novel amphiphilic nanoparticles for controlled and sustained release
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Novel amphiphilic nano-carrier based on PLA-polysaccharide for multi-drug encapsulation and controlled release.
In Vitro evaluationA. Di Martino, P. Kucharczyk, Z. Kucekova, P. Humpolicek, V.Sedlarik
Centre of Polymer Systems, University Institute, Tomas Bata University in Zlín, tr. T. Bati 5678, 76001 Zlin, Czech Republic
«approaches, formulations, technologies for the targeted delivery and/or controlled release of therapeutic agents»
Safe Perform therapeutic function Convenient administration Simple to manufacture
Drug Delivery Systems (DDS)
1950 – 1980 : 1st generation – Basics of controlled release
1980 – 2010 : 2nd generation – Smart delivery
2010 – 2040 : 3rd generation – Modulated delivery
- Zero order- Smart polymers and hydrogels- Peptide and protein- Nanoparticles
- Targeted delivery- Long term delivery systems - Minimal burst- In vitro-in vivo correlation (IVIVC)
Park. Journal of Controlled Release 190 (2014) 3–8
Nanoparticles as DDSWhy use Nanoparticles?
Dispersion or solid form Various morphologies – nanospheres, nanocapsules……. Drug(s) can be dissolved, entrapped, encapsulated or attached High Encapsulation and Loading Efficiency Protection Controlled and sustained release Side effects reduction
Polysaccharides in Drug delivery
Hyaluronic acidAlginate
Pectic acid
Dextran sulfate Cyclodextrins
Chondroitin sulfate
Chitosan
5
Small molecules
Proteins Peptides
CyclodextrinesPolysaccharides Drugs
Chitosan and derivatives
Synthetic PolymersLMW, MMW,HMW
-C3-OH-C6- OH
-NH2
D-Glucosamine N-Acetyl -D-Glucosamine
Polylactic acid (PLA)
Biomedical application of PLA
LPLA – Low molecular weight linear PLACPLA – Low molecular weight Carboxy enriched PLABPLA – Low molecular weight Branched PLA
GoalsPreparation of a set of amphiphilic carriers
Single and Multiple Encapsulation of anticancer drugs
Improve drug release performance and stability
Reduction of burst effect
Increase drug cytotoxicity
Chitosan-g-PLA : synthesis and characterization
Synthesis Coupling reaction between CS-NH2 and PLA-COOH EDC/NHS Low conjugation degree Further conjugation (Folic acid, Fluorescein, DTPA..) CS properties conserved
Characterization : FTIR-ATR 1H-NMR
Di Martino et al. Int.J.Pharm. 2015 Dec 30;496(2):912-21
CS-PLA based nanoparticles Polyelectrolytes Complexation (PEC)
Ionotropic Gelation (IG)
Fast and simple Solvent free Not needs special equipment Dimension and surface charge control Low P.D.I. Good reproducibility
PEC Dextran sulfate • + charges / - charges•Mw•Concentration
IG• + charges / - charges•Concentration
Characterization : DLS, SEM, TEM
Anticancer drugs
Suicide inhibitor Inhibition of thymidylate synthase Antimetabolite
Doxorubicin Temozolomide 5-Fluorouracil
Alkylate/methylate DNA N-7 or O6 guanine Resistance mechanism
DNA intercalation Inhibits topoisomerase II Block the DNA replication
SIDE EFFECTSHYDROLYSIS
CIRCULATION TIME SIDE EFFECTSADMINISTRATION ROUTE
Nanoparticles characterization
- Single loading not influence average dimension - Simultaneous loading increase average dimension
PLA side chain structure direct influences nanoparticles size
Increase in dimension up to 50 %
Average dimension is around 150nm
Encapsulation Efficiency- single loading
Environment Presence of side chain (-COOH, branched) Drug structure
Influence encapsulation efficiency
Di Martino & Sedlarik . Int.J.Pharm. 2014 Oct 20;474(1-2):134-45
Encapsulation efficiency-multiple loading
DOX conteining formulations are better encapsulated Further investigationsDi Martino & Sedlarik . Int.J.Pharm. 2014 Oct 20;474(1-2):134-45
Bust Effect Reduction
Large amount of drug released immediately upon placement in the media
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
Journal of Controlled Release 73 (2001) 121 –136
What is burst effect?
Time (h)
Cum
ulat
ive
rele
ase
(%)
0 1 2 3 4 5 60
10
20
30
40
50
60
DOX
TMZ
CS
Time (h)
Cum
ulat
ive
rele
ase
(%)
0 1 2 3 4 5 60
10
20
30
40
50
60DOX
TMZ
CS-g-PLA
40%
30%
Time (h)
Cum
ulat
ive
rele
ase
(%)
0 1 2 3 4 5 60
10
20
30
40DOX
TMZ
CS-g-PLACA2%
lag time
20%
Time (h)
Cum
ulat
ive
rele
ase
(%)
0 1 2 3 4 5 60
10
20
30
40DOX
TMZ
CS-g-PLACA5%
lag time10%
Sustained-release Delayed-release
Release kinetic : Burst Effect reduction and Delayed Release
Improve drug stability
N
N
N
NN
ONH2
CH3O
N
NH
O NH2
NN NH
CH3N
NH
NH2
O NH2
N+
NCH3
+TMZ MTIC
AIC
Diazomethane cation
H2O
-CO2
TMZ quickly hydrolyse in physiological condition
Improve stability of TMZ is a challenge
TMZ free in PSTMZ loaded in CS-g-BPLA / CPLA
t1/2 : 35 – 180 min
t1/2 : few minX100 120 140 160 180 200 220 240
0
1
2
3
4
5
6
7
8
9
10
m/z
Cou
nts
x105
TMZPS 6h
100 120 140 160 180 200 220 2400
1
2
3
4
5
6
7
8
9
10
m/z
Cou
nts
x105
TMZPM 6h
TMZ
TMZ
MTIC
AIC
3h
6h
Cell tests - Citotoxicity Citotoxicity evaluation of free and loaded drugs
MEF, NIH/3T3 cell-lines
CS-BPLA CS-BPLA+ 5FUCS-BPLA + TMZCS –BPLA + DOX
CS-LPLACS-BPLA
Presence of PLA side chain increase drug citotoxicity!!!
24h24h 24h 24h
Conclusions Nanoparticless based on chitosan and a set of different PLA were prepared
Dimension up to 200 nm and good stability in various simulated physiological fluid
PLA side chain directs influence the nanoparticles properties
Presence of COOH groups and branched PLA structure increase encapsulation efficiency
Reduction of burst effect BPLA > CPLA > LPLA
Branched PLA prolongs the release of all tested drugs
Prepared CS-PLA based nanoparticles delay TMZ hydrolysis in physiological condition
Cell citotoxicity tests demonstrate an increase in drug toxicity after loading in CS-PLA based formulations
Acknowledgements
grant No. 15-08287Y
grant No. LO1504
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