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Multifunctional nanosheets (HA-GO/Pluronic) with targeted chemo-photothermal properties were successfully developed for controlled delivery of mitoxantrone (MIT) to overcome multidrug resistance (MDR). In vitro release profiles displayed that both an acidic environment and a NIR laser could trigger and accelerate the release of a drug, which ensured nanosheets were stable in blood circulation and released MIT within tumor cells under laser irradiation. HA-GO/Pluronic nanosheets were taken up into MCF-7/ADR cells via receptor-mediated endocytosis, which further facilitated escapement of P-gp efflux. Compared with MIT solution, MIT/HA-GO/Pluronic showed greater cytotoxicity and increase in cellular MIT accumulation in MCF-7/ADR cells. Cell apoptosis and cell cycle arrest studies also revealed that MIT/HA-GO/Pluronic was more potent than MIT/GO/Pluronic and MIT solution. The anticancer efficacy in vivo was evaluated in MCF-7 and MCF-7/ADR-bearing mice, and inhibition of tumors by MIT/HA-GO/Pluronic with NIR laser irradiation was the most effective among all MIT formulations. In summary, the MIT/HA-GO/Pluronic system had striking functions such as P-gp reversible inhibitor and anticancer efficacy, and could present a promising platform for drug-resistant cancer treatment.

Poly(2-methyl-2-oxazoline) (PMOZ), poly(2-propyl-2-oxazoline) (PnPOZ) and poly(2-isopropyl-2-oxazoline) (PiPOZ) were synthesized by hydrolysis of 50 kDa poly(2-ethyl-2-oxazoline) (PEOZ) and subsequent reaction of the resulting poly(ethylene imine) with acetic, butyric and isobutyric anhydrides, respectively. These polymers were characterized by proton nuclear magnetic resonance, FTIR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The poly(2-oxazolines) as well as poly(N-vinyl pyrrolidone) (PVP) were used to prepare solid dispersions with haloperidol, a model poorly soluble drug. Dispersions were investigated by powder X-ray diffractometry, differential scanning calorimetry and FTIR spectroscopy. Increasing the number of hydrophobic groups (-CH 2 -and -CH 3 ) in the polymer resulted in greater inhibition of crystallinity of haloperidol in the order: PVP > PnPOZ=PEOZ > PMOZ. Interestingly, drug crystallization inhibition by PiPOZ was lower than with its isomeric PnPOZ because of the semi-crystalline nature of the former polymer. Crystallization inhibition was consistent with drug dissolution studies using these solid dispersions, with exception of PnPOZ, which exhibited lower critical solution temperature that affected the release of haloperidol.

Recently, nanomaterials with multiple functions, such as drug carrier, magnetic resonance imaging (MRI) and optical imaging, and photothermal therapy, have become more and more popular in cancer research. In this work, a novel redox-sensitive system constructed from hyaluronic acid (HA), single-walled carbon nanotubes (SWCNTs), doxorubicin (DOX), and gadolinium (Gd) was successfully developed. Herein, HA-modified SWCNTs (SWCNTs-HA) was first synthesized, and then DOX was conjugated with HA by disulfide bond (SWCNTs-HA-ss-DOX). Finally, MRI contrast agents, Gd 3+ -ion loading occurred through the sidewall defects of SWCNTs, whose cytotoxicity could be sequestered within the SWCNTs. In vitro release of DOX showed that this system accomplished much faster drug release under reducing condition. Confocal microscopy analysis confirmed that Gd/SWCNTs-HA-ss-DOX were capable of simultaneously delivering DOX and SWCNTs into Michigan Cancer Foundation-7 cells via HA receptor-mediated endocytosis followed by rapid transport of cargoes into the cytosol. Enhanced cytotoxicity of Gd/SWCNTs-HA-ss-DOX further proved that the sensitive system was more potent for intracellular drug delivery as compared with the insensitive control. Meanwhile, tumor cell killing potency was improved when Gd/SWCNTs-HA-ss-DOX were combined with near-infrared irradiation, with IC 50 of 0.61 µg/mL at 48 hours. In vivo investigation demonstrated that Gd/SWCNTs-HA-ss-DOX could effectively accumulate in tumor sites and possessed the greatest synergistic antitumor efficacy, especially under the 808 nm laser irradiation. More importantly, this system could be used as a contrast agent for MRI to identify the location and extent of tumor tissues. These results suggested that Gd/SWCNTs-HA-ss-DOX might be a promising system for targeting chemo-photothermal therapy and MRI diagnosis in future clinical anticancer applications.