Nanoscale Metal-Organic Frameworks-Mediated Degradation of Mutant p53 Proteins and Activation of cGAS-STING Pathway for Enhanced Cancer Immunotherapy.

Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Mesoporous Bi-Containing Radiosensitizer Loading with DOX to Repolarize Tumor-Associated Macrophages and Elicit Immunogenic Tumor Cell Death to Inhibit Tumor Progression.

Tumor-associated macrophages (TAMs) were a major component of tumor, which comprised up to 50% of tumor mass, and correlated with poor prognosis in more than 80% of cases. TAMs were resistant to radiotherapy and chemotherapy, and radiation could further activate TAMs to promote tumor progression. Herein, we explored a kind of Bi-based mesoporous upconversion nanophosphor (UCNP) loaded with doxorubicin (UCNP-DOX) to elicit immunogenic tumor cell death and repolarize TAMs to an antitumor M1-like type for strengthening the tumor-specific antitumor immune effects of X-ray radiotherapy. The repolarization effect of UCNP-DOX with X-ray was confirmed in THP-1 cell line, in vivo mouse model, and hydrothorax of a non-small-cell lung carcinoma patient. Moreover, the UCNP-DOX and X-ray radiation could elicit immunogenic tumor necrosis, presenting more tumor antigens for tumor-specific immune response. In a cell co-incubation system, activated macrophages could significantly inhibit cancer colony formation, migration, and invasion. After treatment, xenografted tumor in mice was also found to be significantly regressed and presented substantial CD8-positive T cells. This study opens the door to further enhance the abscopal effects and inhibit the metastasis in radiotherapy.

Early prediction of tumor response after radiotherapy in combination with cetuximab in nasopharyngeal carcinoma using 99m Tc-duramycin imaging.

PURPOSE: 99mTc-duramycin imaging enables specific visualization of cell death qualitatively and quantitatively. This study aimed to investigate the potential of 99mTc-duramycin imaging in the early prediction of the curative effect of radiotherapy in combination with or without cetuximab in a nasopharyngeal carcinoma (NPC) model. METHODS: Male BALB/c mice bearing NPC xenografts were randomized into four groups (six mice each group). Group 1 received radiotherapy (RT, 15 Gy/mouse) in combination with cetuximab (CTX, 2 mg/mouse), group 2 received RT (15 Gy/mouse), group 3 was treated using CTX (2 mg/mouse), and group 4, the control group, was treated using a vehicle. 99mTc-duramycin imaging was performed before treatment and 24 h after treatment to evaluate tumor response. Tumor uptake of 99mTc-duramycin was validated ex vivo using γ-counting. Treatment response was further validated by cleaved caspase-3 (CC3) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). Another four groups were treated parallelly under the same conditions to observe treatment response by tumor volume changes. RESULTS: After 24 h treatment, 99mTc-duramycin uptake in the NPC tumor models were significantly higher in group 1 than in group 2 (P < 0.05), group 3 (P < 0.05), or group 4 (P < 0.05); the uptake also increased notably in comparison with baseline values (P < 0.05). Compared with group 4, group 2 and group 3 both showed significant 99mTc-duramycin uptake in the tumors (P < 0.05). Although the 99mTc-duramycin uptake of group 2 was moderately higher than group 3, there were no significant differences between these two groups (P >0.05). There was a strong positive correlation between tumor 99mTc-duramycin uptake and CC3 (r = 0.893, p < 0.0001) and TUNEL (r = 0.918, P < 0.0001). Tumor volume decreased remarkably in the RT in combination with CTX group on day 5, in the RT alone group on day 7, and was inhibited on day 8 in the CTX alone group, whereas the tumors grew continuously in the control group. CONCLUSIONS: We demonstrated that RT in combination with CTX treatment significantly improved disease control in a NPC xenograft model compared with monotherapy with either. 99mTc-duramycin imaging might be able to reliably identify response to RT in combination with CTX as early as 24 h after therapy initiation in NPC xenograft models. This might help to isolate non-responding patients in a timely manner and avoid unnecessary side effects in the clinic in the future.

Ultrafast Synthesizing Bismuth Mesoporous Nanolitchi Radiosensitizer Loading High Dose DOX for CT-Guided Enhanced Chemoradiotherapy.

Radiotherapy and chemotherapy are both common clinical treatment methods. The combination of the two treatments can decrease tumor recurrence. In this study, bismuth-based mesoporous litchi-shaped Na0.2Bi0.8O0.35F1.91:20%Yb (NBOF) nanoparticles (NPs) have been reported as a radiosensitizer and as a nanovehicle for loading and slow-releasing doxorubicin (DOX). After assembling with amphiphilic poly(ethylene glycol) (PEG), NBOF-DOX-PEG qualified with excellent aqueous dispersibility and the enhanced tumor radiation and chemo-synergistic therapy characteristics. The formation of NBOF revealed the oxygen element in NBOF came from H2O and air in the synthesis and post-treatment process, and the size of NBOF could be adjusted by changing the concentration of doped Yb ion. The average size of NBOF was ca. 80 nm. Brunauer-Emmett-Teller results demonstrated the mesoporous structure of NBOF. So DOX could be loaded in NBOF and the optimized loading content was 39%. Then, NBOF-PEG exhibited a strong computed tomography signal whitening ability and enhanced radiotherapy effect. Combined with the chemotherapy ability of DOX, NBOF-DOX-PEG NPs presented remarkable synergistic tumor elimination ability. Meanwhile, NBOF-DOX-PEG NPs qualified for excellent biosafety. Our study not only proved the combined chemo- and radiotherapy for enhancing therapeutic effect but also supplied a functional Bi-based mesoporous nanovehicle for constructing an intelligent theranostic platform.

Ultrafast synthesis of fluorine-18 doped bismuth based upconversion nanophosphors for tri-modal CT/PET/UCL imaging in vivo.

A fluorine-18 doped bismuth upconversion luminescence (UCL) nanoprobe (18F-UNBOF) was quickly synthesized within 1 min at room temperature. 18F-UNBOF showed strong X-ray attenuation characteristics, stable radioactive 18F-labeling abilities and UCL properties. 18F-UNBOF nanoparticles could be utilized for tri-modal CT/PET/UCL imaging in vivo.