Multifunctional manganese oxide-based nanocomposite theranostic agent with glucose/light-responsive singlet oxygen generation and dual-modal imaging for cancer treatment.

Development of tumor microenvironment (TME) modifying nanomedicine with cooperative effect between multiple stimuli responsive therapeutic modalities is necessary to achieve lower dosage induced tumor specific therapy. Accordingly, herein, a multifunctional MnOx NSs@BSA-IR780-GOx nanocomposite (MBIG NCs) is developed to modulate the oxidative stress in TME, and thus attain higher therapeutic efficacy. In the presence of glucose, the as-synthesized MBIG NCs are served as a chemodynamic agents and generated reactive oxygen species (ROS) by self-activation through a cascade of reactions from glucose oxidase (GOx) and manganese oxide nanosheets (MnOx NSs). Also, the MBIG NCs demonstrated excellent photodynamic properties upon irradiation with 808 nm laser owing to the presence of IR780. The combination of glucose-mediated chemodynamic and light-mediated photodynamic properties generated higher ROS than that obtained with individual stimuli. Further, the MBIG NCs exhibited photothermal effect with conversion efficiency of 33.8 %, which helped to enhance the enzymatic activities. In in vitro studies, the MBIG NCs exhibited good biocompatibility to cancerous and non-cancerous cells under non-stimulus conditions. Nevertheless, in the presence of glucose and light stimuli, they triggered more than 90 % cell toxicity at 200 ppm concentration via the cooperative effect between starvation therapy, chemodynamic therapy, and phototherapy. Furthermore, the MBIG NCs demonstrated magnetic resonance and fluorescence imaging properties. These results are suggesting that MBIG NCs would be potential theranostic agents to for cancer diagnosis and target specific therapy. More importantly, the fabrication process is paving a way to improve the aqueous dispersibility, stability, and bio-applicability of MnOx NSs and IR780.

Engineering the Surface of Ti3C2 MXene Nanosheets for High Stability and Multimodal Anticancer Therapy.

The surface of Ti3C2 MXene nanosheets (TC NSs) was first modified with the antioxidants sodium ascorbate (SA) and dopamine (DA) (DSTC NS) to improve their stability in oxidative and hydration environments and thereby improve their bioapplications. This novel approach not only improved MXene stability by arresting oxidation but also increased the available functional groups for further functionalization with various biomolecules. The DSTC NSs were then sequentially conjugated with enzyme glucose oxidase (GOx) and photosensitizer Ce6 to render the obtained CGDSTC NSs with glucose starvation and photodynamic therapeutic properties and thus attain high efficiency in killing cancer cells through the cooperative effect. The as-synthesized CGDSTC NSs demonstrated tremendous photothermal effect with conversion efficiency of 45.1% and photodynamic (ROS generation) properties upon irradiation with 808 and 671 nm lasers. Furthermore, it was observed that the enzymatic activity of CGDSTC NSs increased upon laser irradiation due to enhanced solution temperature. During in vitro studies, the CGDSTC NSs exhibited cytocompatability to HePG2 and HeLa cells under nonstimulus conditions. However, they elicited more than 90% cell-killing efficiency in the presence of glucose and laser irradiation via the cooperative effect between starvation therapy and phototherapy. These results indicate that CGDSTC NSs could be used as potential therapeutic agents to eradicate cancers with no or few adverse effects. This surface modification approach is also simple and facile to adopt in MXene-based research.

Biomimetic Nanoreactor for Cancer Eradication via Win-Win Cooperation between Starvation/Photo/Chemodynamic Therapies.

Combining phototherapy with the cancer cell metabolic pathway altering strategies, that is, glucose starvation, would be a promising approach to accomplish high curative efficiency of cancer treatment. Accordingly, herein, we sought to construct a multifunctional biomimetic hybrid nanoreactor by fastening nanozyme AuNPs (glucose oxidase activity) and PtNPs (catalase and peroxidase activity) and photosensitizer Indocyanine green (ICG) onto the polydopamine (PDA) surface (ICG/Au/Pt@PDA-PEG) to attain superior cancer cell killing efficiency though win-win cooperation between starvation therapy, phototherapy, and chemodynamic therapy. The as-synthesized ICG/Au/Pt@PDA-PEG has shown excellent light-to-heat conversion (photothermal therapy) and reactive oxygen species generation (photodynamic therapy) properties upon laser irradiation and also red-shifted ICG absorption (from 780 to 800 nm) and enhanced its photostability. Further, the ICG/Au/Pt@PDA-PEG NRs have reduced the solution glucose concentration and slightly increased solution oxygen levels and also enhanced 3,3',5,5'-tetramethylbenzidine oxidation in the presence of glucose through a cascade of enzymatic activities. The in vitro results demonstrated that the ICG/Au/Pt@PDA-PEG NRs have superior therapeutic efficacy against cancer cells via the cooperative effect between starvation/photo/chemodynamic therapies and not much toxicity to normal cells.

Modulation of tumor microenvironment using a TLR-7/8 agonist-loaded nanoparticle system that exerts low-temperature hyperthermia and immunotherapy for in situ cancer vaccination.

Most cancer vaccines under development are associated with defined tumor antigens rather than with all antigens of whole tumor cells, limiting the anti-tumor immune responses that they elicit. This work proposes an immunomodulator (R848)-loaded nanoparticle system (R848@NPs) that can absorb near-infrared light (+NIR) to cause low-temperature hyperthermia that interacts synergistically with its loaded R848 to relieve the tumor-mediated immunosuppressive microenvironment, generating robust anti-tumor memory immunity. In vitro results reveal that the R848@NPs could be effectively internalized by dendritic cells, causing their maturation and the subsequent regulation of their anti-tumor immune responses. Post-treatment observations in mice in which tumors were heat-treated at high temperatures reveal that tumor growth was significantly inhibited initially but not in the longer term, while low-temperature hyperthermia or immunotherapy alone simply delayed tumor growth. In contrast, a combined therapy that involved low-temperature hyperthermia and immunotherapy using R848@NPs/+NIR induced a long-lasting immunologic memory and consequently inhibited tumor growth and prevented cancer recurrence and metastasis. These results suggest that the method that is proposed herein is promising for generating cancer vaccines in situ, by using the tumor itself as the antigen source and the introduced R848@NPs/+NIR to generate a long-term anti-tumor immunity, for personalized immunotherapy.

Acidity-triggered charge-convertible nanoparticles that can cause bacterium-specific aggregation in situ to enhance photothermal ablation of focal infection.

Focal infections that are caused by antibiotic-resistant bacteria are becoming an ever-growing challenge to human health. To address this challenge, a pH-responsive amphiphilic polymer of polyaniline-conjugated glycol chitosan (PANI-GCS) that can self-assemble into nanoparticles (NPs) in situ is developed. The PANI-GCS NPs undergo a unique surface charge conversion that is induced by their local pH, favoring bacterium-specific aggregation without direct contact with host cells. Following conjugation onto GCS, the optical-absorbance peak of PANI is red-shifted toward the near-infrared (NIR) region, enabling PANI-GCS NPs to generate a substantial amount of heat, which is emitted to their neighborhood. The local temperature of the NIR-irradiated PANI-GCS NPs is estimated to be approximately 5 °C higher than their ambient tissue temperature, ensuring specific and direct heating of their aggregated bacteria; hence, damage to tissue is reduced and wound healing is accelerated. The above results demonstrate that PANI-GCS NPs are practical for use in the photothermal ablation of focal infections.

Photothermal tumor ablation in mice with repeated therapy sessions using NIR-absorbing micellar hydrogels formed in situ.

Repeated cancer treatments are common, owing to the aggressive and resistant nature of tumors. This work presents a chitosan (CS) derivative that contains self-doped polyaniline (PANI) side chains, capable of self-assembling to form micelles and then transforming into hydrogels driven by a local change in pH. Analysis results of small-angle X-ray scattering indicate that the sol-gel transition of this CS derivative may provide the mechanical integrity to maintain its spatial stability in the microenvironment of solid tumors. The micelles formed in the CS hydrogel function as nanoscaled heating sources upon exposure to near-infrared light, thereby enabling the selective killing of cancer cells in a light-treated area. Additionally, photothermal efficacy of the micellar hydrogel is evaluated using a tumor-bearing mouse model; hollow gold nanospheres (HGNs) are used for comparison. Given the ability of the micellar hydrogel to provide spatial stability within a solid tumor, which prevents its leakage from the injection site, the therapeutic efficacy of this hydrogel, as a photothermal therapeutic agent for repeated treatments, exceeds that of nanosized HGNs. Results of this study demonstrate that this in situ-formed micellar hydrogel is a highly promising modality for repeated cancer treatments, providing a clinically viable, minimally invasive phototherapeutic option for therapeutic treatment.