Reduction-Responsive Disassemblable Core-Cross-Linked Micelles Based on Poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)–Lipoic Acid Conjugates for Triggered Intracellular Anticancer Drug Release

Abstract

Reduction-sensitive reversibly core-cross-linked micelles were developed based on poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-lipoic acid (PEG-b-PHPMA-LA) conjugates and investigated for triggered doxorubicin (DOX) release. Water-soluble PEG-b-PHPMA block copolymers were obtained with M(n,PEG) of 5.0 kg/mol and M(n,HPMA) varying from 1.7 and 4.1 to 7.0 kg/mol by reversible addition-fragmentation chain transfer (RAFT) polymerization. The esterification of the hydroxyl groups in the PEG-b-PHPMA copolymers with lipoic acid (LA) gave amphiphilic PEG-b-PHPMA-LA conjugates with degrees of substitution (DS) of 71-86%, which formed monodispersed micelles with average sizes ranging from 85.3 to 142.5 nm, depending on PHPMA molecular weights, in phosphate buffer (PB, 10 mM, pH 7.4). These micelles were readily cross-linked with a catalytic amount of dithiothreitol (DTT). Notably, PEG-b-PHPMA(7.0k)-LA micelles displayed superior DOX loading content (21.3 wt %) and loading efficiency (90%). The in vitro release studies showed that only about 23.0% of DOX was released in 12 h from cross-linked micelles at 37 °C at a low micelle concentration of 40 μg/mL, whereas about 87.0% of DOX was released in the presence of 10 mM DTT under otherwise the same conditions. MTT assays showed that DOX-loaded core-cross-linked PEG-b-PHPMA-LA micelles exhibited high antitumor activity in HeLa and HepG2 cells with low IC(50) (half inhibitory concentration) of 6.7 and 12.8 μg DOX equiv/mL, respectively, following 48 h incubation, while blank micelles were practically nontoxic up to a tested concentration of 1.0 mg/mL. Confocal laser scanning microscope (CLSM) studies showed that DOX-loaded core-cross-linked micelles released DOX into the cell nuclei of HeLa cells in 12 h. These reduction-sensitive disassemblable core-cross-linked micelles with excellent biocompatibility, superior drug loading, high extracellular stability, and triggered intracellular drug release are promising for tumor-targeted anticancer drug delivery.

Glutathione-degradable drug-loaded nanogel effectively and securely suppresses hepatoma in mouse model

“…In addition, Wei et al developed a reduction-responsive reversible core crosslinked micelle based on poly(ethylene glycol)-block-poly((N-2-hydroxypropyl methacrylamide)-co-N-2-hydroxypropyl methacrylamidegraft-lipoic acid) (PEG-b-P(HPMA-co-(HPMA-g-LA))), which was investigated for triggered doxorubicin (DOX) release. 17 As expected, the laden disulfide-crosslinked system exhibited improved intracellular DOX release and enhanced cellular proliferation inhibition in vitro.…”

Synthesis strategies for disulfide bond-containing polymer-based drug delivery system for reduction-responsive controlled release

“…Wei et al synthesized the core-cross-linked micelles based on PEG-b-poly(N-2-hydroxypropyl methacrylamide)-LA (PEG-b-PHPMA-LA) conjugates by RAFT polymerization [60]. The micelles were readily crosslinked with a catalytic amount of DTT.…”

Surfactant‐Free Emulsion‐Based Preparation of Redox‐Responsive Nanogels

“…The formation of crosslink via the intermolecular disulfi de exchange reaction of poly(BAC2-AMPD1)-PEG is important to the fabrication and stability of the nanogels. There are several ways to facilitate the disulfi de exchange reaction such as adding catalytic amount of reducing agents such as dithiothreitol (DTT), [ 42,43 ] tuning to a basic pH [ 17,37 ] or applying heating. [ 41,44 ] In our work, the W/O emulsion was heated to 50 °C for various duration.…”

“…The enhanced stability of the nanogels in saline should be attributed to a higher crosslinking density induced by heating. [ 42 ] For subsequent studies, the nanogels were produced after heating the emulsion for 3 h.…”