This document discusses using star-shaped carboxy-terminated polylactide (SSPLA) grafted onto chitosan (CS) to create nanoparticles for controlled drug release. The nanoparticles were prepared using polyelectrolyte complexation of CS-SSPLA and dextran sulfate, and encapsulated doxorubicin with over 80% efficiency. Release studies showed the SSPLA reduced the initial burst release by up to 100% compared to CS nanoparticles alone. The CS-SSPLA nanoparticles provided a lag time of 1-3 hours before sustained release, indicating their potential for controlled drug delivery applications.

1. NANOPARTICLES BASED ON STAR-SHAPED
CARBOXY-TERMINATED POLYLACTIDE AND
CHITOSAN FOR CONTROLLED RELEASE
APPLICATIONS
Antonio Di Martino
Centre of polymer systems
dimartino@ft.utb.cz

2. 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

3. Bioactive Molecules
Vincristine
Progesterone
Antibiotics
Steroids
Antineoplastics
Paclitaxel Doxorubicin
Testosterone
Amoxicillin Sultamicillin Methicillin
Estradiol

4. Burst Effect
Large 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

5. 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….

6. 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)

7.  CS modification by grafting Star Shaped carboxy terminated
Poly Lactic Acid (SSPLA)
 Reduction of Burst Intensity

8. Methods

9. SSPLA synthesis
O
OH
N
O
OH
N
O
OH
N
O
OH
OOH
CH
CH3
O
OH
O
O
N
O
O
N
O
O
N
O
O
OO
CH3
O
OH
CH3
O
OH
CH3
OH
O
CH3
O
OH
+ lactic acid, MSA
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

10. 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

11. Encapsulation Efficiency (EE) &
Release kinetic
100
D
DD
(%)EE
t
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

13. SSPLA and CS-SSPLA
 SSPLA
 CS-SSPLA
Mn = 1900 g/mol
Mw = 4000 g/mol
Mw/Mn = 2.4
 GPC
 1H- 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

14. 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 p
2 = 8.23 s p
2 =12.62 sp
2 =1.92 sp
2 =2.06
+ 8%
sp
2 = 30.25

15. DOX Release kinetics
CS CS-SSPLA
 pH
 Swelling
 SSPLA
Release rate
 SSPLA Does not significantly
influence the swelling

16. DOX Release kinetics
 pH
 SSPLA
Burst Intensity ( reduction up to 100 % compare to CS )
Lag time (1 – 3 h)

17. 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

18. Future Perspectives
 Multi-drug encapsulation
 Combination of hydrophilic and hydrophobic drugs
 Peptides or proteins
 Optimization of release profile according with therapeutic goals