di martino nanocon 2015
TRANSCRIPT
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NANOPARTICLES BASED ON STAR-SHAPED CARBOXY-TERMINATED POLYLACTIDE AND
CHITOSAN FOR CONTROLLED RELEASE APPLICATIONS
Antonio Di MartinoCentre of polymer systems
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Drug Delivery Systems (DDS)Drug delivery systems : approaches, formulations, technologies for the targeted delivery and/or controlled release of therapeutic agents
Safe Perform therapeutic function Convenient administration Ease of manufacturing
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Bioactive Molecules
Vincristine
Progesterone
Antibiotics
Steroids
Antineoplastics
Paclitaxel Doxorubicin
Testosterone
Amoxicillin Sultamicillin Methicillin
Estradiol
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Burst EffectLarge amount of drug released immediately upon placement in the media
Journal of Controlled Release 73 (2001) 121 –136
Advantages Wound treatment Targeted delivery (triggered burst release) Pulsatile release
Disadvantages Local or systemic toxicity In vivo short t1/2 Waste of drug Short release profile Frequent administration Difficult to predict intensity
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Burst Effect
Surface extraction
Drug loading distribution
Surface modification
Polymer morphology and composition
• preparation steps • cost
Process conditions Surface characteristics Morphology Carrier-Drug interactions
Causes
How to reduce….
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Chitosan (CS) Biocompatibility Biodegradability Not toxic Not immunogenic Chemical modification Soluble in mild acidic aqueous media Well known behavior
Glucosamin
N-Acetyl glucosamin
chemotherapy drug Anthracycline antibiotic DNA intercalant Widely used Side effects
Doxorubicin (DOX)
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CS modification by grafting Star Shaped carboxy terminated Poly Lactic Acid (SSPLA)
Reduction of Burst Intensity
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Methods
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SSPLA synthesis
O
OH
N
O
OH
N
O
OH
N
O
OH
OOH
CHCH3
OOH
O
O
N
O
O
N
O
O
N
O
O
OO
CH3
OOH
CH3
O
OHCH3
OH
O
CH3
O
OH
+ lactic a cid , M SA
130°C, vacuum
main product: star shaped poly(lactic acid)
a
b
c
d
e
-(a+b+c+d+e+n)H2O
• Polycondensation reaction
• Pentetic acid as core molecule
• Methansulfonic acid as catalyst
• Coupling reaction
CS-SSPLA
EDC, NHS
48h , RT+
CS
SSPLA CS-SSPLA
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CS-SSPLA NPs preparation PolyElectrolytes Complexation method
Dextran sulfate (DS, Mw 40 kDa)
CS-SSPLA / DS (w/w): 2
1 mg DOX
Fast Low cost Solvent free NPs size related to the polymers weight ratio
DS
CS-SSPLA
DOX
+
I. Add DS + DOX solution
DS
DOX
CS-SSPLA
II. 30 min stirring , RT
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Encapsulation Efficiency (EE) & Release kinetic
100DDD(%)EEt
ft
Encapsulation and Release were evaluated by UV-Vis at 480nm
Phosphate Buffer (PBS) : pH 7.4 Preparation Media (PM) : pH 5 Simulated Gastric Fluid (SGF): pH 1.8 Temperature : 37 ˚C 180 rpm shake
Dt = amount of DOX added (mg/ml) Df = amount of DOX free after encapsulation (mg/ml)
Release conditions
Encapsulation
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SSPLA and CS-SSPLA SSPLA
CS-SSPLA
Mn = 1900 g/molMw = 4000 g/molMw/Mn = 2.4
GPC
H- NMR (-COOH/-OH ratio) = I 5.01/ I 4.2 = 3.45
CCOOH = 0.979 mmol/g
FTIR-ATR = presence of amide bond
1H-NMR
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NPs characterization and Encapsulation
Efficiency
+ 30% - 30%
Average dimension < 200 nm z-potential : 20-35 mV Dimension increases 12-18% after 1 month storage
EE > 80% 200-220 mg DOX/mg carrier SSPLA side chain increase EE
s p2 = 8.23s p
2 =12.62 sp2 =1.92 sp
2 =2.06
+ 8%
sp2 = 30.25
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DOX Release kineticsCS CS-SSPLA
pH Swelling SSPLA
Release rate
SSPLA Does not significantly influence the swelling
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DOX Release kinetics
pH SSPLA
Burst Intensity ( reduction up to 100 % compare to CS )
Lag time (1 – 3 h)
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Conclusions Nanoparticles dimension < 200 nm
Nanoparticles are stable up to 1 month at room temperature
DOX EE > 80 %
The presence of SSPLA side chain increase 8% EE
Lag time from 1-3 h according with pH
Reduction of Burst Intensity in all media
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Future Perspectives Multi-drug encapsulation
Combination of hydrophilic and hydrophobic drugs
Peptides or proteins
Optimization of release profile according with therapeutic goals