We describe a biodegradable amphiphilic polyurethane (PU) with disulfide bonds in the main chain [PEtOz-b-PU(SS)-b-PEtOz]. This multi-block PU was synthesized using poly (ε-caprolactone) diol (PCL-SS-PCL) and poly (2-ethyl-2-oxazoline) (PEtOz-OH) as soft segments, and bis (2-isocyanatoethyl) disulfide as the hard segment. Acid-sensitive PEtOz-OH was used as a hydrophilic segment for pH sensitivity. And reduction sensitivity was induced via disulfide bonds incorporated into the hydrophobic poly (ε-caprolactone) segment of the amphiphilic PUs. The system can self-assemble to form micelles responsive to pH and reducing conditions. The properties of the micelle were studied with dynamic light scattering and scanning electron microscopy. Doxorubicin (DOX) was chosen as a model drug. The in vitro release studies showed that PEtOz-b-PU(SS)-b-PEtOz micelle could degrade more rapidly and completely in a reductive and acidic environment [10 mM dl-Dithiothreitol, pH 5.0]. The methyl tetrazolium (MTT) assay and fluorescent microscopy confirmed the cytotoxicity of the DOX-loaded micelles. This work provides a promising dual-responsive drug carrier based on amphiphilic PU to achieve efficient drug delivery.

Reduction responsive biodegradable core-cross-linked micelles are developed form lipoic acid and cholic acid decorated poly(ethylene glycol)-b-poly(l-glutamic acid) block copolymers and investigated for intracellular doxorubicin release.

A series of disulfide-linked amphiphilic polymers polyoxaline-SS-poly(lactide) (PEtOx-SS-PLA) were prepared and self-assembled into nano-micelles in water. The anticancer drug curcumin (Cur) was selected as a model drug, the entrapment of Cur in PEtOx-SS-PLA micelles was investigated and the intracellular transport and release of Cur-loaded micelles was studied in C6 cells. The preparation of Cur-loaded polymer micelles showed that micelle size decreased after drug loading, favoring cell phagocytosis. MTT experiments showed that PEtOx-SS-PLA 52 micelles have a small IC₅₀ (2.05 μg mL⁻¹). The release behavior of PEtOx-SS-PLA 52 drug-loaded micelles in C6 cells showed that polymer micelle enhanced the intracellular release of Cur, and increased the inhibition effect of cancer cells. In a word, these reduction and pH-dual sensitive, biodegradable, hydrophilic shell-discarding PEtOx-SS-PLA micelles have great potential for future tumour administration.

Reversibly shell cross-linked micelles based on a lipoic acid (LA) decorated triblock copolymer poly(ethylene glycol)-b-poly(γ-benzyl-L-glutamate)-b-poly(L-phenylalanine) (PEG–PGlu(EDA–LA)–PPhe) have been developed for active loading and efficient intracellular delivery of DOX. The triblock copolymer was synthesized through consecutive ring-opening polymerization of cyclic monomers γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and L-phenylalanine N-carboxyanhydride (Phe-NCA) using amino-terminated poly(ethylene glycol) (PEG–NH₂) as macroinitiator, followed by conjugation with LA for reversible cross-linking. The amphiphilic polymer was self-assembled to core shell corona micelles, which could be further crosslinked in the presence of a catalytic amount of dithiothreitol (DTT) in phosphate buffer (pH 7.4) to form shell-cross-linking micelles (SCLM). The SCLM showed excellent stability under physiological conditions but rapid dissociation and drug release in reductive environments mimicking those of the cytoplasm and the cell nucleus. Confocal laser scanning microscopy further demonstrated that DOX was delivered and released into the nuclei of HeLa cells following 12 h incubation with DOX-loaded SCLM. MTT assays revealed that DOX-loaded SCLM had similar anti-tumor activity as non-cross-linked micelles (NCLM) for HeLa cells following 48 h incubation. PEG–PGlu(EDA–LA)–PPhe micelles displayed low cytotoxicity up to a concentration of 1.0 mg mL⁻¹. These biodegradable reversibly shell-cross-linked micelles provide a promising platform for intelligent intracellular drug delivery in clinical chemotherapy.

The survival rate of osteosarcoma therapy still lags behind overall cancer therapies due to the intrinsic or acquired drug resistance. Developing novel drug delivery systems that may overcome drug resistance would greatly facilitate osteosarcoma therapy. Poly(ethylene glycol) (PEG)-sheddable reduction-sensitive polyurethane (SS-PU-SS-PEG) was synthesized using a disulfide-containing polycaprolactone diol as the hydrophobic block and a cystamine-functionalized PEG as the hydrophilic block. SS-PU-SS-PEG micelles were then prepared to load the anti-tumor drug Doxorubicin (DOX) in order to achieve triggered intracellular drug delivery to improve the efficacy of osteosarcoma therapy. When DOX was used as a model drug, the drug-loaded SS-PU-SS-PEG micelles were about 82∼94 nm in diameter and exhibited good stability in phosphate buffer saline (PBS). The micelles could release about 80% DOX in a quantitative fashion within 5 hours under a reductive environment. The intracellular drug release of DOX-loaded SS-PU-SS-PEG micelles increased upon incubation with Saos-2 cells in vitro. The micelles had good biocompatibility. In vitro, DOX-loaded SS-PU-SS-PEG micelles showed significant antitumor activity toward Saos-2 cells, which was close to that of free DOX. In vivo, DOX-loaded SS-PU-SS-PEG micelles exhibited better antitumor activity than free DOX. Findings from this study suggest that the SS-PU-SS-PEG micelles could achieve well-controlled triggered drug release in a reduction environment and could therefore improve the antitumor efficacy of osteosarcoma therapies. In this study we developed PEG-sheddable reduction-sensitive polyurethane micelles (SS-PU-SS-PEG), which were able to achieve well-controlled triggered release of anti-tumor drug Doxorubicin (DOX) in an intracellular reduction environment. DOX-loaded SS-PU-SS-PEG micelles markedly improved the antitumor efficacy in a Saos-2 cells-bearing xenograft tumor model. Therefore, such micelles might be used as a novel drug delivery system for osteosarcoma treatment.