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  1. 1. Drug release from Nanoparticles
  2. 2. Farmaco convenzionale
  3. 3. Oral intake
  4. 4. When a pharmaceutical agent is encapsulated within, or attached to, a polymeror lipid, drug safety and efficacy can be greatly improved and new therapiesare possible.• Drug targeting is concerned with modulation and control of the biodistributionof a drug based on a suitable delivery system.• The biodistribution of the drug is not governed by the drug itself but by thedelivery system.• The biomedical design of the delivery system depends on the properties of thetarget in combination with those of the drug and the needs of the patient.
  5. 5. 2000-2009Temporal evolution in the number of scientific papers publishedinvolving drug delivery using nanoparticles. 5000 4520 4500 2000 64 1090 2000 5.8764 % 4000 2001 84 1302 2001 6.4584 % 3500 2002 124 3173 1444 2002 8.59 % 124 3000 2003 153 2710 1716 2003 8.92 % 153 2004 2459 209 1978 2004 10.57 % 209 2500 2005 1978 364 2459 2005 14.80 % 364 2000 1716 2006 525 2710 2006 19.37 % 525 1444 1500 1302 2007 686 3173 1175 2007 21.62 % 686 1090 1000 2008 1175 4520 2008 26.00 % 1175 686 2009 364 154 525 446 446 2009 34.53 % 154 500 209 64 84 124 153 154 0 2010 = 1941 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Search terms: ‘drug delivery’ Search terms: ‘drug delivery’ and ‘nanoparticles’ (Source: ISI Web of Knowledge ©)
  6. 6. Nanoparticles as drug delivery systems
  7. 7. 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 thevicinity of the target;• Decreased number of dosages and possibly less invasive dosing• Reduction of harmful side effects due to targeted delivery (reduced concentration of thedrug at non-target sites);Facilitation of drug administration for pharmaceuticals with short in vivo half-lives (forexample peptides and proteins).Advantages must be weighed against the following concerns in the developmentof 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.
  8. 8. METHODS OF DRUG DELIVERY•epicutaneous (application onto the skin). the active substance diffuses throughskin in a transdermal route.•intradermal, (into the skin itself) is used for skin testing some allergens, and alsofor 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-termpsychoactive 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 intravenousaccess because the bone marrow drains directly into the venous system•intrathecal (into the spinal canal) is most commonly used for spinal anesthesia andchemotherapy•intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis•Intravesical infusion is into the urinary bladder.•intravitreal, through the eye
  9. 9. NP drug delivery systemsPossible 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 & Abribad, Nature Reviews 2005
  10. 10. DIFFUSION
  11. 11. Ways of controlling drug release locally: Smart Stimuli-responsive NPsStimuli-responsive NPs show a sharp change in properties upon asmall or modest variations of the environmental conditions suchas temperature, light, salt concentration or pH.Different organs, tissues and cellular compartments may havelarge differences in pH, which is considered the most suitablestimulus.This behavior can be used for the preparation of so-called ‘smart’drug delivery systems, which mimic biological response behaviorto a certain extent. Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006
  12. 12. Ways of controlling drug release locally• pH• Light• Thermally• Ultrasound• Magnetically• Enzyme-induced
  13. 13. pH in living systems[Compartment pHGastric acid 1Lysosomes 4.5Granules of chromaffin cells 5.5Human skin 5.5Urine 6.0Cytosol 7.2Cerebrospinal fluid (CSF) 7.5Blood 7.34–7.45Mitochondrial matrix 7.5Pancreas secretions 8.1Solid tumours 6.5
  14. 14. HYDROGELSPolymers or co-polymers (e.g. acrylamide and acrylic acid) createwater-impregnated nanoparticles with pores of well-defined size.Water flows freely into these particles, carrying proteins and othersmall molecules into the polymer matrix.By controlling the pore size, huge proteins such as albumin andimmunoglobulin are excluded while smaller peptides and othermolecules are allowed.The polymeric component acts as a negatively charged "bait" that attracts positivelycharged proteins, improving the particlesperformance.
  15. 15. Polymer-based hydrogels Biodegradable and Biocompatible Polymers• PolyLactic Acid (PLA)• Co-Polymer Lactic-Glycolic (PLGA)• PolyCaproLactone (PCL) PLGA• PolyAlkylCyanoAcrylate (PACA)• Chitosan
  16. 16. Hydrogels are three dimensional networks of polymers
  17. 17. pH-responsive POLYMERIC NP in drug deliveryIonizable polymers with a pKa value between Classical monomers are acrylic acid and3 and 10 are candidates for pH-responsive derivatesystems. Chitosan has received attention recently because it maintained itsThe change of pH triggers the passage from biocompatibilityionized to un-ionized form or vice versa Lactic acid Poly(ethylene imine) (PEI) linear or branched Poly(L-lysine) (PLL) Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006, Oh K.T. et al., J. Mater Chem, 17, 2007
  18. 18. pH Sensitive HydrogelsR R N H3 + N H2 N H3 + N H2 N H y dr o p h o b ic s id e c h a in N H y dr o p h o b ic s id e c h a inR R O O R = p o lym e r b a ckb o n e p H > 6 .5 b u ffe r p H < 6 .5 b u ffe r Crosslinking is based on hydrogen bonding, and secondary hydrophobic interactions. Crosslinking is reversible Control over the pore sizes
  19. 19. Release characteristics are dependent on the chemical nature of the hydrogel Hydrogel Requirements: Controlled or delayed diffusion of moleculesPore size compatibility with the biological molecule Solubility of the biological molecule
  20. 20. pH-sensitive liposomes
  21. 21. pH-sensitive liposomes for intracellular drug deliveryliposomes can either remain bound at the cell surface, disassociate from the receptor, or accumulate in coated ornon-coated invaginations. Following endocytosis (a), can be delivered to lysosomes (c) where may be degraded bylysosomal peptidases and hydrolases. Following acidification of the endosomal lumen, pH-sensitive liposomes aredesigned to either fuse with the endosomal membrane (e), releasing their contents directly into the cytoplasm, orbecome destabilized and subsequently destabilize the endosomal membrane (d) resulting in leakage of theendosomal contents into the cytosol.
  22. 22. Liposomes containing cationic lipids escape the lysosomal pathway
  23. 23. DOPE (phosphatidylethanolamine)-NH2  -NH3+
  24. 24. Inserito in bilayer di liposomi
  25. 25. Thermally sensitive phospholipidsDipalmitoyl (C16) phosphatidylcholine 41 °C
  26. 26.                     37°C  41°C
  27. 27. Thermo-responsive POLYMERS in drug deliveryTemperature-responsive polymers and hydrogels exhibit a volume phase transition at acertain temperature, which causes a sudden change in the solvation state. Upper critical solution Lower critical solution temperature (UCST) temperature (LCST) PNIPAM in drug delivery 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
  28. 28. Microwaves 39°C 41° 43°C C 39°C 39°C
  29. 29. Ultrasound-triggered drug delivery systemsNon-invasively transmitted energy through the skin Elastin-like polypeptidecan be focused on a specific location and employedfor enhanced drug release.Triggering mechanism: Enhanced cavitation activity Pluronic
  30. 30. O/W EmulsionsThe o/w submicron LEs has many appealing properties as drug carriers. They arebiocompatible, biodegradable, physically stable and relatively easy to produce on alarge scale using proven technology. Tamilvanan S., Prog Lipid Res, 43, 2004
  31. 31. Date A.A., Adv. Drug Deliv. Rev, 59 2007