Molecular nanoconjugates modified with ligands for active drug targeting

GLISONI R.J.

Ciudad Autónoma de Buenos Aires

Jornada; Primera Jornada Latinoamericana de Nanomedicinas; 2015

Asociación Argentina de Nanomedicinas

Ponencia Oral. INTRODUCTION. Curcumin (CUR), a polyphenolic anti-inflammatory, antioxidant, anti-proliferative and antiangiogenic compound derived from Curcuma longa has gained interest in the therapy of different disease, including cancer (1). However, its poor aqueous solubility (0.011 ug/mL) challenges the oral and parenteral administration (2). The goal of this work was to explore the encapsulation of CUR into polymeric micelles (PMs) of made of pristine poly(ethylene oxide)-b-poly(propylene oxide) block copolymers (PEO-PPO) and their glucosylated derivatives and evaluate their antitumoral activity in vitro employing a murine mammary cell line (3).EXPERIMENTAL METHODS. Encapsulation and characterization of CUR-loaded PMs. CUR-loaded PMs were prepared by means of a direct method in a linear PEO-PPO, Pluronic® F127 and branched derivative, Tetronic® 1107 and their glucosylated counterpart, F127-Glu and T1107-Glu, respectively. Glucosylation was shown to increase the micellization trend and the encapsulation capacity of PMs (4). CUR-loaded micelles were characterized for size, size distribution and zeta- potential employing DLS and the morphology by TEM. Cell viability. The viability of 4T1, a murine mammary tumor cell line, was assessed by the MTT method. In vivo uptake of the micelles. The different formulations were administered to BALB/c mice bearing primary subcutaneous mammary tumors and the uptake of the micelles by the tumor visualized. RESULTS AND DISCUSSION. F127, T1107, F127-Glu and T1107-Glu PMs (10% w/v) increased the solubility of CUR by 52909, 7564, 58175 and 16327, respectively. CUR-loaded micelles displayed hydrodynamic size between 40 and 900 nm. The antitumoral activity of the different CUR-loaded micelles in vitro was compared to that of free CUR in the concentration range 1-25μM at 48 h. Results showed a significant increase of the efficacy for all the micellar formulations containing 5-25 μM, the effect being slightly stronger for T1107-Glu. CUR-free micelles did not affect the viability. Then, CUR-loaded micelles were administered to mice bearing subcutaneous tumors, tumors explanted after 48h and the uptake visualized employing the fluorescence of CUR. Tumors treated with the micelles showed a higher CUR uptake than the controls with the free drug. In addition, glucosylated micelles increased the uptake probably due to higher physical stability.CONCLUSION. The encapsulation efficiency of CUR was evaluated in different PEO-PPO PMs. Nanoencapsulation increased significantly the antitumoral activity in vitro in a model of mammary cancer. Moreover, glucosylation increased the encapsulation efficiency and the uptake of the micelles in vivo. Additional studies on the antitumor effectiveness in vivo are being conducted to support the usefulness of this approach to improve the therapeutic performance of CUR. REFERENCES1. Anand P. et al. Mol. Pharmaceutics 4:807-818, 2007.2. Chiappetta D. & Sosnik A. Eur. J. Pharm. Biopharm. 66:303-317, 2007.3. Ghatak C. et al. J. Phys. Chem. B 116:3369−3379, 2012.4. Glisoni R. & Sosnik A., Macromol. Biosci. 14, 1639-1651, 2014.