Abstract
In this study, stimuli-responsive polymersomes were developed from spontaneous co-association of two graft copolymers both comprising acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone (copolymer A) or both PNIPAAm and monomethoxy poly(ethylene glycol) (mPEG) chain segments as the grafts (copolymer B) via hydrogen bonding of unionized AAc with NIPAAm moieties with medium pH being lowered from 7.4 to 3.0 at 25 oC. The PAAc/PNIPAAm-rich hydrophobic membranes of polymersomes were further cross-linked upon photo-initiated radical polymerization of the MEA units. The cross-linked (CL) polymersomes exhibited an obvious structural regulation in response to changes in external pH and temperature. In addition, through hydrophobic AAc/doxorubicin (DOX) complexes formed via complementary electrostatic attraction of DOX molecules with ionized AAc residues and then stabilized by hydrogen bonding between DOX and PNIPAAm, DOX was successfully encapsulated into CL polymersomes. These results of in vitro drug release, cellular uptake and cytotoxicity indicate that after being internalized by HeLa cells via endocytosis, DOX-loaded CL polymersomes are capable of releasing rapidly drug within acidic endosomes and lysosomes upon extensive disruption of the originally formed electrostatic attraction and hydrogen bonding, thereby resulting in a high intracellular drug concentration to maintain therapeutic efficacy for anticancer treatment. Therefore, such polymersomes with pH- and thermo-responsive CL membranes show great potentiality of effective intracellular DOX delivery. On the other hand, to develop multifunctional polymeric assemblies for drug delivery and enhanced MR imaging, through co-association of citric acid-modified iron oxide nanoparticles (IOPs) with copolymer B via extensive hydrogen bonding of unionized carboxyl acid and NIPAAm residues with medium pH being adjusted from pH 7.4 to pH 3.0, the copolymer-caged IOPs (CCIOPs) were attained and then cross-linked upon photo-initiated radical polymerization of the MEA units. The obtained cross-linked (CL) CCIOPs have a particles size of ca. 200 nm in diameter and superparamagnetic property. Moreover, the CL CCIOPs with a high DOX payload (ca. 88.3 %) exhibit superior pH-controlled drug release profiles. Interestingly enough, the transverse relaxivity (r 2 ) of the CL CCIOPs was appreciably enhanced and changed by varying external solution pH. After being internalized by HeLa cells via endocytosis, the CL CCIOPs still showed significantly dark images. The results of in vitro cytotoxicity of CL CCIOPs further illustrate their potential application as a theranostic platform.