In this study, we describe an intratumoral injectable, electrostatic, cross-linkable curcumin (Cur) drug depot to enhance anticancer activity. The key concept in this work was the preparation of an electrostatic, cross-linked carboxymethyl cellulose (CMC) and chitosan (CHI) hydrogel containing Cur-loaded microcapsules (Cur-M). The CMC and CHI solutions existed as a liquid before mixing and formed a CMC and CHI (CCH) hydrogel as a drug depot after mixing via electrostatic interactions between the anionic CMC and cationic CHI. Compared with the individual CMC and CHI solutions, the electrostatic, cross-linked CCH depot persisted in vivo for an extended period. The prepared Cur-M was easily mixed with the CMC and CHI solutions. Cur-M/CMC and Cur-;M/CHI solutions easily formed Cur-M-loaded CCH depots after simple mixing. The in vitro and in vivo Cur-M-loaded CCH depot was designed with Cur-M dispersed inside an outer shell of electrostatically cross-linked CCH. The Cur-M-loaded CCH depot produced greater inhibition of tumor growth than did Cur-M, whereas single and repeated injections of free Cur had the weakest inhibitory effects. The results of this study indicate that the electrostatic, cross-linked, Cur-M-loaded CCH depot described in this study can synergistically enhance anticancer activity in chemotherapeutic delivery systems.
Preparation of Cur-MCur-M was prepared using a monoaxial one-nozzle atomizer (Sono-Tek Crop, Milton, NY, USA). The typical preparation of Cur-M was achieved as follows: PLGA and Cur were dissolved in ethyl acetate and methanol, respectively. The concentrations of PLGA and Cur were 3% and 5% w/v, respectively. The mixtures of PLGA and Cur were fed into the ultrasonic atomizer at flow rates of 4 ml min − 1 . Microdroplets were produced by atomizing the mixed solutions of PLGA and Cur for~5 s at a vibration frequency of 3 W per 60 kHz and the microdroplets were then immediately collected in a 0.5% w/v poly(vinyl alcohol) solution for 2 min. The distance between the atomizer head and the aqueous poly(vinyl alcohol) solution was 1 cm, and the stirring speed of the poly(vinyl alcohol) solution was 1000 r.p.m. The resulting mixtures were gently stirred for 2 h to allow solidification of the microcapsules and were then filtered and washed with distilled water. The Cur-M was frozen at − 75°C, followed by freeze-drying over 4 days. The morphology of Cur-M was confirmed using an optical microscope (Carl Zeiss MicroimagingThe encapsulation efficiency of Cur was determined using acetonitrile and DW. Cur-M (4 mg) was placed into a test tube and 0.6 ml acetonitrile was added to Injectable, electrostatic, cross-linkable curcumin SH Park et al