Biostable Poly(ethylene oxide)-b-poly(methacrylic acid) Micelles forpH-triggered Release of Doxorubicin

Abstract

ABSTRACT − pH-sensitive cross-linked polymeric micelles were synthesized by using block ionomer complexes of poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) with calcium ions as micellar templates. An anticancer drug, doxorubicin (DOX) was conjugated on the cross-linked ionic cores of micelles via acid-labile hydrozone bonds. The result-ing DOX-conjugated, pH-sensitive micelles are stable at physiological conditions, whereas the release of DOX was sig-nificantly increased at the acidic pH. Such micelles were internalized to lysosomes, and acidic pH in lysosomes triggers the release of DOX upon internalization in MCF-7 breast cancer cells. The released DOX entered the cell nucleus and even-tually killed cancer cells. Therefore, these data demonstrate that the pH-sensitive micelles could be a promising nanocarrier for delivery of anticancer drug, DOX.Key words− Doxorubicin, Block ionomer, Calcium, Cross-linked, Polymeric micelles Self-assembled polymeric micelles formed by amphilphilic block copolymers have been utilized as potential drug delivery vehicles for anti-cancer drugs (Allen et al., 1999; Cohy, 2005; Croy et al., 2006; Duncan, 2003; Kabanov et al., 2009; Lavasanifara et al., 2002; Riess, 2003; Rosler, 2001). They are nanoparticles prepared by self-assembly of block copolymers consisted of two different blocks, which are hydrophilic and hydrophobic blocks. Advantages of polymeric micelles for tumor targeting include core-shell type architecture with nanoscale size (10 to 100 nm in diameter), which prolong cir-culation time of polymeric micelles in the body. Hydrophilic nonionic shell such as poly(ethylene oxide) allows for long-cir -culation of nanocarriers by reducing non-specific uptake and clearance by the macrophages of the reticuloendothelial sys-tem (RES). Interestingly, such polymeric nanocarriers have been shown to accumulate in tumors and improve anti-tumor activity of anti-cancer drugs (Alakhov et al., 1999; Yokoyama et al., 1999; Lavasanifara et al., 2002; Duncan, 2003; Davis et al., 2008), by the enhanced permeability and retention effect (EPR effect) (Maeda, 2001). Nanofabrication of the polymeric micelles has been exten-sively advanced through employment of double hydrophilic diblock copolymers, one of which is hydrophilic ionic block and the other is hydrophilic nonionic block. These copolymers spontaneously form nanoparticles called “block ionomer com-plexes (BIC)” or “polyion complex micelles (PIC)”, through electrostatic interaction with oppositely charged molecules. However, the stability of polymeric micelles can be signif-icantly affected by environmental factors such as pH, ionic strength, dilution and shear forces after administration in the blood stream, which may lead to loss of their ability to deliver chemotherapeutic drugs to target tissues.In order to address this problem, nano-sized polymeric micelles based on a cross-linked network of amphiphilic block copolymers have been developed for delivery of anti-cancer drugs (Bronich et al., 2005; Bontha et al., 2006; Kim et al., 2009; Kim et al., 2010). It contains several key features such as cross-linked ionic core, a hydrophilic PEO shell and nanos-cale size. Due to cross-linked ionic cores of micelles, these micelles exhibited distinctive properties as drug delivery carriers, such as their high loading capacity, high stability, and responses to environmental stimuli, such as ionic strength, pH, and temperature (Bontha et al., 2006; Kim et al., 2009).Furthermore, the entry of the cross-linked micelles is inhibited in tight junctions in normal epithelial cells but permitted in cancer cells that do not form tight junctions, via caveolae-mediated endocytosis (Sahay et al., 2010). These favorable characteristics of cross-linked micelles can lead to develop-