Instructor: Dr. Marinella Sandros

1. Nanochemistry NAN 601 Instructor: Dr. MarinellaSandros Lecture 24: Drug Delivery Systems

2. Methods of Drug Delivery • Oral Delivery • Inhalation • Transdermal http://www.slimmingpillsreview.com/wpcontent/uploads/2008/08/energy-pill.jpg http://weblogs.fox61.com/features/family/mommy-minute/Child_using_inhaler.jpg http://www.wellsprings-health.com/images/articles/transdermal-cream.jpg

3. Methods of Drug Delivery • Implantation • Injection http://www.medgadget.com/archives/img/hydron_sm.jpg http://portfolio.flashwebmaster.com/graphics/graphics_illustrations_medical_injection_3.gif

4. Current Problems in Drug Delivery • High initial release (burst) • Loss of bioactivity • Delivery to incorrect sites

5. Nanomedicine • The term Nanomedicine refers to the application of nanotechnology to diagnosis and treatment of diseases. • It deals with the intercations of nanomaterials (surfaces, particles, etc.) or analytical nanodevices with “living” human material (cells, tissue, body fluids) • It is an extremely large field ranging from in vivo and in vitro diagnostics to therapy including targeted delivery and regenerative medicine. www.certh.gr/dat/E2353434/file.pdf

6. Using Nanoscience to make Drugs Soluble • Up to 50% of existing drugs are classified as `Poorly-water soluble` or `in soluble` • Thus, Bioavailability is very poor. pharm.swu.ac.th/web_npec/content/JOURNAL/j_club.pdf

7. Nanocarriers for Drugs • Safe • Non-toxic, non-immunogenic, non-inflammatory • Biodegradable and/or biocompatible • Degradation products readily eliminated from body or used by the body. • Ideally , excipients have GRAS designation by the FDA • Compatible with drug • Compatible with cells and tissues No platelet aggregation, RBC lysis, neutrophil activation, etc. • Manufacturing: ease and low cost • Stable *Gras: Generally Regarded as Safe.

8. Nanocarriers in DDS • Exhibit higher intracellular uptake • Can penetrate the submucosal layers while the microcarriers are predominantly localized on the epithelial lining. • Can be administered into systemic circulation without the problems of particle aggregation or blockage of fine blood capillaries. • The development of targeted delivery is firmly built on extensive experience in pharmaco-chemistry, pharmacology, toxicology, and nowadays is being pursued as a multi- and interdisciplinary effort. www.certh.gr/dat/E2353434/file.pdf

9. Challenges in DDS • Prevention of drug from biological degradation • Effective Targeting • Patient Compliance • Cost effectiveness • Product life extension www.photonics.com/Article.aspx?AID=45177 api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

10. Selected Nanocarriers ☛Dendrimers ☛Liposomes ☛Micelles

11. Courtesy of: http://www.uea.ac.uk/cap/wmcc/anc.htm Dendrimers: What are They? • Tree-like polymers, branching out from a central core and subdividing into hierarchical branching units - Not more that 15 nm in size, Mol. Wt very high - Very dense surface surrounding a relatively hollow core (vs. the linear structure in traditional polymers) • Dendrimers consist of series of chemical shells built on a small core molecule - Surface may consist of acids or amines  means to attach functional groups  control/modify properties - Each shell is called a generation (G0, G1, G2….) - Branch density increases with each generation - Contains cavities and channels  can be used to trap guest molecules for various applications.

12. Dendrimer Platform

13. Dendrimers • Dendrimers have a high degree of molecular uniformity, narrow molecular weight distribution, specific size and shape characteristics, and a highly- functionalized terminal surface. • The manufacturing process is a series of repetitive steps starting with a central initiator core. Each subsequent growth step represents a new "generation" of polymer with a larger molecular diameter, twice the number of reactive surface sites, and approximately double the molecular weight of the preceding generation. api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

14. Dendrimer Size Comparison www.avidimer.com

15. Liposomes are microscopic spherical vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. What is a liposome? Hydrophilic Hydrophobic

16. Diagram to show a lipid bilayer and comparison of a liposome and a micelles

17. Diagram representing a liposome encapsulating an active drug in its aqueous core.

18. Cell Membrane Phospholipids Phospholipids are the major structural components of biological membranes such as the cell membrane

19. Phospholipids • Phospholipids are amiphathic in nature, containing a hydrophobic tail and hydrophilic head. • When placed in water, the fatty acid tail associates and excludes the water, hence orientating the hydrophilic heads towards the water. • This leads to a bilayer configuration .

20. Main component of liposomes are phospholipids • Spontaneously orientate in water to give a bilayer, • Tails are rearranged away from the water • Spherical structure reduces exposure at the edges • Produces a thermodynamically stable structure

21. Liposome Discovery • They were first discovered by Alec D. Bangam in the early 1960’s while investigating the role of phospholipids in the clotting cascade. • The phospholipid bilayer enables the liposomes to be encapsulate active drugs for drug delivery.

22. Depending on the solubility of the drug, it can be: Encapsulated in aqueous core Interacting with surface Of liposome via Electrostatic interaction Taken up by bilayer

23. Figure : Liposomes - (left) A = aqueous soluble drug encapsulated in aqueous compartment; (centre) B = a hydrophobic drug in the liposome bilayer; (right) C = hydrophilic polyoxyethylene lipids incorporated into liposome

24. Why Use Liposomes in Drug Delivery? Drug Targeting • Inactive: Unmodified liposomes gather in specific tissue • reticuloendothelial system • Active: alter liposome surface with ligand (antibodies, • enzymes, protein A, sugars) Physical:temperature or pH sensitive liposomes • Directly to site

25. Why Use Liposomes in Drug Delivery? Pharmokinetics - efficacy and toxicity Changes the absorbance and biodistribution Deliver drug in desired form Protection Decrease harmful side effects Change where drug accumulates in the body Protects drug

26. Why Use Liposomes in Drug Delivery? Release Affect the time in which the drug is released Prolong time -increase duration of action and decrease administration Dependent on drug and liposome properties Liposome composition, pH and osmotic gradient, and environment

27. Liposomes • Their exterior lipid bilayer is very chemically reactive, thereby providing a means to conveniently couple “tags” on a covalent basis.  • Such “tags” can be antibodies, antigens, cell receptors, nucleic acid probes, etc.  • This provides significant versatility in assay formats (i.e., immunoassay, receptor-based, nucleic acid probe, etc.) possible.  • With  diameters ranging in size from approximately 50 nm to 800 nm, their aqueous core encapsulates up to millions of molecules of signal generating “markers” that can be detected in a variety of different way. api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

28. Micelles • Micelle is an aggregate of amphipathic molecules in water, with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water. • Amphiphilic molecules form micelle above a particular concentration which is called as critical micellar concentration (CMC).   • Micelles are known to have an anisotropic water distribution within their structure, means  water concentration decreases from the surface towards the core of the micelle, with a completely hydrophobic (water-excluded) core. • Hydrophobic drugs can be encapsulated/solubalized, into inner core. • The spatial position of a solubilized drug in a micelle will depend on its polarity, nonpolar molecules will be solubilized in the micellar core, and substances with intermediate polarity will be distributed along the surfactant molecules in certain intermediate positions.   api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

29. What is Cool Whip? Whipped toppings are essentially an emulsion of oil (usually around 35%) and sweetened water (around 60%) with an emulsifier, like phosphatidyl choline (lecithin), to maintain the suspension. The oil used for whipped toppings, like Cool Whip™, is hydrogenated vegetable oil, and after hydrogenation (saturation with hydrogen), all vegetable oils are the same (saturated), regardless of where they come from. So hydrogenated olive oil could easily be used to make whipped toppings.

30. What is Cool Whip? Oils (and fats) are fatty acids—phospholipids—have two parts (as their name suggests): a phosphate "head", and a long hydrocarbon "tail" (the fatty part). “tail” “head”

31. What is Cool Whip? An emulsion of oil and water is really just water with microscopic oil droplets floating in it (this is called a colloidal suspension). To get the oil to form these droplets, called micelles, the molecules of fatty acid have to pack together as closely as possible to minimize the volume of the micelle. To form a micelle, the heads of the molecules, which are soluble, form the outside of the drop, while the tails fill the inside. micelle Lots of micelles suspended in water No water wants to be here!

32. What is Cool Whip? The defining characteristic of unsaturated fats is that their tails have kinks in them. These kinks prevent the molecules from packing close together, so they tend to disrupt the micelles - the more unsaturated fats, the fewer and larger the micelles. Without good micelles, the emulsion will separate into its two phases (oil and water), and without a good emulsion, you can't whip the suspension into a dessert topping. kinks

33. What is Cool Whip? Compare to a saturated— hydrogenated— fat

34. Advantages of Nanocarrier Systems • Decreasing the non-specific delivery of the drug to non- target tissues. • Increasing the drug concentration at its site of action (be it intracellular or extracellular). • Prolonging the residence time of the drug at its site of action by reducing clearance. • Decreasing toxicity due to high initial doses of the drug. • Improving the stability of the drug in vivo. • Decreasing irritation caused by the drug. • Improving taste of the product. • Improving shelf life of the product. api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

35. Polymeric Nanoparticles • In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in drug targeting to particular organs/tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through a per oral route of administration. api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

36. Drug Delivery System (DDS) www.certh.gr/dat/E2353434/file.pdf

37. Interactions between Biological Systems and Nanomaterials www.certh.gr/dat/E2353434/file.pdf

38. Targeted Drug Delivery • Protected Drug delivery to target sites: • – Nanoparticles • – Miniature devices • • Higher doses • • Healthy tissue not affected • • Theranostics

39. Targeted Drug Delivery • Conventional drug delivery systems(DDS) such as oral ingestion or intravascular injection, the drug is distributed throughout the body through the systemic blood circulation. • For most therapeutic agents, only a small portion of the drug reaches the affected organ. • For example distribution of aspirin.

40. Targeted Drug Delivery

41. Some Real World Examples

42. Examples of Nanoparticles for Drug Delivery • AmBisome is an antifungal agent consisting of a liposomal preparation of amphotericin B that is administered by intravenous injection. • AmBisome is a true single bilayer liposomal drug delivery system, consisting of unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. • Treatment of cryptococcal meningitis in HIV-infected patients. • Liposomal formulation is preferred because of decreased side effects and prolonged drug exposure (due to slow release).

43. Shortcomings for Liposomes • Poor scale-up • Cost • Short shelf life • In some cases toxicity and off target effects.

44. Targeted Liposomal Drug Delivery toMonocytesandMacrophages • The effect of liposome size and charge on the bioactivity of liposomal bisphosphonates in a wide range of cell types in vitro including monocyte/macrophage cell lines was recently investigated. • Liposomes ranged in size from 50 to 800nm in diameter and were composed of lipids with neutral, positive, or negative charge. • It was concluded that small (85 nm) negatively charged liposomes composed of neutral 1,2-distearoylsn-glycero-3-phosphocholine (DSPC), anionic distearoylphophatidylglycerol (DSPG), and cholesterol at a molar ratio 3 : 1 : 2 were optimum for internalisation by MPS cells while large and positively charged liposomes induced cytokine activation and toxicity. J Drug Deliv. 2011;2011:727241.

45. Targeted Liposomal Drug Delivery toMonocytesandMacrophages • Optimal size therefore is likely to be dependent on multiple factors including the target cell and specific properties of the liposome formulation, for example, receptor mediated or nonreceptor mediated uptake. • Additionally in vitro results often differ from in vivo findings. Particularly when administered parentally, liposomes will interact with various circulatory components and are then cleared by hepatocytes in vivo. J Drug Deliv. 2011;2011:727241.

46. Avidimer Therapeutics

47. The Value of Avidimersfor Drug Delivery • Molecules have a uniform size and shape • Globular, true nanoscale dendrimer platform (~ 5nm diameter) • Ability to move in and out of vascular pores and pass through the filter organs • Targeted drug delivery • Ligands on the surface direct the drug to target cells • Attachment of multiple drug molecules allow increased drug concentration within the cell • Improved therapeutic index • Improved efficacy over traditional therapies • Lower systemic toxicity to non-targeted cells • Potential for faster drug development • Well-known and/or approved drugs • Well-characterized targeting ligands www.avidimer.com

48. Liposomal enhanced targeting • Liposomes have demonstrated the tendency to collect in a specific tissue • There is some evidence that liposomes gather in the tissue of tumors • Liposomes can take the form of positively charged, negatively charged and neutral – charge can help direct particles to specific oppositely charged locations • Liposomes largely consist of Lecithin and cholesterol, naturally occurring substances in the body, therefore well tolerated and have some naturally occurring collection sites

49. Surfactants enhanced targeting • Increase absorption into cell membrane • Acting as a wetting agent surfactants, increases the contact area between the drug and cell wall, facilitating the absorption of molecules into the cell membrane • Increase solubility of drug into carrier • Introduction of a surfactant into a solvent lowers the surface tension thereby increasing solubility limits • Increase stability of vehicle