1. II. Nanoparticles preparation TMZ stability evaluation
Improvement of Temozolomide Stability by Loading in Chitosan-carboxy Enriched Polylactide Nanoparticles: In Vitro Evaluation.
Di Martino A., Kucharczyk P., Kucekova Z., Humpolicek P., Sedlarik V.
Centre of Polymer Systems, University Institute, Tomas Bata University in Zlín, tr. T. Bati 5678, Zlin, Czech Republic
INTRODUCTION
METHODS
II. Nanoparticles preparation
Polyelectrolites complexation method
Temozolomide (TMZ) is an alkylating agent considered one of the most effective for treating grade IV glioma and metastatic melanoma [1]. However, due to its fast hydrolysis in physiological media (half-life less than 1.8 h) TMZ has to be administered in high systemic doses to reach the required therapeutic concentration, which unfortunately brings on side effects such as bone marrow depression, oral ulcerations, nausea, vomiting, fatigue and headaches. To improve TMZ stability various formulation has been developed mainly based on polyacrylates and polysorbates [2].
In this work a formulation based on chitosan grafted by carboxy-enriched polylactide (CS-PLACA) was prepared to encapsulate, release and prolong the stability of TMZ in physiological like media. Evaluation of free and TMZ loaded in CS-PLACA cytotoxicity was investigated in MEFs cell line over time to shown the advantages of the use the carrier compare to free drug.
I. CS-PLACA synthesis
Simple
Solvent free
High reproduciblity
III. Encapsulation and TMZ stability
UV-Vis 275 nm
LC-MS - determination of TMZ release after 6h and 24h
IV. Cell test
MEF cell line - Evaluation of free and TMZ loaded in CS-PLACA nanoparticles cytotoxicity
RESULTS
Nanoparticles characterization
TMZ stability evaluation
Control
OBJECTIVES
The main aims of the presented works are:
I) Preparation of an amphiphilic carrier (CS-PLACA)
II) Encapsulation of TMZ in CS-PLACA
based nanoparticles
III) Improved stability of TMZ in
physiological solution
IV) Reduction of In Vitro TMZ cytotoxicity
Nanoparticles dimeter: nm
PDI =
z-potential : 27 mV ± 5 at pH 5.5
TMZ released
6 h
CS-PLACA
PLACA increases TMZ encapsulation
about 10%
500 mg TMZ / 1 mg of CS-PLACA
TMZ released
12 h
MEFs micrographs
CS-PLACA + TMZ
24h
CS-PLACA + TMZ
48h
CS-PLACA
CONCLUSIONS
ACKNOWLEDGEMENTS
This work was funded by the Czech Science Foundation
(grant No Y) and Ministry of Education, Youth and Sports
of the Czech Republic (grant No. LO1504).
Prepared system posses important properties such as i) mild preparation conditions; ii) valuable drug-loading capacity, continuous and sustainable release iii) protection of encapsulated drug. The absence of any interference between TMZ and the carrier during loading and release process stand out as important findings, suggesting CS-PLACA as an interesting candidates for TMZ controlled delivery. Moreover, no structural alteration occurred in TMZ after release, indicative the protective role against hydrolysis.
REFERENCES
[1] Trinh, V.A. Expert. Opin. Drug. Saf. 2009,8, 4,
[2] Zhou, Q. J.Pharmacol. Exp.Ther. 2007, 321, 1,