1. Drug release from nanoparticles can occur through different mechanisms such as diffusion, degradation of polymers through hydrolysis of bonds, or enzymatic reactions. 2. Stimuli-responsive or "smart" nanoparticles can be designed to release drugs in response to specific stimuli in the body such as pH, temperature, light, or enzymes to target drug delivery. 3. pH-responsive nanoparticles are of particular interest as they can be designed to release drugs on demand in different pH environments in the body, like the acidic environment of tumors or endosomes. Liposomes, polymers, and hydrogels have all been engineered to respond to changes in pH.

1. Drug release from
Nanoparticles

2. Farmaco convenzionale
BIODISPONIBILITA’

3. Biodegradable Polymers
• Carbonyl bond to
O
N
S
R1 C X
O
R2
OH2
R1 C OH
O
+HX R2
Where X= O, N, S
R1 C O
O
R2
Ester
R1 C NH
O
R2
Amide
R1 C S
O
R2
A.
Thioester

4. X C X'
O
R2R1
OH2
+ HX' R2X C OH
O
R1
Where X and X’= O, N, S
B.
O C O
O
R2R1 NH C O
O
R2R1 NH C NH
O
R2R1
Carbonate Urethane Urea
C. R1 C X
O
C
O
R2
OH2
+R1 C OH
O
HX C
O
R2
R1 C NH
O
C
O
R2 R1 C O
O
C
O
R2
Imide Anhydride
Where X and X’= O, N, S
Biodegradable Polymers

5. Oral intake

6. or hyperglycosilation

7. 1. Prodrugs to increase lipophilicity
Lin JH Pharmacol. Rev. 1997

9. • 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.
Pegylated carriers for prolonged half lives

10. 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.

11. (Source: ISI Web of Knowledge ©)
2000-2013
Temporal evolution in the number of scientific papers published
involving drug delivery using nanoparticles.
Search terms: ‘drug delivery’
Search terms: ‘drug delivery’
and ‘nanoparticles’
1090
1302
1444
1716
1978
2459
2710
3173
4520
446
64 84 124 153 209
364
525
686
1175
154
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
2013 = 2379

12. Enhanced permeability and retention
(EPR effect)

13. NP drug delivery systems
Possible mechanisms by which drugs are released:
1. Diffusion of the drug species from or through the system.
2. Water activation, either through swelling or erosion of the
system.
3. A chemical or enzymatic reaction leading to degradation of
the system, or cleavage of the drug from the system.
Rosen H & Abribat T, Nature Reviews 2005

14. DIFFUSION

15. Drug release by
swelling and erosion

16. Drug release through enzymatic reaction
• NP covalently modified with drugs through an enzyme cleavable linker
• NP degradation can be programmed to be triggered by an enzyme
Gly-Phe-Leu-Gly

17. Ion-dipole binding = NP
disassembly
R. De la Rica et al. Small 7 (2011) 66-69

18. 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

19. Ways of controlling drug release locally
• pH
• Light
• Thermally
• Ultrasound
• Magnetically
• Enzyme-induced

20. pH in living systems
Compartment pH
Gastric acid 1
Lysosomes 4.5
Granules of chromaffin cells 5.5
Human skin 5.5
Urine 6.0
Cytosol 7.2
Cerebrospinal fluid (CSF) 7.5
Blood 7.34–7.45
Mitochondrial matrix 7.5
Pancreas secretions 8.1
Solid tumours 6.5

21. 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

22. Polymer-based hydrogels
Biodegradable and Biocompatible Polymers
• PolyAlkylCyanoAcrylate
PLGA
chitosan
CH2OH
Targets for chemical modification
Poly-hydroxy-ethil-
metacrylate

23. Hydrogel formation
Ionic hydrogels
Hoffman AS, Adv Drug Deliv Rev, 2002
egg box structure
Hydrogels from hydrophobic
polymers

24. 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

25. pH Sensitive Hydrogels
R
R
NH3+
NH3+
N Hydrophobic side chain
O
R
R
NH2
NH2
N Hydrophobic side chain
O
pH<6.5 buffer pH>6.5 bufferR= polymer backbone
Crosslinking is based on hydrogen
bonding, and secondary hydrophobic
interactions.
Crosslinking is reversible
Control over the pore sizes
Wang J Colloids Surfaces B. 2014

27. pH-responsive POLYMERIC NP
Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006,
Oh K.T. et al., J. Mater Chem, 17, 2007
Ionizable polymers with a pKa value between
3 and 10 are candidates for pH-responsive
systems.
Poly(ethylene imine) (PEI)
linear or branched
Poly(L-lysine) (PLL)
The change of pH triggers the passage from
ionized to un-ionized form or vice versa
“proton sponge” hypothesis

28. pH-sensitive liposomes

29. 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.
pH-sensitive liposomes for
intracellular drug delivery

31. Inverted hexagonal phase
Lamellar phase
Micelles
+

32. DOPE
Guo X et al. Biophys. J. 84(3) 1784–1795
pH-sensitive liposomes
From lamellar to
hexagonal phase
transition
Drug release

33. pH-sensitive polymersomes
degradation of
the block
copolymer
Drug release
Cleavage of
pH-Sensitive
Bonds
blue, hydrophilic block; red, groups responsible
for the dissolution
Meng et al. Biomacromolecules,
Vol. 10, No. 2, 2009
pH-Induced
Solubility
dissolution of
the
polymersome

35. 























37°C
41°C

36. Thermally sensitive phospholipids
H. Grüll, S. Langereis / J Control Release 161 (2012) 317–327

37. 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.
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
LCST: lower critical solution temperature
UCST: upper critical solution temperature

38. Microwaves
39°C
41°
C
43°C
39°C
39°C

39. 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.
Triggering mechanism: Enhanced cavitation activity
PEO PEOPPO
Pluronic

40. Different lipid carriers