Bentham & Hooker's Classification. along with the merits and demerits of the ...
Chitosan grafted carboxy functionalized polylactide nanoparticles for multidrug controlled and sustained release
1. Chitosan grafted carboxy functionalized polylactide
nanoparticles for multidrugs controlled and sustained
release
Antonio Di Martino
Center of Polymer Systems
Tomas Bata University in Zlin
Czech Republic
dimartino@ft.utb.cz
National Research
Tomsk Polytechnic University
Russia
2. Drug Delivery Systems (DDS)
Traditional drug delivery systems
Oral
Injection based
Inhalational/Pulmonary
Transdermal
Why new delivery systems?
Targeted drug delivery
Maximum efficacy with minimum side sffects
Controlled drug delivery
Optimize drug’s therapeutic effects, convenience and dose
Enhance product life-cycle
Improve patient compliance
Control over all healthcare cost
Systems for the delivery of drugs to target sites of pharmacological actions
3. Nanoparticles as DDS
I) Dispersion or solid form with size in the range 10-700 nm
II) Various morphologies – nanospheres, nanocapsules, nanomicelles, nanoliposomes etc…
III) Drug (s) can be : dissolved, entrapped, encapsulated or attached to the nanoparticle matrix
IV) High Encapsulation Efficiency
V) Drug protection
VI) Controlled Release
VII) Decrease side effects
VIII) Reverse tumor multidrug resistance
IX) Cell Internalization
Why Nanoparticles ?
4. Polysaccharides based Nanoparticles
Polysaccharides have been considered as one of the most promising
material for drug delivery
Various Sources : Algae , Microbial,
Plants and Animals
Abundant
Low Cost
Large number of Reactive Groups
Chemical composition
Wide range of Mw
Biocompatible
Biodegradable
Low Immunogenity
Not Toxic
Chitosan Hyaluronic Acid
Alginate Cyclodextrin
Dextran
Pectin
6. Aim of the work
Preparation and characterization of amphiphilic nanoparticles based
on chitosan grafted carboxy functionalized polylactide
Encapsulation of Doxorubicin , Temozolomide, 5-Fluorouracil
Influence of environment on the release trend
Doxorubicin (DOX) Temozolomide (TMZ) 5-Fluorouracil (5-FU)
7. Polylactide-citric acid synthesis (PLACA)
Carboxy functionalized PLA has been obtained through direct melt polycondensation
of Lactic acid (LA) and Citric acid (CA)
Methanesulfonic acid (MSA) as initiator. More effective compared to metal salts
MSA is adapt to obtain low Mw PLA
Lactic acid
Citric acid
Carboxy functionalized polylactide (PLACA)
Kucharczyk et al. Journal of Applied polymer Science 2011, 122,1275-1285
8. CS-g-PLACA synthesis
Coupling reaction between CS amino groups and PLACA carboxy groups
EDC as COOH activator
R1-NH2 + HOOC-R2 → R1-NH-CO-R2 + H2O
Improve chitosan stability in solution
Encapsulate hydrophobic and hydrophilic drugs simultaneously
Di Martino, Sedlarik, Int. J.Pharm . 2014 Oct 20, 474, 1-2, 134-45
9. CS-g-PLACA Nanoparticles preparation
Polyelectrolytes complexation method
Easy
Fast
Low cost
Solvent-free
Possibility to modulate size and surface charge
of nanoparticles
Dextran sulfate ( Mw 50 kDa ) as polyanion
Polymer to DS ratio (w/w) : from 0.1 to 5
10. TMZ – DOX – 5-FU : Encapsulation and Release
EE(%) = (Dt−Df / Dt)×100
Dt = total theoretical amount of drug added (mg/mL)
Df = concentration of free drug after encapsulation (mg/mL)
Release kinetic mathematical models
Zero-order
First order
Higuchi
Hixson-Crowell
Kosmeyer-Peppas
tKQQt 00
tKQQt 10loglog
5.0
0 tKQQ Ht
tKQQ HCt 3
0
n
KPt tKQ
UV-Vis spectroscopy
DOX 480 nm TMZ 328 nm 5-FU 525 nm
17. Results: CS-g-PLACA- Release kinetics
0
20
40
60
80
100
0 100 200 300 400 500
Cumulativerelease(%)
Time (h)
DOX TMZ 5-FU
0
10
20
30
40
50
60
70
0 10 20 30
Cumulativerelease(%)
Time (h)
DOX, TMZ and 5-FU loaded separately
Physiological solution (pH 7.4)
T : 37 °C
No initial burst effect is observed in all formulations
Release begin after 5 hours
tlag
Common trend
18. Results: CS-g-PLACA-Release kinetics
DOX, TMZ and 5-FU loaded simultaneously
Physiological solution (pH 7.4)
T : 37° C
0
20
40
60
80
100
0 100 200 300 400
Cumulativeco-release(%)
Time (h)
DOX TMZ 5-FU
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30
Cumulativeco-release(%)
Time (h)
Common trend
DOX, TMZ and 5-FU are released concurrently
No initial burst effect is observed in all formulations
Release begin after 4 hours
tlag
19. Release Kinetic mathematical analysis
Zero-order
(R2)
First-order
(R2)
Higuchi
(R2)
Hixson-
Crowell
(R2)
Korsmeyer-
Peppas
(R2)
TMZ 0.73 0.83 0.97 0.97 0.90
DOX 0.88 0.85 0.98 0.98 0.91
5-FU 0.79 0.81 0.98 0.91 0.92
Physiological solution pH 7.4
T : 37° C
CS-g-PLACA
Higuchi model shows the best fit
Drugs are released by diffusion
R2 values in Korsmeyer-Peppas models indicates that the Fickian diffusion
represents the controlling factor
Results related to Hixson-Crowell model demonstrate that a slight change
in the nanoparticles surface area is induced by the media
20. Conclusions
CS-g-PLACA based nanoparticles show dimension in the range 100-200 nm
Nanoparticles show good stability as far as 10 days
Up to 70% of encapsulation efficiency of TMZ, 5-FU and DOX
No initial burst effect at physiological condition
Balanced release of drugs when loaded simultaneously
21. Outlooks
Cell uptakes studies
Evaluation of citotoxicity in different cancer cells lines
In vivo tests