent clearance, binds to biomarker/particular receptor – homing mechanism, active target, drug binds to particular receptor

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Give examples of soluble macromolecular carriers

Antibodies or ligands with polymers. Poly(hydroxypropylmethacrylate). Poly(lysine). Polyaspartic acid. Poly (styrene co-maleic acid anhydride). Polyethylene glycol (PEG)

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Give examples of particle carriers

Liposomes. Micelles. Nanoparticles. Microspheres. Proteins. Solid Lipid Nanoparticles. Dendrimers (branched structures)

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What is the limitation of using PEG as a soluble molecular carrier?

Can be in increasing mwt (no standard size). Filtration cut off 40,000 Da (if PEG is above is weight, it will circulated/excreted forever, not filtered, PEG is not degradable/no mechanism to be degraded)

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Which particle carrier is most widely used?

Liposomes (structure of lipid bilayer to encapsulate drug)

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Which factors affect DDTS?

Endothelial lining in blood circulation. Anatomical location of target (accessibility, blood supply, barriers). Macrophages (MPS) mononuclear phagocytic system or reticuloendothelial system (RES)

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What is the route of administration for specific site drug delivery?

IV administration

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Which targets are the most difficult to access?

Tumours in the brain (have a blood-tumour barrier, different characteristics compared to BBB) and pancreas (surrounding of fibrotic tissue surrounding cancer to prevent anti-cancer passing through)

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Describe features of the different tissues in the blood capillary which the drug carrier would encounter (1)

Continuous capillary found in general circulation. Sub-endothelial basement membrane is also continuous. Fenestrated capillary (exocrine glands/pancreas). Fenestrations sealed by membraneous diaphragm. Sub-endothelial basement membrane is continuous

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Describe features of the different tissues in the blood capillary which the drug carrier would encounter (2)

Sinusoid capillary (discontinuous) as found in liver, spleen, bone marrow. Endothelium contains gaps (varied size). Sub-endothelial basement membrane is absent (liver) or fragmented interrupted structure (spleen, bone marrow)

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Describe features of the different tissues in the blood capillary which the drug carrier would encounter (3)

Sinusoid capillary – in liver, spleen and bone marrow, Kupffer cells with gaps in tissue makes clearance of particles easy, larger molecules will pass through gaps, encounter Kupffer cells (part of MPS system

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Describe features of the different tissues in the blood capillary which the drug carrier would encounter (4)

Responsible for breaking down large carriers), initiate degradation – responsible for clearance of drug delivery system

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What are the types of cells in the mononuclear phagocytic system?

Fixed cells (macrophages in liver, Kupffer cells, spleen, lung, bone marrow and lymph nodes). Mobile cells (blood monocytes and tissue macrophages)

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What are the functions of the MPS?

Removal/destruction of bacteria. Removal/destruction of denatured proteins. Antigen processing and presentation. Storage of inert colloids. Assisting in cellular toxicity. Mononuclear phagocytic system (considered in site specific delivery)

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Describe features of MPS particle clearance (1)

Particle size (0.1-7 microns are cleared by Kupffer cells in liver). Particle charge (liposomes +/-ve charged vesicles are rapidly cleared, neutral vesicles remain longer)

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Describe features of MPS particle clearance (2)

Surface hydrophobicity (hydrophobic particles are covered by blood proteins, opsonins which help phagocytosis)

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Describe features of MPS particle clearance (3)

Large hydrophobic molecules – could cause large aggregates in the blood which are cleared by MPS

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Describe features of opsonisation (1)

Large barrier in site specific delivery (need to overcome opsonisation issue) – not a desirable mechanism when designing drug delivery systems

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Describe features of opsonisation (2)

Natural process in the blood, MPS cells/macrophages secrete proteins which adhere onto the surface, adhere better on charged/large particle/hydrophobic surface, proteins have rough specificity, proteins coat/cover foreign carrier

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Describe features of opsonisation (3)

Signalling process, opsonins recognised by MPS cells/macrophages, particle coated on opsonin becomes a target for macrophages, attracts macrophages, results in degradation of particle (phagocytosis – immune mechanism)

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Which design for specific site drug delivery is used to overcome opsonisation? (1)

Drug conjugated to polymer/encapsulated in particle – conjugation of polymer used to minimise the chance of the delivery system being subject to opsonisation (liposome has surface which would be required to attract proteins for opsonisation)

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Which design for specific site drug delivery is used to overcome opsonisation? (2)

Polymer is more flexible

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Which condition is the main target for drug delivery?

Cancer. Need to develop site/target specific drug delivery

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Describe features of the enhanced permeation and retention effect (designed for solid tumours) - 1

In certain types of cancers, blood vessels can be different compared to ones of healthy tissue e.g. breast cancer, blood vessels are leaky (angiogenic blood vessels), when tumour is formed new blood vessels are formed

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Describe features of the enhanced permeation and retention effect (2)

Angiogenic blood vessels formed – different structure (concept which can be used in targeted drug delivery)

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Describe features of the enhanced permeation and retention effect (3)

Normal blood vessels – tight, smooth endothelium, certain ratio of pericytes around blood vessel and endothelial cells (lined with blood vessel), pericytes and basement membrane, cells are tight, endothelial cells have tight junctions

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Describe features of the enhanced permeation and retention effect (4)

Pericytes and basement membrane, cells are tight, endothelial cells have tight junctions, pericytes hold cells together (don’t want content of blood to diffuse everywhere), P/EC ratio ~1

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Describe features of the enhanced permeation and retention effect (5)

Tumour blood vessels – P/EC ratio changes to <<1, pericytes are loosely to attached onto blood vessel/loose structure doesn’t hold blood vessel together, gaps in between, poor structure, (poor blood supply for certain tumours due to gaps)

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Describe features of the enhanced permeation and retention effect (6)

Drugs can leave the bloodstream if attached to the carrier (larger gaps <200 micrometres), drugs can stay in the tumour (tumours have impaired lymphatic drainage)

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Describe features of the enhanced permeation and retention effect (7)

Healthy tissue – lymphatic drainage removes metabolites from blood supply/body. Cancer tissue – uptake increased but lymphatic drainage is decreased

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Describe features of the enhanced permeation and retention effect (8)

Take advantage of increased blood/drug supply – achieved selective drug delivery to tumour, drug remains there for longer. Larger carrier – more retained in the tumour.

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Describe features of the enhanced permeation and retention effect (9)

Change size – increase circulation time, more chance of drug carrier to get trapped by tumour blood vessel via enhanced permeation and retention effect

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What are the three aims of targeted drug delivery to cancer?

Increase circulation time. Enhance uptake in cancer. Enhance specificity

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How does a drug get taken up into a tumour?

Drug enters interstitial tissue of tumour (surrounds the cancer cells)

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How does a drug get taken up into cancer cells? (1)

Uptake from cancer cells – express receptors on surface, drug interacts with receptors on cancer cell surface, encourage drug to be endocytosed into cancer cell via active transport

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How does a drug get taken up into cancer cells? (2)

(induce receptor mediated endocytosis – cancer cell engulfs drug, drug in endosome, drug remains inside cancer cell), make drugs available inside cell when reaching the interstitial space. Liposomes/endosomes – degradation enzymes

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State features of specific site delivery and the enhanced permeation and retention effect (1)

Rapid vascularisation in fast growing cancerous tissues results in leaky, defective structure with impaired lymphatic drainage. Structure allows EPR effect, leads to accumulation of nanoparticles in tumour site

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State features of specific site delivery and the enhanced permeation and retention effect (2)

For a passive targeting mechanism to work, the size/surface properties of drug delivery nanoparticles must be controlled to avoid uptake by RES

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State features of specific site delivery and the enhanced permeation and retention effect (3)

To maximise circulation time/targeting ability, optimal size should be <100 nm in diameter with hydrophilic surface to prevent clearance via macrophages. Hydrophilic surface provides protection against plasma protein adsorption (achieved using PEG)

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State features of specific site delivery and the enhanced permeation and retention effect (4)

Particle size <100 nm in diameter and hydrophilic surface – size to avoid clearance via macrophages, plasma protein absorption. Hydrophilic surface achieved using PEG

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Describe features of nanoparticle kinetics (1)

PEG – used to improve circulation of liposomes, increased circulation in tumours via enhanced permeating/retention effect. Sarcoma – affected patients with HIV (co-morbidity). Doxorubicin – approved as anti-cancer agent but had very strong adverse

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Describe features of nanoparticle kinetics (2)

Aim to improve doxorubicin, protection from cardiac tissue • Use lipid bilayer structures to encapsulate doxorubicin (issue - lipophilic, particle size, subject to CL/macrophage uptake, liposomes cleared rapidly, not helping doxorubicin to act)

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Describe features of nanoparticle kinetics (3)

Introduction of PEG on the surface on the liposomes, coupled to lipids, forms a hydrophilic surface – no chance for opsonins to adhere to liposomes (not able to recognise surface anymore)

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Describe features of nanoparticle kinetics (4)

Pegylated liposomes – 30 min half-life with doxorubicin alone (liposome half-life of 4 hours) changed to 55 hours (enhance circulation, increase chance of uptake into target site)

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Describe features of nanoparticle kinetics (5)

First injection – initially a large uptake by organs (drug remains in blood compartment, in organs with high blood supply), 24 hours (drug accumulation/increased drug uptake in the sarcomas)

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Describe features of nanoparticle kinetics (6)

Due to leaky blood vessels/impaired lymphatic drainage, drug trapped in tumours, 48 hours (drug remains in liver and spleen but drug in sarcoma remains, improved distribution in tumours, selectively send drug to tumours

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Describe features of nanoparticle kinetics (7)

Improves efficacy and avoiding exposure to the heart). Pegylated liposomes provided high drug concentration at the correct site • Doesn’t affect cardiac tissue due to particles protecting doxorubicin

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Describe features of nanoparticle kinetics (8)

Less/little exposure of doxorubicin to cardiac tissue. Excretion of PEG (<2000 mwt), liposomes are flexible structures, can pass through membranes

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What is passive targeting?

EPR. Targeting of RES cancers. Size/surface chemistry. Particles trapped in tumours due to size, take advantage of targeting tumours in the liver

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What is active targeting?

Surface chemistry allows functionalisation with targeting molecules. Antibodies, herceptin attached to nanoparticles. Folic acid attached to dendrimers. Carbohydrates attached to gold nanoparticles. Target specific tumours

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Describe the difference between the biodistribution of a drug and the biodistribution of nanoparticles

Biodistribution of drug – large Vd, small molecules, diffuse every, unlikely to remain in blood compartment. Nanoparticles – trapped by liver, kidneys, bone marrow, lungs, can modify size/surface to go to specific organs (or pass BBB -> brain)

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Describe features of soluble macromolecular carriers - monoclonal antibodies for the treatment of cancer (1)

Targeting-recognise tumour associated antigens or angiogenic vessel antigens. MOA - induce apoptosis, induce cytolysis, carry toxic payload of drug/toxin, inhibit angiogenesis, cause blood coagulation in angiogenic vessels

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Describe features of soluble macromolecular carriers - monoclonal antibodies for the treatment of cancer (2)

Enhance natural immune responses - cancer vaccine. Couple mAbs with drug – antibody drug conjugates (specific targeting for cancer) – limited drug carrier capacity but not taken up by Kupffer cells, small carrier payload, can be therapeutics

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Describe features of soluble macromolecular carriers - monoclonal antibodies for the treatment of cancer (3)

Difficult to label mAbs for MRI – requires large change in structure. Novel immunotherapies

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Describe features of soluble macromolecular carriers - polymer-drug conjugates (1)

Polymers used in biomedical materials (scale up manufacture proven, safety implantable materials known). Pharmacy - pharmaceutical excipients (oral formulations), components of devices/CR products, solubilisers in parenteral formulations

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Describe features of soluble macromolecular carriers - polymer-drug conjugates (2)

Polymer drug conjugates – introduced to take advantage of enhanced permeation and retention effect. Polymer-drug conjugates – tested for specific site delivery for cancer therapies, can couple number of molecules with polymer

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Describe features of polymer-drug conjugates for lysosomotropic delivery for doxorubicin or cisplatin (1)

(Low wt chemotherapy readily diffuses into cells). Polymer-drug conjugate, targeting group, biodegradable spacer

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Describe features of polymer-drug conjugates for lysosomotropic delivery for doxorubicin or cisplatin (2)

Permeates membranes easily, best diffusing drug for cancer therapy, selective (diffusion into cancer cells)

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Describe features of polymer-drug conjugates for lysosomotropic delivery for doxorubicin or cisplatin (3)

Drug coupled with polymer – polymer-drug endocytosed, moves into lysosome (in cancer cells, has different enzymes compared to healthy cells, in lysosomes of cancer cells, cathepsin B breaks down biodegradable spacer, release of drug in cancer cell)

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Describe features of polymer-drug conjugates for lysosomotropic delivery for doxorubicin or cisplatin (4)

Amino acid link with drug (e.g. doxorubicin) – stable in circulation/not broken down, but in cancer cells, lysosomal protease releases drug from linker. Drug released where drug needs to be – in cancer cell

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State features of HPMA co-polymer-doxorubicin

HPMA co-polymer doxorubicin mwt ~ 30,000 – ensure clearance without damaging tissues. Slow blood clearance (graph)

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State features of active targeting (1)

Liver selective delivery for treatment of primary and secondary liver cancer. Active targeting – bind to receptors of e.g. liver tumours, have liver specific uptake of drug

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State features of active targeting (2)

Galactose promotes targeting to asialoglycoprotein receptor in the liver. Designed for receptor-mediated targeting of liver hepatocytes and hepatoma

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What are the clinically viable particles for tumour targeting?

Membranes (liposomes - most advanced). Matris (GRAS polymers, lipids, proteins, least advanced). Solid core (metals, useful for imaging, better detection, very small). (Surface on all particles, universal symbol for PEG, all particles require PEG)

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Describe features of Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel (1)

Paclitaxel has issue with being delivered to target. Hydrophobic drug administered via IV with castor oil/toxic due to not being dissolved in anything

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Describe features of Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel (2)

Paclitaxel encapsulated – one albumin protein surrounds one molecule of paclitaxel, becomes hydrophilic, designed properties of drug release, aims to minimise exposure of free paclitaxel to healthy tissue, paclitaxel and albumin has 1:1 association

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Describe features of Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel (3)

Nanospheres, cremophor free (strong surfactant used in paclitaxel and castor oil in IV formulation)

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Describe features of Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel (4)

Nanoparticle dissociate, released to tumour, albumin receptors on cancer cells interact with albumin carrying paclitaxel, able to place paclitaxel inside cancer cells, small units release from larger unit whilst in circulation

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Describe features of Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel (5)

(bigger formulation decomposes into smaller formulations which reaches to tumour – large reduction in tumour volume)

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State features of liposomes (1)

Large multilamellar vesicles (0.1-10 microns, high uptake in liver, poor stability, large liposomes used in vaccines). Small unilamellar vesicles (80-100 nm, sonication to make smaller, improved stability, less liver uptake)

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State features of liposomes (2)

PEGlyated stealth liposomes (much more stable and long circulation)

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State features of liposomes (3)

Liposomes mimic cell membranes – phospholipid bilayer. PEGylated liposomes – targeting therapy

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Describe features of the types of liposomes (1)

Liposomes with water soluble drug (hydrophilic) incorporated into core. Hydrophobic drug incorporated into bilayer (association).

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Describe features of the types of liposomes (2)

Long-circulating liposome grafted with a protective polymer such as PEG, which shields the liposome surface from the interaction with opsonins. Immunoliposome. Large structures incorporated into liposome e.g. DNA. RNA

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Describe features of the types of liposomes (3)

Liposomes – alternative to gene therapy. PEG on surface of liposomes. Liposome changes due to triggers (e.g. make liposome release drug, or remove PEG), responsive

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Describe features of DaunoXome - first line therapy for HIV associated Kaposi's sarcoma (1)

First liposome introduced, half-life increased. Nanoparticle carriers for use in cancer – based on the concept of enhanced permeation/retention effect for tumours.

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Describe features of DaunoXome - first line therapy for HIV associated Kaposi's sarcoma (2)

Dendrimers – branched structure (in clinical trials)

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Describe features of DaunoXome - first line therapy for HIV associated Kaposi's sarcoma (3)

Clinical dose = 40mg/m2 by infusion over 60 min every 2 weeks. Diluted 1:1 with dextrose before use. Half life of ~ 4h

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Describe features of Doxil - second line therapy for HIV associated Kaposi's sarcoma (1)

Stealth liposome. 10-20 mg/m2 every 3 weeks by 30 min infusion. Limited to max cumulative dose of 550 mg/m2. (Nanobased carriers for cancer detection/therapy)

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What are the therapeutic benefits of nanoparticles? (1)

Increased solubility/stability/specificity/efficacy, reduced toxicity. Solubility - carrier for hydrophobic entities. Multifunctional capability. Active/passive targeting - ligands, size exclusion

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What are the therapeutic benefits of nanoparticles? (2)

Need to use chemical methods to degrade nanoparticle – consider pH (humoral pH lower than normal pH), enzyme activity, (diagram for activation from circulation to tumoral EC matrix via weak pH and enzyme activity)

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Describe the use of nanotheranostics and image guided drug delivery (1)

Nanoparticle containing anticancer drug/photosensitiser/imaging agent. Nanoparticles injected via IV. Porous blood vessels at tumour enhance nanoparticle extravasation into tumour interstitial space

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Describe the use of nanotheranostics and image guided drug delivery (2)

Hyperthermia induced through PF, MW or HIFU, destroying cancer cells and facilitating drug release from nanoparticles. NIR light activates photo-sensitisers producing singlet oxygen

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Describe the use of nanotheranostics and image guided drug delivery (3)

Fractures/pores generated in nanoparticles allow drug to be released into tumour/diffuse out into tumour space. Apoptosis/necrosis occur from heat, anticancer drugs and generation of ROS

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Describe the use of nanotheranostics and image guided drug delivery (4)

Imaging, induced hyperthermia on one side on tumour, breaks out tumour, use nanoparticles/liposomes to target delivery, increase in temperature, trigger full release of drug in short time period - image guided drug delivery

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Describe the use of nanotheranostics and image guided drug delivery (5)

Nanodevices - link between detection, diagnosis, treatment (more efficient than DaunoXome and Doxorubicin)

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Site Specific Delivery

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