Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines).

Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properties affected drug dissolution, where PnPOZ exhibited lower critical solution temperature that inhibited the release of IB, whereas drug release from other systems was consistent with the degree of ibuprofen crystallinity within the dispersions.

Polymer structure and property effects on solid dispersions with haloperidol: Poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies.

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 (-CH2- and -CH3) 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.

Copper sulfide nanoparticle-based localized drug delivery system as an effective cancer synergistic treatment and theranostic platform.

Localized cancer treatment with combination therapy has attracted increasing attention for effective inhibition of tumor growth. In this work, we introduced diffusion molecular retention (DMR) tumor targeting effect, a new strategy that employed transferrin (Tf) modified hollow mesoporous CuS nanoparticles (HMCuS NPs) to undergo extensive diffuse through the interstitium and tumor retention after a peritumoral (PT) injection. Herein, HMCuS NPs with strong near-infrared (NIR) absorption and photothermal conversion efficiency could serve as not only a drug carrier but also a powerful contrast agent for photoacoustic imaging to guide chemo-phototherapy. The iron-dependent artesunate (AS), which possessed profound cytotoxicity against tumor cell, was used as model drug. As a result, this AS loaded Tf-HMCuS NPs (AS/Tf-HMCuS NPs) system could specially target to tumor cells and synchronously deliver AS as well as irons into tumor to achieve enhanced antitumor activity. It was found that AS/Tf-HMCuS NPs was taken up by MCF-7 cells via Tf-mediated endocytosis, and could effectively convert NIR light into heat for photothermal therapy as well as generated high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, in vivo antitumor efficacy studies showed that tumor-bearing mice treated with AS/Tf-HMCuS NPs through peritumoral (PT) injection under NIR laser irradiation displayed the strongest inhibition rate of about 74.8%, even with the reduced frequency of administration. Furthermore, to demonstrate DMR, the optical imaging, photoacoustic tomography and immunofluorescence after PT injection were adopted to track the behavior of AS/Tf-HMCuS NPs in vivo. The results exhibited that Tf-HMCuS NPs prolonged the local accumulation and retention together with slow vascular uptake and extensive interstitial diffusion, which was consistent with the biodistribution studies of AS/Tf-HMCuS NPs. Therefore, the approach of localized delivery through DMR combined with multi-mechanism therapy may be a promising method for cancer treatment. STATEMENT OF SIGNIFICANCE: In recent years, localized cancer treatment using different biomaterials has attracted increasing attention for effective inhibition of tumor growth. However, it is still challenging for this kind of system to achieve a high drug loading, overcome biological barriers from the site of injection to the site of action, and combine synergetic therapy with diagnosis without adversely affecting the formation process. This study provides a localized diffusion molecular retention (DMR) tumor targeting drug delivery system based on hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) entrapment of anticancer drug for the first time, which can achieve high drug loading, improve local drug accumulation and retention, accomplish synergistic combination of chemo-phototherapy, and finally enhance antitumor effect. In addition, HMCuS NPs also possesses the property suitable for photoacoustic imaging, which could offer us a theranostic platform.

Tumor-targeted and multi-stimuli responsive drug delivery system for near-infrared light induced chemo-phototherapy and photoacoustic tomography.

UNLABELLED: In this work, a tumor-targeted and multi-stimuli responsive drug delivery system has been developed for combining photoacoustic tomography imaging with chemo-phototherapy. We utilized a kind of near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) to encapsulate doxorubicin (DOX). After that, the outer surface of HMCuS NPs was capped with multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety. Herein, HMCuS-HA could serve as a powerful contrast agent for photoacoustic tomography (PAT) to guide chemo-phototherapy by providing the identification of cancerous lesions. In vitro and in vivo studies, the nanoplatform (DOX/HMCuS-HA) pinpointed MCF-7 cells via CD44 receptor-mediated endocytosis pathway. Subsequently, intracellular enzyme-responsive controlled drug release would take place in lysosome after the HA degradation by hyaluronidase. Under near infrared (NIR) light irradiation, HMCuS NPs could not only effectively convert NIR light into heat for photothermal therapy, but also generate high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, NIR light and low pH environment could facilitate intracellular tunable drug release with spatial/temporal resolution, and thus synergistic combination of chemo-phototherapy should be simultaneously driven by an 808nm laser irradiation, which brought out an outstanding therapeutic effect. In vivo optical imaging demonstrated that HMCuS-HA significantly enhanced targeting and accumulation capacity in tumor site. Furthermore, tumor-bearing mice treated with DOX/HMCuS-HA under NIR irradiation (808nm, 2W/cm(2), 0.5min) in vivo displayed the highest inhibition ratio of about 88.9%. Taken together, our present study of the tumor-targeted and multi-stimuli responsive drug delivery system provides new insights into multimodality theranostic applications in cancer treatment. STATEMENT OF SIGNIFICANCE: Until now, chemotherapy is still the major therapeutic approach applied in oncology. Despite their pharmacologically efficacy in cancer treatments, most chemotherapeutic agents without tumor-specific targeting ability have brought out serious toxicities to normal tissues. This study provides a promising near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) with capping of multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety to address the above problem. After the nanoplatform (DOX/HMCuS-HA) pinpointed breast cancer cells via CD44 receptor-mediated endocytosis pathway, intracellular multi-stimuli responsive controlled drug release would take place with remarkable spatial/temporal resolution. Then photoacoustic tomography (PAT) and synergistic combination of chemo-phototherapy would be simultaneously driven by the same NIR irradiation in a coordinated way, which brought out an outstanding theranostic effect. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system.

A novel redox-sensitive system based on single-walled carbon nanotubes for chemo-photothermal therapy and magnetic resonance imaging.

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 IC50 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.

Multifunctional hyaluronic acid modified graphene oxide loaded with mitoxantrone for overcoming drug resistance in cancer.

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.

[Enhancing stimulated Raman scattering of water and heavy water lattice vibration by laser induced plasma].

Stimulated Raman scattering was studied in water and heavy water using pulse laser at the wavelength of 532nm, not only obtaining the stimulated Raman of O-H and O-D stretching vibration, but also obtaining the stimulated Raman lattice vibration. When the laser energy was 130 mJ, the low frequency Stokes and anti-Stokes 313 cm(-1) line of water could be observed; When the laser energy was 160 mJ, the low frequnecy Stokes and anti-Stokes 280 cm(-1) line of heavy water could be observed. The results were explained by physics mechanism of laser induced plasma.