A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis.

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. STATEMENT OF SIGNIFICANCE: Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.

Size-Switchable Nanoparticles with Self-Destructive and Tumor Penetration Characteristics for Site-Specific Phototherapy of Cancer.

The normoxic and hypoxic microenvironments in solid tumors cause cancer cells to show different sensitivities to various treatments. Therefore, it is essential to develop different therapeutic modalities based on the tumor microenvironment. In this study, we designed size-switchable nanoparticles with self-destruction and tumor penetration characteristics for site-specific phototherapy of cancer. This was achieved by photodynamic therapy in the perivascular normoxic microenvironment due to high local oxygen concentrations and photothermal therapy (PTT) in the hypoxic microenvironment, which are not in proximity to blood vessels due to a lack of effective approaches for heat transfer. In brief, a poly(amidoamine) dendrimer with photothermal agent indocyanine green (PAMAM-ICG) was conjugated to the amphiphilic polymer through a singlet oxygen-responsive thioketal linker and then loaded with photosensitizer chlorin e6 (Ce6) to construct a nanotherapy platform (denoted as SNPICG/Ce6). After intravenous injection, SNPICG/Ce6 was accumulated at the perivascular sites of the tumor. The singlet oxygen produced by Ce6 can ablate the tumor cells in the normoxic microenvironment and simultaneously cleave the thioketal linker, allowing the release of small PAMAM-ICGs with improved tumor penetration for PTT in the hypoxic microenvironment. This tailored site-specific phototherapy in normoxic and hypoxic microenvironments provides an effective strategy for cancer therapy.

Bioorthogonal Turn-On Probe Based on Aggregation-Induced Emission Characteristics for Cancer Cell Imaging and Ablation.

Bioorthogonal turn-on probes have been widely utilized in visualizing various biological processes. Most of the currently available bioorthogonal turn-on probes are blue or green emissive fluorophores with azide or tetrazine as functional groups. Herein, we present an alternative strategy of designing bioorthogonal turn-on probes based on red-emissive fluorogens with aggregation-induced emission characteristics (AIEgens). The probe is water soluble and non-fluorescent due to the dissipation of energy through free molecular motion of the AIEgen, but the fluorescence is immediately turned on upon click reaction with azide-functionalized glycans on cancer cell surface. The fluorescence turn-on is ascribed to the restriction of molecular motion of AIEgen, which populates the radiative decay channel. Moreover, the AIEgen can generate reactive oxygen species (ROS) upon visible light (λ=400-700 nm) irradiation, demonstrating its dual role as an imaging and phototherapeutic agent.

Conjugated polymer and drug co-encapsulated nanoparticles for chemo- and photo-thermal combination therapy with two-photon regulated fast drug release.

The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin αvß3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 µg mL(-1), while the IC50 for chemotherapy and photothermal therapy alone is 147.8 µg mL(-1) and 36.2 µg mL(-1), respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy.

Biocompatible conjugated polymer nanoparticles for efficient photothermal tumor therapy.

Conjugated polymers (CPs) with strong near-infrared (NIR) absorption and high heat conversion efficiency have emerged as a new generation of photothermal therapy (PTT) agents for cancer therapy. An efficient strategy to design NIR absorbing CPs with good water dispersibility is essential to achieve excellent therapeutic effect. In this work, poly[9,9-bis(4-(2-ethylhexyl)phenyl)fluorene-alt-co-6,7-bis(4-(hexyloxy)phenyl)-4,9-di(thiophen-2-yl)-thiadiazoloquinoxaline] (PFTTQ) is synthesized through the combination of donor-acceptor moieties by Suzuki polymerization. PFTTQ nanoparticles (NPs) are fabricated through a precipitation approach using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000 ) as the encapsulation matrix. Due to the large NIR absorption coefficient (3.6 L g(-1) cm(-1) ), the temperature of PFTTQ NP suspension (0.5 mg/mL) could be rapidly increased to more than 50 °C upon continuous 808 nm laser irradiation (0.75 W/cm(2) ) for 5 min. The PFTTQ NPs show good biocompatibility to both MDA-MB-231 cells and Hela cells at 400 µg/mL of NPs, while upon laser irradiation, effective cancer cell killing is observed at a NP concentration of 50 µg/mL. Moreover, PFTTQ NPs could efficiently ablate tumor in in vivo study using a Hela tumor mouse model. Considering the large amount of NIR absorbing CPs available, the general encapsulation strategy will enable the development of more efficient PTT agents for cancer or tumor therapy.