Post on 01-Jun-2015
description
Chitosan-Folic Acid as system for site specific drug delivery
Antonio Di Martino
Tomas Bata University in Zlin Czech Republic
dimartino@ft.utb.cz
ChitosanObtained from Chitin by partial or total deacetylation
Deacetylation Chemical Enzimatic
Chitosan properties are related to Deacetylation Degree (DD) Molecular Weight (Mw)
Chitosan properties-I
Chemical properties
Cationic polyamine with low pKa High charge density at pH below 6.5 Forms gels with polyanions Adheres to negatively charged surfaces Chelates transition metals Amenable to chemical modification Both amino and hydroxyl groups can be selectively modified
CH2OH
HO
O
ONH-C-CH3
O
CH2OH
O
NH2O
NH2HO
CH2OH
O O
HO
x
Chitosan properties-IIBiological properties
Biocompatible Biodegradable Hemostatic Bacteriostatic Fungistatic Spermicidal Anti-cancer Anticholesterolemic
Folic Acid Its biological importance is due to tetrahydrofolate and other derivatives after its
conversion to dihydrofolic acid
Humans cannot synthesize folate de novo
It is essential for numerous bodily function synthesize DNA repair DNA methylate DNA aiding cell rapid division and growing cofactor in many biological reaction
Folic Acid receptors
Folate Receptor 1 –FOLR1 (adult) Folate Receptor 2 – FOLR2 (fetal) Folate Receptor 3 – FOLR3 RTBDN
FOLR1 FOLR2
Folate Receptors
FOLR1can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain
FOLR2 was originally thought to exist only in placenta, but is also detected in spleen, bone marrow, and thymus
Chitosan – Folic Acid
+
Reaction is carried out in presence of EDC and NHS
Degree of functionalization is related with the Folic Acid concentration, the DD and Mw of Chitosan
Not necessary to obtain high degree of functionalization
Chitosan-Folic Acid Nanoparticles Nanoparticles can be prepared by Polyelectrolytes Complexation (PEC) Method
using Dextran Sulfate as polyanions
PEC is an easy, low cost and solvent free method to prepare nanoparticles in suspension
Particles dimension, PDI and z-potential can be changed according with the positive and negative charges ratio
Possibility to encapsulate more than one drug simultaneously
Possibility to encapsulate pDNA or linear DNA
Simultaneous encapsulation of DNA and drug is also possible
PolyElectrolyte Complexation method (PEC)
Polyanion solution
Step I: Add the solution containing drug to polyanion solution
Drug in solution
Drug + Polyanion in solution
Step II
Step II: Add drop-wise A to B under magnetic stirring
Drug + Polyanion in solution
(A)
CS-Folic Acid in solution(B)
Nanocomplex in suspension
Polycation Polyanion
Drug
Encapsulation Efficiency The Encapsulation Efficiency is related with
the positive- negative charges ratio
Chemical and physical properties of the drug in solution ( positive or negative charged, polar or apolar)
CS-Folic Acid – drug ratio (w/w) In case of DNA encapsulation is necessary to consider the
(N/P ratio) Encapsulation Efficiency can be calculate by
spectrophotometric methods ( UV-Vis)
Release Kinetic
• Generally, in this kind of systems the release rate is strictly influenced by the pH of the media
• Chitosan based system show prolonged release (even 2-3 weeks) at pH lower than 4.5. The release rate is related with the kind of drug and the encapsulation efficiency.
• An in initial burst often occurs, especially when high amount of drug is loaded
Conclusion
• Chitosan represents one of the more suitable biopolymer for controlled drug and gene delivery
• The presence of amino groups make chitosan easy to functionalize with different kind of molecules in order to improve the cell uptake
• Chitosan based nanoparticles can be prepared by solvent free methods
• Possibility to change size and z-potential of the nanoparticles• Possibility to encapsulate different kind of molecules by
electrostatic interactions• Release rate is pH and Temperature dependent