Redox ferrocenylseleno compounds modulate longitudinal and transverse relaxation times of FNPs-Gd MRI contrast agents for multimodal imaging and photo-Fenton therapy.

Developing a feasible way to feature longitudinal (T1) and transverse (T2) relaxation performance of contrast agents for magnetic resonance imaging (MRI) is important in cancer diagnosis and therapy. Improved accessibility to water molecule is essential for accelerating the relaxation rate of water protons around the contrast agents. Ferrocenyl compounds have reversible redox property for modulating the hydrophobicity/hydrophilicity of assemblies. Thus, they could be the candidates that can change water accessibility to the contrast agent surface. Herein, we incorporated ferrocenylseleno compound (FcSe) with Gd3+-based paramagnetic UCNPs, to obtain FNPs-Gd nanocomposites using T1-T2 MR/UCL trimodal imaging and simultaneous photo-Fenton therapy. When the surface of NaGdF4:Yb,Tm UNCPs was ligated by FcSe, the hydrogen bonding between hydrophilic selenium and surrounding water molecules accelerated their proton exchange to initially endow FNPs-Gd with high r1 relaxivity. Then, hydrogen nuclei from FcSe disrupted the homogeneity of the magnetic field around the water molecules. This facilitated T2 relaxation and resulted in enhanced r2 relaxivity. Notably, upon the near-infrared light-promoted Fenton-like reaction in the tumor microenvironment, hydrophobic ferrocene(II) of FcSe was oxidized into hydrophilic ferrocenium(III), which further increased the relaxation rate of water protons to obtain r1 = 1.90±0.12 mM-1 s-1 and r2 = 12.80±0.60 mM-1 s-1. With an ideal relaxivity ratio (r2/r1) of 6.74, FNPs-Gd exhibited high contrast potential of T1-T2 dual-mode MRI in vitro and in vivo. This work confirms that ferrocene and selenium are effective boosters that enhance the T1-T2 relaxivities of MRI contrast agents, which could provide a new strategy for multimodal imaging-guided photo-Fenton therapy of tumors. STATEMENT OF SIGNIFICANCE: T1-T2 dual-mode MRI nanoplatform with tumor-microenvironment-responsive features has been an attractive prospect. Herein, we designed redox ferrocenylseleno compound (FcSe) modified paramagnetic Gd3+-based UCNPs, to modulate T1-T2 relaxation time for multimodal imaging and H2O2-responsive photo-Fenton therapy. Selenium-hydrogen bond of FcSe with surrounding water molecules facilitated water accessibility for fast T1 relaxation. Hydrogen nucleus in FcSe perturbed the phase coherence of water molecules in an inhomogeneous magnetic field and thus accelerated T2 relaxation. In tumor microenvironment, FcSe was oxidized into hydrophilic ferrocenium via NIR light-promoted Fenton-like reaction which further increased both T1 and T2 relaxation rates; Meanwhile, the released toxic •OH performed on-demand cancer therapy. This work confirms that FcSe is an effective redox mediate for multimodal imaging-guided cancer therapy.

Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor.

Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nanocomposites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.

NIR stimulus-responsive core-shell type nanoparticles based on photothermal conversion for enhanced antitumor efficacy through chemo-photothermal therapy.

A novel core-shell type nanoparticle (CSNP) was designed here to target co-delivery of doxorubicin (DOX) and photosensitizer indocyanine green (ICG) to tumor sites by the aid of NIR induced photothermal conversion effect for the purpose of synergistic chemo-photothermal cancer therapy. The electrostatically self-assembled CSNPs were prepared by amino-functionalized mesoporous silica nanoparticles (MSN-NH2) as the positive inner core and DSPE-PEG2000-COOH and DSPE-PEG2000-FA modified lecithin as the negative outer shell. The obtained CSNPs were nanospheres with a uniform size of 47 nm, which were kept stable at 4 °C in PBS (pH = 7). Research on the release of NIR stimulus (808 nm, 1.54 W cm-2, 6 min) manifested that the release property of the CSNPs was controllable under low pH conditions. In addition, specific concentration (40 µg ml-1) ICG-loaded CSNPs, achieving an appropriate temperature up to 45 °C, indicated a desired photothermal conversion efficiency. For targeting the folate receptor, the folate modified CSNPs enabled us to reach a higher cellular uptake by the mean fluorescence intensity. In vitro cell assay, the prepared CSNPs showed outstanding inhibitory efficiency (2.07% cell viability and 91.8% cell apoptosis) on MCF-7 cells for 24 h when irradiated by an 808 nm laser with a power of 1.54 W cm-2 for 6 min. Our research highlights that the prepared nanoparticles hold potential promise for cancer treatment based on photothermal conversion performance and FA-targeted delivery.

A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles.

The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC-7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer.

Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy.

Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy.

FA and cRGD dual modified lipid-polymer nanoparticles encapsulating polyaniline and cisplatin for highly effective chemo-photothermal combination therapy.

A combination of chemotherapy and photothermal therapy as a promising strategy has exhibited noticeable therapeutic effect on cancer therapy. To ensure the exertion of synergistic effect on a tumor region, a multifunctional vehicle for selectively delivering therapeutic agent into tumor cells is highly desirable. Thus, folate-poly (ethylene glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE), cRGD [cyclic (Arg-Gly-Asp-D-Phe-Lys)]-PEG-DSPE and lecithin were employed to develop dual modified nanoparticles (FA/cRGD-PNPs) encapsulating polyaniline and cisplatin by a film-ultrasonic dispersion method. The FA/cRGD-PNPs showed a uniform size of 102.7 nm, remarkable stability and monodispersity, and highly localized temperature respond. Compared to chemo or photothermal treatment alone, the combined treatment on cells in vitro significantly suppressed the survival rate of MDA-MB-231 cells (1.87%) and MGC-803 cells (2.37%) treated for 48 h. The results further indicated the induced cell apoptosis rate of MDA-MB-231 cells reached to 92.6% with treatment for 24 h. Hence, our research highlights the great potential in drug delivery and the combination of chemotherapy and photothermal therapy.