Robust O2 Supplementation from a Trimetallic Nanozyme-Based Self-Sufficient Complementary System Synergistically Enhances the Starvation/Photothermal Therapy against Hypoxic Tumors.

Much effort has been focused on novel nanomedicine for cancer therapy. However, tumor hypoxia limits the efficacy of various cancer therapeutics. Herein, we constructed a self-sufficient hybrid enzyme-based silk fibroin hydrogel system, consisting of Pt-decorated hollow Ag-Au trimetallic nanocages (HGN@Pt) and glucose oxidase (GOx), to supply O2 continuously and consume glucose concurrently and, thereby, synergistically enhance the anti-cancer efficacy of a combined starvation and photothermal therapy operating in a hypoxic tumor microenvironment. Thanks to the cooperative effects of the active surface atoms (resulting from the island-like features of the Pt coating), the intrinsically hollow structure, and the strain effect induced by the trimetallic composition, HGN@Pt displayed efficient catalase-like activity. The enhancement in the generation of O2 through the decomposition of H2O2 mediated by the as-designed nanozyme was greater than 400% when compared with that of hollow Ag-Pt bimetallic nanospheres or tiny Pt nanoparticles. Moreover, in the presence of HGN@Pt, significant amounts of O2 could be generated within a few minutes, even in an acidic buffer solution (pH 5.8-6.5) containing a low concentration of H2O2 (100-500 µM). Because HGN@Pt exhibited a strong surface plasmon resonance peak in the near-infrared wavelength range, it could be used as a photothermal agent for hyperthermia therapy. Furthermore, GOx was released gradually from the SF hydrogel into the tumor microenvironment to mediate the depletion of glucose, leading to glucose starvation-induced cancer cell death. Finally, the O2 supplied by HGN@Pt overcame the hypoxia of the microenvironment and, thereby, promoted the starvation therapeutic effect of the GOx-mediated glucose consumption. Meanwhile, the GOx-produced H2O2 from the oxidation of glucose could be used to regenerate O2 and, thereby, construct a complementary circulatory system. Accordingly, this study presents a self-sufficient hybrid enzyme-based system that synergistically alleviates tumor hypoxia and induces an anti-cancer effect when combined with irradiation of light from a near-infrared laser.

Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis.

Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs)--PEG-PLGA NPs (PEG-PLGA/PLGA=10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA=5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.

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.

Comparison study of gold nanohexapods, nanorods, and nanocages for photothermal cancer treatment.

Gold nanohexapods represent a novel class of optically tunable nanostructures consisting of an octahedral core and six arms grown on its vertices. By controlling the length of the arms, their localized surface plasmon resonance peaks could be tuned from the visible to the near-infrared region for deep penetration of light into soft tissues. Herein we compare the in vitro and in vivo capabilities of Au nanohexapods as photothermal transducers for theranostic applications by benchmarking against those of Au nanorods and nanocages. While all these Au nanostructures could absorb and convert near-infrared light into heat, Au nanohexapods exhibited the highest cellular uptake and the lowest cytotoxicity in vitro for both the as-prepared and PEGylated nanostructures. In vivo pharmacokinetic studies showed that the PEGylated Au nanohexapods had significant blood circulation and tumor accumulation in a mouse breast cancer model. Following photothermal treatment, substantial heat was produced in situ and the tumor metabolism was greatly reduced for all these Au nanostructures, as determined with (18)F-flourodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). Combined together, we can conclude that Au nanohexapods are promising candidates for cancer theranostics in terms of both photothermal destruction and contrast-enhanced diagnosis.