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Polysaccharide hydrogels: a versatile tool
for biomedical and pharmaceutical
applications
Department of Drug Chemistry and Technologies
Sapienza University of Rome
Rome, Italy
Pietro	Matricardi
XVII Brazil
MRS Meeting
September,16th -20th, 2018
Natal
Hydrogels for food
“molecular cuisine”
Hydrogels for personal care
Hydrogels for health
and wellness
Hydrogels for pharma
The colloid condition, the gel, is one which is easier to
recognize than to define
Dorothy Jordan Lloyd (1926)
Or, in other words, “if it looks Jello, it must be a gel”
What is a hydrogel
• Like a “fourth state” of matter
ü polymer network (10-20%) and water
ü the concepts of solute and solvent from a “classical”
thermodynamic point of view are unable to describe the system
• Depending on its nature:
ü self sustaining under its own weight
ü able to shear under the action of a stress
Some characteristics
Hydrogel network structures
Based on polymers
Chemical hydrogels
Physical hydrogels
reversible
crosslinks
covalent
crosslinks
10
From a rheological point of view
(Ross-Murphy and Burchard):
viscoelastic behaviour
Solution
Strong gel
Weak gel
Polysaccharides
ü Most of them are abundant in nature (commodities or mass-market
products)
ü Readily available from renewable sources (algal and plant kingdoms,
cultures of microbial selected strains, recombinant DNA techniques)
ü Large variety of compositions and properties
ü Biocompatible (food, medical device or pharma applications)
ü Often cheaper than synthetic polymers
ü Favourable chemical and physico-chemical properties due to the wide
variety of functional groups, macromolecular architecture and molecular
weights
Dextran
Gellan Gum
Guar Gum
Locust Bean Gum
Hyaluronic acid
Alginate
Xanthan Gum
Scleroglucan
SOME POLYSACCHARIDES
As “inert” drug carrier in conventional formulations:
• Filler (bulk formulation)
• Film forming (tablets or capsules)
• Viscosity agent in liquid formulations
Hydrogels & Polysaccharides
Ionotropic gelation
Chemical cross-linking
Calcium alginate hydrogels
Dextran methacrylate hydrogels
Hydrogels & Polysaccharides
Drug and Protein
Delivery
Tissue
Engineering
Bulk hydrogel
Nano hydrogel
GEL FOR DENTAL APPLICATIONS
HYDROGEL FOR DENTAL APPLICATIONS
üComplete filling of confinedspaces, such as gum pockets
üAble to carry
q Drugs
q Biologically Active Substances
üThe gel adheres to soft tissues due to the film-formingproperties
of one of the polymer component
üObtained by means of ionotropic gelation so no chemical
reactionsare involved nor toxic substances are formed as
byproducts
IONOTROPIC GELATION
Ions
Synthetic polymer
Polysaccharide
To improve bone growth for implant
On the market
Ø Homologous bone - animal derived products - synthetic
bone
Ø Osteocompatible resins
Pilot study #1 - Hydroxyapatite
ü Treatement of severe periodontitis
ü Cleaning of the pocket by curette
ü Applications of the drug loaded-hydrogel
ü New implant after 8 weeks
Pilot study #2 - nimesulide
NB
BM
n-MT
NB
NB
n-MT
BM
NB
Ematossilina-Eosina 4X
% n-MT (non-Mineralized Tissue): 65%
% BM (Biomaterial): 5%
% NB (New Bone): 30%
üFilling effect
üPain relief (with and without drug) in all
patiences
üHydrogel resorption in 4 weeks and
promotion of new bone formation
Results
Hydrogel
for heritage protection
Stone materials
and
Biodeterioration
ü Cleaning and protection of stone materials
ü Bio-colonization
ü Organic solvent-free product
Why polysaccharide hydrogels
Italy possesses a huge heritage
(45% of the world cultural heritage?!?!?)
Surface
Hydrogel on
the surface
After film removal
Duchessa di Genova
(1900)
by Pietro Canonica
Polysaccharide nanohydrogels for drug
delivery applications
Drug Delivery – Controlled release
Polymeric nanoparticle
Liposome
dendrimer
Inorganic nanoparticle
“MAGIC BULLET”
A substance or therapy capable of destroying pathogenic agents
(as bacteria or cancer cells) or providing a remedy for a disease
or condition without deleterious side effects, by specifically
targeting the diseased tissue
Dr. Paul Ehrlich
Solid Lipid Nanoparticle
Nanogels
Nanoscale hydrogels
POLYSACCHARIDE-BASED NANOHYDROGELS
SELF-ASSEMBLING
IN WATER
HYDROPHOBIC MOIETY
POLYSACCHARIDE
ü Nanosized hydrogels (150-300 nm)
ü Nanoparticulate drug carriers
ü High water content
ü High biocompatibility
ü Mucoadhesive properties
gellan gum
or
hyaluronan
prednisolone
cholesterol
riboflavin derivatives
HYDROPHOBIC	MOIETY
POLYSACCHARIDE
CRYO-TEM micrographs
Optical image
10	µm
100	nm 50	nm
* new patented method
AFM image
by several approaches
POLYSACCHARIDE-BASED NANOHYDROGELS
(121°C, 1.10 bar, 20 min)
1) preparation of
sterile NHs
2) Reduction of the NHs
polydispersity
3) Simultaneous formation, loading*
and sterilization of NHs
HYDROPHOBIC	MOIETY
POLYSACCHARIDE
Autoclave treatment *
* new patented method:
• WO2014199318 (A2) ― 2014-12-18 MC De Rugeriis, E. Montanari, C. Di Meo, P. Matricardi - METHOD FOR PREPARING NANOHYDROGELS
• WO2014199319 (A2) ― 2014-12-18 G. D’Arrigo, C. Cencetti, C. Di Meo, P. Matricardi - METHOD FOR THE TREATMENT OF NANOHYDROGELS
An innovative method for sterile polysaccharide NHs production
Cryo -TEM
100 nm
Autoclave
121°C
1.10 bar, 20 min
* For thermo-stable drugs
polymerdrug
Co-suspension in water Film-casting technique
drug film
polymer suspension
Long-term storage
0
50
100
150
NHs before freeze-
drying
NHs + dextrose
before freeze-drying
NHs + dextrose after
freeze-drying
d (nm)
0
0.2
0.4
0.6
0.8
1
PDI
diameter PDI
E. Montanari, M.C. De Rugeriis, C. Di Meo, R. Censi, T. Coviello, F. Alhaique, P. Matricardi Journal of Materials Science: Materials in Medicine , 2015,26:32
Freeze-drying
HACH
HARfv
NHs self assembly
~ 200 - 300 nm
(hydrophobic interactions)
Autoclave
20 min 121 °C
CAC = 134 µg/mL
scattering intensity
mean size
scattering intensity
mean size
CAC = 235 µg/mL
NHs properties
ü Stability
Denaturating agent: urea
Dilution test
37
HACH NHs
Dry conditions
SWELLING	RATIO
ü Atomic Force Microscopy
Wet conditions
Dry conditions:TAPPING MODE (Substrate: mica + MgCl₂ 10mM)
Wet conditions:CONTACTMODE/ScanAsyst® (Substrate: Si 1,0,0 derivatised with APTES((3-amminopropil)-trietossisilane)
NHs HACH NHs HARfv
Mean diameter 330 ± 20 nm 180 ± 24 nm
PDI 0.120 ÷ 0.250 0.100 ÷ 0.200
ζ Potential -46.7 ± 1.8 mV -40.5 ± 4.5 mV
Q: swelling ratio 6200 4400
Young Modulus 108 KPa 610 KPa
Fluorescence No Yes
hydrophilic drug
hydrophobic drug
empty NHs
Loading within
hydrophilic
domains
Loading within
hydrophobic
domains
Loaded molecules
Paclitaxel
Levofloxacin
Piroxicam
Dexamethasone
DRUGS
NATURAL SUBSTANCES
Curcumin
Resveratrol
Annona extracts
PROTEINS
BSAO
by nanoprecipitation, autoclave treatment, solvent casting….
ALGINATE LYASE
Highly versatile drug carriers
Gellan-prednisolone (Ge-pred) and Gellan-cholesterol (Ge-CH) NHs
for dual drugs therapy
Advantages:
ü Prednisolone is already clinically used in combination with chemotherapeutics in
several anticancer protocols (e.g. prostate cancer) to prevent or reduce side
effects.
ü Inflammation contributes	to	tumor	initiation,	 induces	proliferation	 of	malignant	
cells,	enhances	their	survival,	and	stimulates	angiogenesis	and	metastatic	spread.
ü Cancer,	in	turn,	takes	advantage	of	inflammatory	mediators to	grow,	thereby	
generating	an	inflammatory	 microenvironment	 in	tumors	for	which	there	is	no	
underlying	 inflammatory	 condition.
Paclitaxel (PCT)
Prednisolone
Mw reduction
by Ultrasonication
Sonication time
Mw/Mn
Sonication time1
3
2
4
5
1
3
2
4
5
1
3
2
4
5
1
32
4
5
6 6’
6 6’
-CH3
1.40 1.30 1.20
18
20
22
ppm
Gellan Gum
Glc Glc haGlc
GPC
ü Mw reduction of gellan by probe ultrasonication
1
H-13
C HSQC NMR map
ü Synthesis of polymer derivatives
Same steps with cholesterol (dd = 10%)
derivatization degree (dd) = 10% m/m
yield = 50%
ü NHs formation and stability
PREDNISOLONE	or	CHOLESTEROL
GELLAN	GUM
nanoprecipitation ultrasound treatment
or
25°C
ü Cell biocompatibility
G. D'Arrigo, C. Di Meo, E. Gaucci, S. Chichiarelli, T. Coviello, D. Capitani, F. Alhaique, P. Matricardi Soft Matter 2012, 8, 11557
Fibroblast
Heart myoblast
Prostate cancer
ü Anti-inflammatory activity
• Paclitaxel loading into Ge-pred and Ge-CH NHs by
solvent casting technique
• Paclitaxel concentration reached in NHs suspension =
140 µg/mL (free Paclitaxel in water = 0.1 µg/mL)
Paclitaxel (PCT)
Prednisolone
ü Loading with anticancer drug
PCT release in vitro
PC-3 cells, 72h
PCT 3 nM
IC50
Paclitaxel: 33.7 nM
Paclitaxel in NHs: 15.1 nM
Paclitaxel in NHs + Prednisolone: 7.7 nM
G. D'Arrigo, G. Navarro, C. Di Meo, P. Matricardi, V. Torchilin, European Journal of Pharmaceutics and Biopharmaceutics 2014, 87, 208
Skov-3 cell line
Anticancer activity of PCT-loaded NHs
Hyaluronan-cholesterol (HA-CH) NHs
for antibiotic delivery
A new challenge
• Antibiotic resistance due to the intracellular escape (for
facultative or obligate pathogens)
• Levofloxacine: poorly effective against intracellular bacteria
(efflux pump)
Levofloxacin
• Levofloxacin loading into HA-CH NHs by autoclave technique
• Levofloxacin concentration reached in NHs suspension = 12 ± 1 %
w/w
• Antibacterial activity against S. Aureus and P. Aeruginosa strains
• Cell (HeLa) infection by S. Aureus and P. Aeruginosa and treatment
with free LVF and LVF-loaded NHs
Levofloxacin
MIC values of Levoflloxacin (LVF) and NH-encapsulated
Levofloxacin (NH-LVF) on S. aureus ATCC6538P, S.aureus
USA300-0114 and P. aeruginosa PAO-1.
Comparable MIC
E. Montanari, G. D’Arrigo, C. Di Meo, A. Virga, T. Coviello, C. Passariello, P. Matricardi. Eur. J. of Pharmaceutics and Biopharmaceutics, 2014, 87, 518
FREE LVF: no significant activity
on intracellular bacteria
Activity of LVF and NH-LVF (both freshly prepared and resuspended
after freeze-drying) on intracellular P. aeruginosa PAO-1 and S.
aureus USA 300-0114.
LVF-NHs: > 90% eradication
of intracellular bacteria
Levofloxacin
Gentamicin
Topical applications
• Levofloxacin (LVF) and gentamicin(GM) loading into HA-CH NHs
• Antiibacterial activity against S. Aureus
• Human keratinocites (HaCaT) infection by S. Aureus and treatment
with free LVF and GM drug-loaded NHs
Scheme of the intracellular fate of free GM, LVF and their nanoformulations in
S. aureus-infected keratinocytes.
E. Montanari, A.Oates, C. Di Meo, J. Meade, R. Cerrone, A. Francioso, S. Devine, T. Coviello, P. Mancini, L. Mosca and P. Matricardi Adv. Healthcare Mater. 2018, 1701483
Topical applications of NHs
Topical applications of NHs -1
Piroxicam
Ge-CH
Ge-Rfv
U.M. Musazzi, C. Cencetti, S. Franzé, N. Zoratto, C. Di Meo, P. Procacci, P. Matricardi, F. Cilurzo, Mol. Pharmaceutics 2018, 15, 1028−1036
Baicalin
Ge-CH
M. Manconi, M.L. Manca C. Caddeo, C. Cencetti, C. Di Meo, N. Zoratto, .. P. Matricardi Eur. J. Pharm. Biopharm. 2018, 127, 244–249
Topical applications of NHs -2
Other applications
ü NHs in aesthetic surgery
ü Antioxidant for cardiovascular applications
ü Anti-inflammatory-loaded NHs for the treatment of primary
sclerosing cholangitis
ü NHs formulations for ocular applications
ü HA-based NHs in cosmetics
Special thanks to:
Franco Alhaique
Tommasina Coviello
Chiara Di Meo
Elita Montanari
Nicole Zoratto
Thank you for your kind attention

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Polysaccharide Hydrogels: a versatile tool for biomedical and pharmaceutical applications.

  • 1. Polysaccharide hydrogels: a versatile tool for biomedical and pharmaceutical applications Department of Drug Chemistry and Technologies Sapienza University of Rome Rome, Italy Pietro Matricardi XVII Brazil MRS Meeting September,16th -20th, 2018 Natal
  • 6.
  • 7. The colloid condition, the gel, is one which is easier to recognize than to define Dorothy Jordan Lloyd (1926) Or, in other words, “if it looks Jello, it must be a gel” What is a hydrogel
  • 8. • Like a “fourth state” of matter ü polymer network (10-20%) and water ü the concepts of solute and solvent from a “classical” thermodynamic point of view are unable to describe the system • Depending on its nature: ü self sustaining under its own weight ü able to shear under the action of a stress Some characteristics
  • 9. Hydrogel network structures Based on polymers Chemical hydrogels Physical hydrogels reversible crosslinks covalent crosslinks
  • 10. 10 From a rheological point of view (Ross-Murphy and Burchard): viscoelastic behaviour Solution Strong gel Weak gel
  • 11. Polysaccharides ü Most of them are abundant in nature (commodities or mass-market products) ü Readily available from renewable sources (algal and plant kingdoms, cultures of microbial selected strains, recombinant DNA techniques) ü Large variety of compositions and properties ü Biocompatible (food, medical device or pharma applications) ü Often cheaper than synthetic polymers ü Favourable chemical and physico-chemical properties due to the wide variety of functional groups, macromolecular architecture and molecular weights
  • 12. Dextran Gellan Gum Guar Gum Locust Bean Gum Hyaluronic acid Alginate Xanthan Gum Scleroglucan SOME POLYSACCHARIDES
  • 13. As “inert” drug carrier in conventional formulations: • Filler (bulk formulation) • Film forming (tablets or capsules) • Viscosity agent in liquid formulations
  • 15. Ionotropic gelation Chemical cross-linking Calcium alginate hydrogels Dextran methacrylate hydrogels
  • 19. GEL FOR DENTAL APPLICATIONS
  • 20. HYDROGEL FOR DENTAL APPLICATIONS üComplete filling of confinedspaces, such as gum pockets üAble to carry q Drugs q Biologically Active Substances üThe gel adheres to soft tissues due to the film-formingproperties of one of the polymer component üObtained by means of ionotropic gelation so no chemical reactionsare involved nor toxic substances are formed as byproducts
  • 22. To improve bone growth for implant On the market Ø Homologous bone - animal derived products - synthetic bone Ø Osteocompatible resins Pilot study #1 - Hydroxyapatite
  • 23. ü Treatement of severe periodontitis ü Cleaning of the pocket by curette ü Applications of the drug loaded-hydrogel ü New implant after 8 weeks Pilot study #2 - nimesulide NB BM n-MT NB NB n-MT BM NB Ematossilina-Eosina 4X % n-MT (non-Mineralized Tissue): 65% % BM (Biomaterial): 5% % NB (New Bone): 30%
  • 24. üFilling effect üPain relief (with and without drug) in all patiences üHydrogel resorption in 4 weeks and promotion of new bone formation Results
  • 25. Hydrogel for heritage protection Stone materials and Biodeterioration
  • 26. ü Cleaning and protection of stone materials ü Bio-colonization ü Organic solvent-free product Why polysaccharide hydrogels Italy possesses a huge heritage (45% of the world cultural heritage?!?!?)
  • 27.
  • 29. Duchessa di Genova (1900) by Pietro Canonica
  • 30. Polysaccharide nanohydrogels for drug delivery applications
  • 31. Drug Delivery – Controlled release Polymeric nanoparticle Liposome dendrimer Inorganic nanoparticle “MAGIC BULLET” A substance or therapy capable of destroying pathogenic agents (as bacteria or cancer cells) or providing a remedy for a disease or condition without deleterious side effects, by specifically targeting the diseased tissue Dr. Paul Ehrlich Solid Lipid Nanoparticle Nanogels Nanoscale hydrogels
  • 32. POLYSACCHARIDE-BASED NANOHYDROGELS SELF-ASSEMBLING IN WATER HYDROPHOBIC MOIETY POLYSACCHARIDE ü Nanosized hydrogels (150-300 nm) ü Nanoparticulate drug carriers ü High water content ü High biocompatibility ü Mucoadhesive properties gellan gum or hyaluronan prednisolone cholesterol riboflavin derivatives
  • 33. HYDROPHOBIC MOIETY POLYSACCHARIDE CRYO-TEM micrographs Optical image 10 µm 100 nm 50 nm * new patented method AFM image by several approaches POLYSACCHARIDE-BASED NANOHYDROGELS
  • 34. (121°C, 1.10 bar, 20 min) 1) preparation of sterile NHs 2) Reduction of the NHs polydispersity 3) Simultaneous formation, loading* and sterilization of NHs HYDROPHOBIC MOIETY POLYSACCHARIDE Autoclave treatment * * new patented method: • WO2014199318 (A2) ― 2014-12-18 MC De Rugeriis, E. Montanari, C. Di Meo, P. Matricardi - METHOD FOR PREPARING NANOHYDROGELS • WO2014199319 (A2) ― 2014-12-18 G. D’Arrigo, C. Cencetti, C. Di Meo, P. Matricardi - METHOD FOR THE TREATMENT OF NANOHYDROGELS An innovative method for sterile polysaccharide NHs production Cryo -TEM 100 nm Autoclave 121°C 1.10 bar, 20 min * For thermo-stable drugs polymerdrug Co-suspension in water Film-casting technique drug film polymer suspension
  • 35. Long-term storage 0 50 100 150 NHs before freeze- drying NHs + dextrose before freeze-drying NHs + dextrose after freeze-drying d (nm) 0 0.2 0.4 0.6 0.8 1 PDI diameter PDI E. Montanari, M.C. De Rugeriis, C. Di Meo, R. Censi, T. Coviello, F. Alhaique, P. Matricardi Journal of Materials Science: Materials in Medicine , 2015,26:32 Freeze-drying
  • 36. HACH HARfv NHs self assembly ~ 200 - 300 nm (hydrophobic interactions) Autoclave 20 min 121 °C CAC = 134 µg/mL scattering intensity mean size scattering intensity mean size CAC = 235 µg/mL NHs properties
  • 37. ü Stability Denaturating agent: urea Dilution test 37
  • 38. HACH NHs Dry conditions SWELLING RATIO ü Atomic Force Microscopy Wet conditions Dry conditions:TAPPING MODE (Substrate: mica + MgCl₂ 10mM) Wet conditions:CONTACTMODE/ScanAsyst® (Substrate: Si 1,0,0 derivatised with APTES((3-amminopropil)-trietossisilane)
  • 39. NHs HACH NHs HARfv Mean diameter 330 ± 20 nm 180 ± 24 nm PDI 0.120 ÷ 0.250 0.100 ÷ 0.200 ζ Potential -46.7 ± 1.8 mV -40.5 ± 4.5 mV Q: swelling ratio 6200 4400 Young Modulus 108 KPa 610 KPa Fluorescence No Yes
  • 40. hydrophilic drug hydrophobic drug empty NHs Loading within hydrophilic domains Loading within hydrophobic domains Loaded molecules Paclitaxel Levofloxacin Piroxicam Dexamethasone DRUGS NATURAL SUBSTANCES Curcumin Resveratrol Annona extracts PROTEINS BSAO by nanoprecipitation, autoclave treatment, solvent casting…. ALGINATE LYASE Highly versatile drug carriers
  • 41. Gellan-prednisolone (Ge-pred) and Gellan-cholesterol (Ge-CH) NHs for dual drugs therapy
  • 42. Advantages: ü Prednisolone is already clinically used in combination with chemotherapeutics in several anticancer protocols (e.g. prostate cancer) to prevent or reduce side effects. ü Inflammation contributes to tumor initiation, induces proliferation of malignant cells, enhances their survival, and stimulates angiogenesis and metastatic spread. ü Cancer, in turn, takes advantage of inflammatory mediators to grow, thereby generating an inflammatory microenvironment in tumors for which there is no underlying inflammatory condition. Paclitaxel (PCT) Prednisolone
  • 43. Mw reduction by Ultrasonication Sonication time Mw/Mn Sonication time1 3 2 4 5 1 3 2 4 5 1 3 2 4 5 1 32 4 5 6 6’ 6 6’ -CH3 1.40 1.30 1.20 18 20 22 ppm Gellan Gum Glc Glc haGlc GPC ü Mw reduction of gellan by probe ultrasonication 1 H-13 C HSQC NMR map
  • 44. ü Synthesis of polymer derivatives Same steps with cholesterol (dd = 10%) derivatization degree (dd) = 10% m/m yield = 50% ü NHs formation and stability PREDNISOLONE or CHOLESTEROL GELLAN GUM nanoprecipitation ultrasound treatment or 25°C
  • 45. ü Cell biocompatibility G. D'Arrigo, C. Di Meo, E. Gaucci, S. Chichiarelli, T. Coviello, D. Capitani, F. Alhaique, P. Matricardi Soft Matter 2012, 8, 11557 Fibroblast Heart myoblast Prostate cancer
  • 47. • Paclitaxel loading into Ge-pred and Ge-CH NHs by solvent casting technique • Paclitaxel concentration reached in NHs suspension = 140 µg/mL (free Paclitaxel in water = 0.1 µg/mL) Paclitaxel (PCT) Prednisolone ü Loading with anticancer drug PCT release in vitro PC-3 cells, 72h PCT 3 nM
  • 48. IC50 Paclitaxel: 33.7 nM Paclitaxel in NHs: 15.1 nM Paclitaxel in NHs + Prednisolone: 7.7 nM G. D'Arrigo, G. Navarro, C. Di Meo, P. Matricardi, V. Torchilin, European Journal of Pharmaceutics and Biopharmaceutics 2014, 87, 208 Skov-3 cell line Anticancer activity of PCT-loaded NHs
  • 51.
  • 52.
  • 53. • Antibiotic resistance due to the intracellular escape (for facultative or obligate pathogens) • Levofloxacine: poorly effective against intracellular bacteria (efflux pump) Levofloxacin
  • 54. • Levofloxacin loading into HA-CH NHs by autoclave technique • Levofloxacin concentration reached in NHs suspension = 12 ± 1 % w/w • Antibacterial activity against S. Aureus and P. Aeruginosa strains • Cell (HeLa) infection by S. Aureus and P. Aeruginosa and treatment with free LVF and LVF-loaded NHs Levofloxacin MIC values of Levoflloxacin (LVF) and NH-encapsulated Levofloxacin (NH-LVF) on S. aureus ATCC6538P, S.aureus USA300-0114 and P. aeruginosa PAO-1. Comparable MIC E. Montanari, G. D’Arrigo, C. Di Meo, A. Virga, T. Coviello, C. Passariello, P. Matricardi. Eur. J. of Pharmaceutics and Biopharmaceutics, 2014, 87, 518
  • 55. FREE LVF: no significant activity on intracellular bacteria Activity of LVF and NH-LVF (both freshly prepared and resuspended after freeze-drying) on intracellular P. aeruginosa PAO-1 and S. aureus USA 300-0114. LVF-NHs: > 90% eradication of intracellular bacteria
  • 57. • Levofloxacin (LVF) and gentamicin(GM) loading into HA-CH NHs • Antiibacterial activity against S. Aureus • Human keratinocites (HaCaT) infection by S. Aureus and treatment with free LVF and GM drug-loaded NHs
  • 58. Scheme of the intracellular fate of free GM, LVF and their nanoformulations in S. aureus-infected keratinocytes. E. Montanari, A.Oates, C. Di Meo, J. Meade, R. Cerrone, A. Francioso, S. Devine, T. Coviello, P. Mancini, L. Mosca and P. Matricardi Adv. Healthcare Mater. 2018, 1701483
  • 60. Topical applications of NHs -1 Piroxicam Ge-CH Ge-Rfv U.M. Musazzi, C. Cencetti, S. Franzé, N. Zoratto, C. Di Meo, P. Procacci, P. Matricardi, F. Cilurzo, Mol. Pharmaceutics 2018, 15, 1028−1036
  • 61. Baicalin Ge-CH M. Manconi, M.L. Manca C. Caddeo, C. Cencetti, C. Di Meo, N. Zoratto, .. P. Matricardi Eur. J. Pharm. Biopharm. 2018, 127, 244–249 Topical applications of NHs -2
  • 62. Other applications ü NHs in aesthetic surgery ü Antioxidant for cardiovascular applications ü Anti-inflammatory-loaded NHs for the treatment of primary sclerosing cholangitis ü NHs formulations for ocular applications ü HA-based NHs in cosmetics
  • 63. Special thanks to: Franco Alhaique Tommasina Coviello Chiara Di Meo Elita Montanari Nicole Zoratto
  • 64. Thank you for your kind attention