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  1. 1. Drug release from Nanoparticles
  2. 2. Farmaco convenzionale
  3. 3. Oral intake
  4. 4. or hyperglycosilation
  5. 5. 1. Prodrugs to increase lipophilicity Lin JH Pharmacol. Rev. 1997
  6. 6. When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible. • Drug targeting is concerned with modulation and control of the biodistribution of a drug based on a suitable delivery system. • The biodistribution of the drug is not governed by the drug itself but by the delivery system. • The biomedical design of the delivery system depends on the properties of the target in combination with those of the drug and the needs of the patient.
  7. 7. 2000-2013 Temporal evolution in the number of scientific papers published involving drug delivery using nanoparticles. 5000 4520 4500 Search terms: ‘drug delivery’ 4000 3500 3173 3000 Search terms: ‘drug delivery’ and ‘nanoparticles’ 2710 2459 2500 1978 2000 1716 1302 1500 1444 1175 1090 1000 500 64 84 124 153 209 2000 2001 2002 2003 2004 364 525 2013 = 2379 686 446 154 0 2005 2006 2007 2008 2009 (Source: ISI Web of Knowledge ©)
  8. 8. Potential advantages of improved drug delivery: Ability to target specific locations in the body • Reduction of the quantity of drug needed to attain a particular concentration in the vicinity of the target; • Decreased number of dosages and possibly less invasive dosing • Reduction of harmful side effects due to targeted delivery (reduced concentration of the drug at non-target sites); Facilitation of drug administration for pharmaceuticals with short in vivo half-lives (for example peptides and proteins). Advantages must be weighed against the following concerns in the development of each particular drug-delivery system: 1. toxicity of the materials (or their degradation products) from which the drug is released, or other safety issues such as unwanted rapid release of the drug (dose dumping); 2. discomfort caused by the system itself or the means of insertion; 3. expense of the system due to the drug encapsulation materials or the manufacturing process.
  9. 9. METHODS OF DRUG DELIVERY •epicutaneous (application onto the skin). the active substance diffuses through skin in a transdermal route. •intradermal, (into the skin itself) is used for skin testing some allergens, and also for mantoux •subcutaneous (under the skin), e.g. insulin •nasal administration (through the nose) •intravenous (into a vein), e.g. many drugs, total parenteral nutrition •intraarterial (into an artery), •intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term psychoactive agents. •intracardiac (into the heart), e.g. adrenaline during cardiopulmonary resuscitation (no longer commonly performed) •intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system •intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and chemotherapy •intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis •Intravesical infusion is into the urinary bladder. •intravitreal, through the eye
  10. 10. NP drug delivery systems Possible mechanisms by which drugs are released: 1. Diffusion of the drug species from or through the system. 2. A chemical or enzymatic reaction leading to degradation of the system, or cleavage of the drug from the system. 3. Water activation, either through osmosis or swelling of the system. Rosen H & Abribat T, Nature Reviews 2005
  11. 11. DIFFUSION
  12. 12. Drug release by swelling and erosion
  13. 13. Ways of controlling drug release locally: Smart Stimuli-responsive NPs Stimuli-responsive NPs show a sharp change in properties upon a small or modest variations of the environmental conditions such as temperature, light, salt concentration or pH. Different organs, tissues and cellular compartments may have large differences in pH, which is considered the most suitable stimulus. This behavior can be used for the preparation of so-called ‘smart’ drug delivery systems, which mimic biological response behavior to a certain extent. Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006
  14. 14. Ways of controlling drug release locally • • • • • • pH Light Thermally Ultrasound Magnetically Enzyme-induced
  15. 15. pH in living systems Compartment Gastric acid Lysosomes Granules of chromaffin cells Human skin Urine pH 1 4.5 5.5 5.5 6.0 Cytosol Cerebrospinal fluid (CSF) Blood Mitochondrial matrix Pancreas secretions Solid tumours 7.2 7.5 7.34–7.45 7.5 8.1 6.5
  16. 16. HYDROGELS Polymers or co-polymers (e.g. acrylamide and acrylic acid) create water-impregnated nanoparticles with pores of well-defined size. Water flows freely into these particles, carrying proteins and other small molecules into the polymer matrix. By controlling the pore size, huge proteins such as albumin and immunoglobulin are excluded while smaller peptides and other molecules are allowed. flexibility
  17. 17. Polymer-based hydrogels Biodegradable and Biocompatible Polymers Targets for chemical modification CH2OH chitosan Poly-hydroxy-ethilmetacrylate PLGA • PolyAlkylCyanoAcrylate
  18. 18. Hydrogel formation Hydrogels from hydrophobic polymers Ionic hydrogels Hoffman AS, Adv Drug Deliv Rev, 2002 egg box structure
  19. 19. Hydrogels are three dimensional networks of polymers
  20. 20. Hydrogels as Drug Delivery Systems Hydrogel Requirements: Controlled or delayed diffusion of molecules Pore size compatibility with the biological molecule Solubility of the biological molecule Release characteristics are dependent on the chemical nature of the hydrogel  orally delivered insulin C.B. Woitiski et al. Eur. J. Pharm. Sci. 41 (2010) 556
  21. 21. pH Sensitive Hydrogels R R NH3+ NH2 NH3+ NH2 R R O pH<6.5 buffer Hydrophobic side chain N Hydrophobic side chain N R= polymer backbone O pH>6.5 buffer Crosslinking is based on hydrogen bonding, and secondary hydrophobic interactions. Crosslinking is reversible Control over the pore sizes Wang J Colloids Surfaces B. 2014
  22. 22. pH-responsive POLYMERIC NP Ionizable polymers with a pKa value between 3 and 10 are candidates for pH-responsive systems. The change of pH triggers the passage from ionized to un-ionized form or vice versa Poly(ethylene imine) (PEI) linear or branched Poly(L-lysine) (PLL) “proton sponge” hypothesis Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006, Oh K.T. et al., J. Mater Chem, 17, 2007
  23. 23. pH-sensitive liposomes
  24. 24. pH-sensitive liposomes for intracellular drug delivery liposomes can either remain bound at the cell surface, disassociate from the receptor, or accumulate in coated or non-coated invaginations. Following endocytosis (a), can be delivered to lysosomes (c) where may be degraded by lysosomal peptidases and hydrolases. Following acidification of the endosomal lumen, pH-sensitive liposomes are designed to either fuse with the endosomal membrane (e), releasing their contents directly into the cytoplasm, or become destabilized and subsequently destabilize the endosomal membrane (d) resulting in leakage of the endosomal contents into the cytosol.
  25. 25. Liposomes containing cationic lipids escape the lysosomal pathway
  26. 26. DOPE (phosphatidylethanolamine) -NH2  -NH3+
  27. 27. pH-sensitive liposomes From lamellar to hexagonal phase transition Drug release DOPE Guo X et al. Biophys. J. 84(3) 1784–1795
  28. 28. pH-sensitive polymersomes Cleavage of pH-Sensitive Bonds pH-Induced Solubility degradation of the block copolymer dissolution of the polymersome Drug release blue, hydrophilic block; red, groups responsible for the dissolution Meng et al. Biomacromolecules, Vol. 10, No. 2, 2009
  29. 29.                 37°C       41°C 
  30. 30. Thermally sensitive phospholipids Dipalmitoyl (C16) phosphatidylcholine 41°C H. Grüll, S. Langereis / J Control Release 161 (2012) 317–327
  31. 31. Thermo-responsive POLYMERS in drug delivery Temperature-responsive polymers and hydrogels exhibit a volume phase transition at a certain temperature, which causes a sudden change in the solvation state. LCST: lower critical solution temperature UCST: upper critical solution temperature Poly-N-IsoPropylAcrilAmide (PNIPAM) is the most prominent candidate as thermo-responsive polymer. PNIPAM copolymers have been mainly studied for the oral delivery of calcitonin and insulin. Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006 M.Nakayama et al. Material Matters 2010
  32. 32. Microwaves 39°C 41° 43°C C 39°C 39°C
  33. 33. Ultrasound-triggered drug delivery systems Non-invasively transmitted energy through the skin can be focused on a specific location and employed for enhanced drug release. Elastin-like polypeptide Triggering mechanism: Enhanced cavitation activity Pluronic
  34. 34. O/W Emulsions The o/w submicron LEs has many appealing properties as drug carriers. They are biocompatible, biodegradable, physically stable and relatively easy to produce on a large scale using proven technology. Tamilvanan S., Prog Lipid Res, 43, 2004
  35. 35. Date A.A., Adv. Drug Deliv. Rev, 59 2007