Intracellular Criegee's mechanism-based synergistic ozone therapy mediated by oleogels for cancer treatment.

Broad cellular components-initiated efficient chemical reactions that occur in malignant cells may contribute to exploring emerging strategies for cancer treatment. Herein, an ozonated oleogel (OG(O)) was developed to achieve cancer ozone therapy (O3-T) based on intracellular Criegee's reaction. By integrating the chemo-drug, the ozone-loaded oleogel (Dox@OG(O)) was prepared as a chemotherapeutic agent for local O3-T, associated with chemotherapy (CT)/radiotherapy (RT)/immunotherapy and wound healing. The in vitro results showed that, Dox@OG(O) could achieve high ozone loading efficiency and ensure its stability. This Oleogel-mediated O3-T could directly destroy tumor cells via intracellular Criegee's reaction occurred on cell membranes, as well as the effects of tumor microenvironment (TME) regulation by the generation of oxygen/reactive oxygen species (ROS) and depletion of glutathione (GSH). Meanwhile, under the stimulation of X-ray, an accelerated free radical's production was observed, further combined with the radio-sensitivity after TME regulation, an effective anti-tumor effect would be achieved. Further on, in vivo results demonstrated that the locally implanted Dox@OG(O) could effectively inhibit the growth of both primary and secondary tumors. Considering these results above, it will serve as inspiration for future studies investigating of O3-T, especially for postoperative skin diseases.

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis.

Cell necroptosis has presented great potential, acting as an effective approach against tumor apoptotic resistance, and it could be further enhanced via accompanying reactive oxygen species (ROS) overexpression. However, whether overproduced ROS assists the necroptotic pathway remains unclear. Thus, iron-palladium nanozyme (FePd NZ)- and shikonin (SKN)-encapsulated functional lipid nanoparticles (FPS-LNPs) were designed to investigate the ROS overexpression-enhanced SKN-induced necroptosis. In this system, SKN acts as an effective necroptosis inducer for cancer cells, and FePd NZ, a sensitive Fenton reaction catalyst, produces extra-intracellular ROS to reinforce the necroptotic pathway. Both in vitro and in vivo antitumor evaluation revealed that FPS-LNPs presented the best tumor growth inhibition efficacy compared with FP-LNPs or SKN-LNPs alone. Meanwhile, induced necroptosis by FPS-LNPs can further trigger the release of damage-associated molecular patterns (DAMPs) and antigens from dying tumor cells to activate the innate immune response. Taking biosafety into consideration, this study has provided a potential nanoplatform for cancer nanotherapy via inducing necroptosis to avoid apoptosis resistance and activate CD8+ T cell immune response.

The Modified Neo-Bioscore System for Staging Breast Cancer Treated with Neoadjuvant Therapy Based on Prognostic Significance of HER2-Low Expression.

Background: Recently, the classification of HER2 status evolves from binary to ternary, and HER2-low expression may exhibit prognostic significance. We aimed to investigate whether HER2-low tumor is distinct from HER2-zero or HER2-positive tumors, and then to develop a modified staging system (mNeo-Bioscore) that incorporates HER2-low status into Neo-Bioscore. Patients and Methods: This cohort study was conducted using data from the prospective database on breast cancer patients between January 2014 and February 2019. Results: Among 259 patients enrolled in the study, the HER2-low tumor exhibited significantly lower histological grade, pathological staging and Ki-67 level than the other two groups. HER2-low patients and HER2-positive patients receiving concurrent HER2-directed therapy may have similar LRFS (p = 0.531) and OS (p = 0.853), while HER2-zero peers may have significantly worse LRFS (p = 0.006) and OS (p = 0.017). In particular, a similar trend was also found in the patients without pathological complete response after surgery. Incorporation of HER2-low status made improvement in fit: 5-year OS rate estimates ranged from 33.33% to 100% for mNeo-Bioscore vs 61.36% to 100% for Neo-Bioscore. Conclusions: This study demonstrated that HER2-low tumor may exhibit prognostic significance. The innovative mNeo-Bioscore, based on a new classification of HER2 status, may serve as a prognostic staging system superior to Neo-Bioscore.

Cancer nutritional-immunotherapy with NIR-II laser-controlled ATP release based on material repurposing strategy.

Enlightened by the great success of the drug repurposing strategy in the pharmaceutical industry, in the current study, material repurposing is proposed where the performance of carbonyl iron powder (CIP), a nutritional intervention agent of iron supplement approved by the US FDA for iron deficiency anemia in clinic, was explored in anti-cancer treatment. Besides the abnormal iron metabolic characteristics of tumors, serving as potential targets for CIP-based cancer therapy under the repurposing paradigm, the efficacy of CIP as a catalyst in the Fenton reaction, activator for dihydroartemisinin (DHA), thus increasing the chemo-sensitivity of tumors, as well as a potent agent for NIR-II photothermal therapy (PTT) was fully evaluated in an injectable alginate hydrogel form. The CIP-ALG gel caused a rapid temperature rise in the tumor site under NIR-II laser irradiation, leading to complete ablation in the primary tumor. Further, this photothermal-ablation led to the significant release of ATP, and in the bilateral tumor model, both primary tumor ablation and inhibition of secondary tumor were observed simultaneously under the synergistic tumor treatment of nutritional-photothermal therapy (NT/PTT). Thus, material repurposing was confirmed by our pioneering trial and CIP-ALG-meditated NT/PTT/immunotherapy provides a new choice for safe and efficient tumor therapy.

Sentinel lymph node identification using NIR-II ultrabright Raman nanotags on preclinical models.

Surface-enhanced Raman spectroscopy (SERS) nanotags have garnered much attention as promising bioimaging contrast agent with ultrahigh sensitivity, but their clinical translation faces challenges including biological and laser safety. As breast sentinel lymph node (SLN) imaging agents, SERS nanotags used by local injection and only accumulation in SLNs, which were removed during surgery, greatly reduce biological safety concerns. But their clinical translation lacks pilot demonstration on large animals close to humans. The laser safety requires irradiance below the maximum permissible exposure threshold, which is currently not achievable in most SERS applications. Here we report the invention of the core-shell SERS nanotags with ultrahigh brightness (1 pM limit of detection) at the second near-infrared (NIR-II) window for SLN identification on pre-clinical animal models including rabbits and non-human primate. We for the first time realize the intraoperative SERS-guided SLN navigation under a clinically safe laser (1.73 J/cm2) and identify multiple axillary SLNs on a non-human primate. No evidence of biosafety issues was observed in systematic examinations of these nanotags. Our study unveils the potential of NIR-II SERS nanotags as appropriate SLN tracers, making significant advances toward the accurate positioning of lesions using the SERS-based tracer technique.

Injectable Magnetic Hydrogel Filler for Synergistic Bone Tumor Hyperthermia Chemotherapy.

The therapeutic efficacy of bone tumor treatment is primarily limited by inadequate tumor resection, resulting in recurrence and metastasis, as well as the deep location of tumors. Herein, an injectable doxorubicin (DOX)-loaded magnetic alginate hydrogel (DOX@MAH) was developed to evaluate the efficacy of an alternating magnetic field (AMF)-responsive, chemothermal synergistic therapy for multimodality treatment of bone tumors. The prepared hydrogel exhibits a superior drug-loading capacity and a continuous DOX release. This multifunctionality can be attributed to the combined use of DOX for chemotherapy and iron oxide nanoparticle-containing alginate hydrogels as magnetic hyperthermia agents to generate hyperthermia for tumor elimination without the limit on penetration depth. Moreover, the hydrogel can be formed when in contact with the calcium ions, which are abundant in bone tissues; therefore, this hydrogel could perfectly fit the bone defects caused by the surgical removal of the bone tumor tissue, and the hydrogel could tightly attach the surgical margin of the bone to realize a high efficacy residual tumor tissue elimination treated by chemothermal synergistic therapy. The hydrogel demonstrates excellent hyperthermia performance, as evidenced by in vitro cytotoxicity tests on tumor cells. These tests reveal that the combined therapy based on DOX@MAH under AMF significantly induces cell death compared to single magnetic hyperthermia or chemotherapy. In vivo antitumor effects in tumor-bearing mice demonstrate that DOX@MAH injection at the tumor site effectively inhibits tumor growth and leads to tumor necrosis. This work not only establishes an effective DOX@MAH system as a synergistic chemothermal therapy platform for treating bone tumors but also sheds light on the application of alginate to combine calcium ions of the bone to treat bone defect diseases.

Apoptosis and Paraptosis Induced by Disulfiram-Loaded Ca2+/Cu2+ Dual-Ions Nano Trap for Breast Cancer Treatment.

Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion "nano trap" to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions "nano trap". The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)-copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.

Treatment patterns for patients initiating novel acute migraine specific medications (nAMSMs) in the context of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway.

BACKGROUND: New acute and preventive migraine medications are available, but data on current treatment patterns are limited. This study describes migraine treatment patterns among patients initiating novel acute migraine specific medications (nAMSMs), overall and by prior use of anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs). METHODS: In this retrospective cohort study using IQVIA open-source pharmacy and medical claims data, we identified patients with ≥ 1 claim for a nAMSM (ubrogepant, rimegepant, lasmiditan) between 01/01/2020 and 09/30/2020 (index period). Patients were indexed on their first nAMSM claim and stratified into 2 cohorts: patients with prior mAb use (≥ 1 claim for erenumab, fremanezumab, galcanezumab in the 6-month pre-index period) or patients without prior mAb use. Treatment patterns were assessed during the 6-month post-index period. RESULTS: Overall, 78,574 patients were identified (63% indexed on ubrogepant, 34% on rimegepant, and 3% on lasmiditan) with 26,656 patients (34%) having had prior mAb use. In the pre-index period, 79% of patients used non-mAb preventive medications and 75% of patients used acute medications. Following the index nAMSM claim, 65% of patients had ≥ 1 refill and 21% had ≥ 4 refills of their index nAMSM; 10% of patients switched to another nAMSM. Post-index mAb use was observed in 82% of patients with a prior mAb and 15% of patients without. Among patients with pre- and post-index use of acute medications, 38% discontinued ≥ 1 acute medication class in the post-index period. Among patients with concomitant use of traditional preventive medications at index, 30% discontinued ≥ 1 concomitant preventive anti-migraine medication in the post-index period. CONCLUSIONS: Most patients initiating nAMSMs had prior treatment with acute and preventive medications. Approximately one-third of patients had prior treatment with anti-CGRP pathway mAbs. After starting nAMSMs, more than one-third of patients discontinued at least one traditional acute medication and one-third of patients discontinued at least one traditional preventive medication. Despite nAMSM initiation, most patients with prior anti-CGRP pathway mAb use continued mAb use. Around 15% of patients without a prior mAb newly started a mAb. These results provide insight into how nAMSMs and mAbs have been integrated into clinical management of migraine in the real-world.

Precise diagnosis of breast phyllodes tumors using Raman spectroscopy: Biochemical fingerprint, tumor metabolism and possible mechanism.

BACKGROUND: Breast fibroadenomas and phyllodes tumors are both fibroepithelial tumors with comparable histological characteristics. However, rapid and precise differential diagnosis is a tough point in clinical pathology. Given the tendency of phyllodes tumors to recur, the difficulty in differential diagnosis with fibroadenomas leads to the difficulty in optimal management for these patients. METHOD: In this study, we used Raman spectroscopy to differentiate phyllodes tumors from breast fibroadenomas based on the biochemical and metabolic composition and develop a classification model. The model was validated by 5-fold cross-validation in the training set and tested in an independent test set. The potential metabolic differences between the two types of tumors observed in Raman spectroscopy were confirmed by targeted metabolomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: A total of 204 patients with formalin-fixed paraffin-embedded (FFPE) tissue samples, including 100 fibroadenomas and 104 phyllodes tumors were recruited from April 2014 to August 2021. All patients were randomly divided into the training cohort (n = 153) and the test cohort (n = 51). The Raman classification model could differentiate phyllodes tumor versus fibroadenoma with cross-validation accuracy, sensitivity, precision, and area under curve (AUC) of 85.58 % ± 1.77 %, 83.82 % ± 1.01 %, 87.65 % ± 4.22 %, and 93.18 % ± 1.98 %, respectively. When tested in the independent test set, it performed well with the test accuracy, sensitivity, specificity, and AUC of 83.50 %, 86.54 %, 80.39 %, and 90.71 %. Furthermore, the AUC was significantly higher for the Raman model than that for ultrasound (P = 0.0017) and frozen section diagnosis (P < 0.0001). When it came to much more difficult diagnosis between fibroadenoma and benign or small-size phyllodes tumor for pathological examination, the Raman model was capable of differentiating with AUC up to 97.45 % and 95.61 %, respectively. On the other hand, targeted metabolomic analysis, based on fresh-frozen tissue samples, confirmed the differential metabolites (including thymine, dihydrothymine, trans-4-hydroxy-l-proline, etc.) identified from Raman spectra between phyllodes tumor and fibroadenoma. SIGNIFICANCE AND NOVELTY: In this study, we obtained the molecular information map of breast phyllodes tumors provided by Raman spectroscopy for the first time. We identified a novel Raman fingerprint signature with the potential to precisely characterize and distinguish phyllodes tumors from fibroadenoma as a quick and accurate diagnostic tool. Raman spectroscopy is expected to further guide the precise diagnosis and optimal treatment of breast fibroepithelial tumors in the future.

Genetic polymorphisms of GGT1 gene (rs8135987, rs5751901 and rs2017869) are associated with neoadjuvant chemotherapy efficacy and toxicities in breast cancer patients.

BACKGROUND: Our previous study illustrated the predictive value of serum gamma-glutamyl transpeptidase (GGT) for neoadjuvant chemotherapy (NAC) sensitivity in breast cancer patients. In this study we aim to determine whether single nucleotide polymorphisms (SNPs) in the gamma-glutamyltransferase 1 (GGT1) gene are related to the NAC response and adverse events and to find out a genetic marker in predicting NAC sensitivity. METHODS: Three SNP loci (rs8135987, rs5751901, rs2017869) of GGT1 gene were selected and tested among breast cancer patients reciving NAC. Four genotype models were used in SNP analysis: co-dominant model compared AA vs. Aa vs. aa; dominant model compared AA vs. Aa + aa; recessive model compared AA + Aa vs. aa; over-dominant model compared AA + aa vs. Aa. Chi-squared test and multivariable logistic regression analysis were performed between SNP genotypes, haplotypes and pathological complete response(pCR), adverse events as well as serum GGT level. RESULTS: A total of 143 patients were included in the study. For SNP rs8135987 (T > C), the TC genotype in over-dominant model was inversely related with pCR (adjusted OR = 0.30, 95% CI 0.10-0.88, p = 0.029) as well as the risk of peripheral neuropathy (adjusted OR = 0.39, 95% CI 0.15-0.96, p = 0.042). The TC genotype in dominant model was significantly associated with elevated serum GGT level (OR = 3.11, 95% CI 1.07-9.02, p = 0.036). For rs2017869 (G > C), the occurrence of grade 2 or greater neutropenia (OR = 0.39, 95% CI 0.08-0.84, p = 0.025) and leukopenia (OR = 0.24, 95% CI 0.08-0.78, p = 0.017) were both significantly reduced in patients with CC genotypes. For rs5751901(T > C), the CC genotype could significantly reduce the risk of grade 2 or greater neutropenia (OR = 0.29, 95% CI 0.09-0.96, p = 0.036) and leukopenia (OR = 0.27, 95% CI 0.09-0.84, p = 0.024) in recessive model. CONCLUSIONS: The GGT1 gene SNPs might be an independent risk factor for poor response of NAC in breast cancer patients, providng theoretical basis for further precision therapy.

Physical Dissolution Combined with Photodynamic Depletion: A Two-Pronged Nanoapproach for Deoxygenation-Driven and Hypoxia-Activated Prodrug Therapy.

Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic-co-glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, in vivo experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.

External magnetic field non-invasively stimulates spinal cord regeneration in rat via a magnetic-responsive aligned fibrin hydrogel.

Magnetic stimulation is becoming an attractive approach to promote neuroprotection, neurogenesis, axonal regeneration, and functional recovery in both the central nervous system and peripheral nervous system disorders owing to its painless, non-invasive, and deep penetration characteristics. Here, a magnetic-responsive aligned fibrin hydrogel (MAFG) was developed to import and amplify the extrinsic magnetic field (MF) locally to stimulate spinal cord regeneration in combination with the beneficial topographical and biochemical cues of aligned fibrin hydrogel (AFG). Magnetic nanoparticles (MNPs) were embedded uniformly in AFG during electrospinning to endow it magnetic-responsive feature, with saturation magnetization of 21.79 emu g-1. It is found that the MNPs under the MF could enhance cell proliferation and neurotrophin secretion of PC12 cellsin vitro. The MAFG that was implanted into a rat with 2 mm complete transected spinal cord injury (SCI) effectively enhanced neural regeneration and angiogenesis in the lesion area, thus leading to significant recovery of motor function under the MF (MAFG@MF). This study suggests a new multimodal tissue engineering strategy based on multifunctional biomaterials that deliver multimodal regulatory signals with the integration of aligned topography, biochemical cues, and extrinsic MF stimulation for spinal cord regeneration following severe SCI.

Acidity-Triggered Charge-Convertible Conjugated Polymer for Dihydroartemisinin Delivery and Tumor-Specific Chemo-Photothermal Therapy.

Since the nonspecificity and nonselectivity of traditional treatment models lead to the difficulty of cancer treatment, nanobased strategies are needed to fill in the gaps of current approaches. Herein, a tumor microenvironment (TME)-responsive chemo-photothermal treatment model was developed based on dihydroartemisinin (DHA)-loaded conjugated polymers (DHA@PLGA-PANI). The synthesized DHA@PLGA-PANI exhibited enhanced photothermal properties under mild-acidic conditions and thus triggered local heat at the tumor site. Meanwhile, these iron-doped conjugated polymers of PLGA-PANI were used as the source of Fe, and benefiting from the Fe-dependent cytotoxicity of DHA, the burst of free radicals could be generated in tumors. Therefore, the combination of TME-responsive chemo-photothermal therapy could achieve effective tumor efficacy.

Nanoheterostructure by Liquid Metal Sandwich-Based Interfacial Galvanic Replacement for Cancer Targeted Theranostics.

Nanoheterostructures with exquisite interface and heterostructure design find numerous applications in catalysis, plasmonics, electronics, and biomedicine. In the current study, series core-shell metal or metal oxide-based heterogeneous nanocomposite have been successfully fabricated by employing sandwiched liquid metal (LM) layer (i.e., LM oxide/LM/LM oxide) as interfacial galvanic replacement reaction environment. A self-limiting thin oxide layer, which would naturally occur at the metal-air interface under ambient conditions, could be readily delaminated onto the surface of core metal (Fe, Bi, carbonyl iron, Zn, Mo) or metal oxide (Fe3 O4 , Fe2 O3 , MoO3 , ZrO2 , TiO2 ) nano- or micro-particles by van der Waals (vdW) exfoliation. Further on, the sandwiched LM layer could be formed immediately and acted as the reaction site of galvanic replacement where metals (Au, Ag, and Cu) or metal oxide (MnO2 ) with higher reduction potential could be deposited as shell structure. Such strategy provides facile and versatile approaches to design and fabricate nanoheterostructures. As a model, nanocomposite of Fe@Sandwiched-GaIn-Au (Fe@SW-GaIn-Au) is constructed and their application in targeted magnetic resonance imaging (MRI) guided photothermal tumor ablation and chemodynamic therapy (CDT), as well as the enhanced radiotherapy (RT) against tumors, have been systematically investigated.

Hypoxia Alleviated and One Photo-Triggered Thermal/Dynamic Nanoplatform for Immunogenic Cell Death-Initiated Cancer Immunotherapy.

Immunogenic cell death (ICD) induced by treatment modalities like chemotherapy, radiotherapy, and photothermal and photodynamic therapy has shown great potential to improve the low response rate of various solid tumors in cancer immunotherapy. However, extensive studies have revealed that the efficacy of cancer treatment is limited by the hypoxia and immunosuppression in the tumor microenvironment (TME). To address these challenges, a hypoxia alleviated and one phototriggered thermal/dynamic nanoplatform based on MnO2@PDA/ICG-BSA (MPIB) is developed for oxygen (O2) self-supply enhanced cancer phototherapy (PT). First, MnO2 transfers intracellular overexpression H2O2 into O2 in the acidic TME through its catalase-like activity to improve the hypoxia and also provide O2 for the following photodynamic therapy. Then, under single NIR-808 nm light irradiation (called the "phototherapeutic window"), excellent photothermal and photodynamic performance of the MPIB is activated for combined PT. Finally, assisted with immune adjuvant cytosine-phospho-guanine, obvious ICD and systemic antitumor immunity was elicited in PT-treated mice and demonstrated significant growth inhibition on distant tumors. This MPIB-based nanoplatform highlights the promise to overcome the limitations of hypoxia and also challenges of immunosuppressive tumor microenvironments for improved cancer immunotherapy.

Ultrafast Fabrication of Iron/Manganese Co-Doped Bismuth Trimetallic Nanoparticles: A Thermally Aided Chemodynamic/Radio-Nanoplatform for Low-Dose Radioresistance.

Low-dose radioresistance continues to be one of the major limitations for clinical curative treatment of cancer. Luckily, nanotechnology mediated by multifunctional nanomaterials provides potential opportunity to relieve the radioresistance via increasing the radiosensitivity of cancer cells. Herein, an ultrafast fabrication strategy is reported to prepare iron/manganese co-doped bismuth trimetallic nanoparticles (pFMBi NPs) as a multifunctional radiosensitizer for combined therapy. The bismuth matrix provides the intrinsic radiosensitization effect under the low and safe radiation dose via Auger electrons, photoelectrons, and Rayleigh scattering. Meanwhile, co-doping of iron and manganese ions endows pFMBi NPs with both the Fenton reaction property for reactive oxygen species (ROS) generation and photothermal conversion performance for heat production. Additional ROS generation enhances the radiosensitization effect by collaborating with Rayleigh scattering-mediated water radiolysis, and endogenous heat production under near-infrared 808 nm laser irradiation makes DNA more sensitive to radiation and ROS damage. Both in vitro and in vivo evaluations demonstrate the effective antitumor and radiosensitization effects via thermally aided chemodynamic/radiotreatment with a low radiation dose (6 Gy). Therefore, this work provides a potential strategy for overcoming the low-dose radioresistance in cancer therapy.

Correction: All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation.

Correction for 'All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation' by Xiao-xiao Guo et al., Nanoscale, 2021, 13, 14525-14537, https://doi.org/10.1039/D1NR03869A.

Local Destruction of Tumors for Systemic Immunoresponse: Engineering Antigen-Capturing Nanoparticles as Stimulus-Responsive Immunoadjuvants.

Immunotherapy has established a new paradigm for cancer treatment and made many breakthroughs in clinical practice. However, the rarity of immune response suggests that additional intervention is necessary. In recent years, it has been reported that local tumor destruction (LTD) can cause cancer cell death and induce an immunologic response. Thus, the combination of immunotherapy and LTD methods will be a promising approach to improve immune efficiency for cancer treatment. Herein, a nanobiotechnology platform to achieve high-precision LTD for systemic cancer immunotherapy has been successfully constructed. Possessing radio-sensitizing and photothermal properties, the engineered immunoadjuvant-loaded nanoplatform, which could precisely induce radiotherapy (RT)/photothermal therapy (PTT) to eliminate local tumor and meanwhile lead to the release of tumor-derived protein antigens (TDPAs), has been facilely fabricated by commercialized SPG membrane emulsification technology. Further on, the TDPAs could be captured and form personal nanovaccines in situ to serve as both reservoirs of antigen and carriers of immunoadjuvant, which can effectively improve the immune response. The investigations suggest that the combination of RT/PTT and improved immunotherapy using adjuvant-encapsulated antigen-capturing nanoparticles holds tremendous promise in cancer treatments.

Breast Cancer Survivorship and Level of Institutional Involvement Utilizing Integrative Oncology.

OBJECTIVE: Integrative oncology is widely used by patients with breast cancer. This study aims to investigate the relationship between the survival outcomes of breast cancer patients and the level of involvement in integrative oncology at the institutions treating them. METHODS: Claims-based data were used to find 4,815 newly diagnosed breast cancer patients treated between January 2013 and December 2014 for survival analysis. A scoring system was developed by asking oncologists about their institutions' efforts to educate, support, and provide funding for 12 complementary and lifestyle approaches. Cohort analysis using two-tailed chi-square and a separate multivariate model using SMOTE and lasso regression were used. Nine variables across patient and institutional profiles were included. The model coefficients were exponentiated and presented as odds ratios. RESULTS: 173 patients mapped to 103 institutions and 103 oncologists. The median patient age was 51, and 8% were metastatic. Institutions were scored for integrative oncology involvement and placed into four cohorts. Low-scoring institutions showed less effort to educate, support, and provide integrative therapies compared to others. The 5-year survival of patients in the low cohort was directionally but not significantly lower than others. In the multivariate model, a composite integrative oncology score was shown to increase 5-year survival odds three times for institutions in the low-mid cohort and 48% in the mid-high, compared to the low. CONCLUSION: Crossing the threshold beyond 'low' involvement in integrative oncology represents a new path to incremental survival benefit for many cancer patients. Entities invested in the survival of breast cancer patients should increase education, access, and funding for a core set of six therapies: nutrition counselling, exercise counselling, patient support groups, spiritual services, meditation, and psycho-oncology support.

All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation.

Radiotherapy (RT) is one of the main treatments for men with prostate cancer (PCa). To date, numerous sophisticated nano-formulations as radiosensitizers have been synthesized with inspiring therapeutic effects both in vitro and in vivo; however, almost all the attention has been paid on the enhanced dose deposition effect by secondary electrons of nanomaterials with high atomic numbers (Z); despite this, cell-cycle arrest, DNA damage, and also reactive oxygen species (ROS) production are critical working mechanisms that account for radiosensitization. Herein, an 'all-purpose' nanostrategy based on dose deposition enhancement, cell cycle arrest, and ROS production as prostate cancer radiosensitizer for potential clinical translation was proposed. The rather simple structure of docetaxel-loaded Au nanoparticles (NPs) with prostate specific membrane antigen (PSMA) ligand conjugation have been successfully synthesized. Enhanced cellular uptake achieved via the selective internalization of the NPs by PCa cells with positive PSMA expression could guarantee enhanced dose deposition. Moreover, the as-synthesized nanosystem could effectively arrest the cell cycle at G2/M phases, which would reduce the ability of DNA damage repair for more irradiation sensitive of the PCa cells. Moreover, the G2/M phase arrest would further promote cascade retention and the enrichment of NPs within the cells. Furthermore, ROS generation and double strand breaks greatly promoted by NPs under irradiation (IR) could also provide an underlying basis for effective radiosensitizers. In vitro and in vivo investigations confirmed the as-synthesized NPs as an effective nano-radiosensitizer with ideal safety. More importantly, all moieties within the present nanosystem have been approved by FDA for the purpose of PCa treatment, thus making it highly attractive for clinical translation.