Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy.

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2'-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Copper-based metal-organic framework impedes triple-negative breast cancer metastasis via local estrogen deprivation and platelets blockade.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Abnormally estrogen level and activated platelets are the key driving forces for TNBC metastasis. Herein, an "ion/gas" bioactive nanogenerator (termed as IGBN), comprising a copper-based MOF and loaded cisplatin-arginine (Pt-Arg) prodrug is developed for metastasis-promoting tumor microenvironment reprogramming and TNBC therapy. The copper-based MOF not only serves as a drug carrier, but also specifically produces Cu2+ in tumors, which catalytic oxidizing estrogen to reduce estrogen levels in situ. Meanwhile, the rationally designed Pt-Arg prodrug reduced into cisplatin to significantly promote the generation of H2O2 in the tumor, then permitting self-augmented cascade NO gas generation by oxidizing Arg through a H2O2 self-supplied way, thus blocking platelet activation in tumor. We clarified that IGBN inhibited TNBC metastasis through local estrogen deprivation and platelets blockade, affording 88.4% inhibition of pulmonary metastasis in a 4T1 mammary adenocarcinoma model. Notably, the locally copper ion interference, NO gas therapy and cisplatin chemotherapy together resulted in an enhanced therapeutic efficacy in primary tumor ablation without significant toxicity. This "ion/gas" bioactive nanogenerator offers a robust and safe strategy for TNBC therapy.

Dendritic Cell-Hitchhiking In Vivo for Vaccine Delivery to Lymph Nodes.

Therapeutic cancer vaccines are among the first FDA-approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph-node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated-DCs homing from the periphery to the LNs, an injectable hydrogel-based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine "hitchhiking" on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve "antigen anchoring" on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and "hitchhiking" subcutaneous Migrated-DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six-fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN-resident APCs via the "One-to-Many" strategy (One Migrated-DC corresponding to Many LN-resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.

MUC-1 recognition-based activated drug nanoplatform improves doxorubicin chemotherapy in breast cancer.

Tumor-targeted drug delivery systems with stimuli-response drug release have been increasingly used to improve the therapeutic efficacy of antitumor drugs. Here, we report a specific molecular recognition activation drug nanoplatform based on specially designed DNA sensor-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs), designated as specific molecular recognition-activated nanoparticle (SMRAN). DNA sensors on the targeted nanoparticles can trigger DOX release through a conformational switch induced by MUC-1. This causes a significant difference in cell viability between breast cancer MCF-7 and normal breast Hs578bst cells (24.8% and 86.0%). In vivo experiments showed that the tumor volume was reduced 1.5-times in the SMRAN treatment group. Compared with that in the DOX group, due to significantly improved tumor accumulation and retention of DOX. The strategy of the MUC-1 activated drug delivery system is expected to provide a new perspective for clinical application.

Association between HER2 germline mutation A270S and prognosis in patients with primary breast cancer.

PURPOSE: To investigate the association between the HER2 germline mutation Ala270Ser (A270S), located in HER2 extracellular domain, and survival in breast cancer patients. METHODS: HER2 germline mutation A270S was identified in 5395 consecutive patients with operable primary breast cancer using direct Sanger sequencing analysis. Survival curves for patients with HER2 A270S mutation were compared using the Kaplan-Meier method with log-rank test. RESULTS: We identified that 31 cases carried HER2 germline mutation A270S in 5395 patients (0.6%, 31/5395). The HER2 A270S mutation was significantly associated with recurrence-free survival (RFS) and distant recurrence-free survival (DRFS) in the entire cohort of 5395 patients (RFS, unadjusted hazard ratio [HR] = 2.23; 95% confidence interval [CI] = 1.00-5.00; P= 0.045; DRFS, unadjusted HR = 2.80; 95% CI = 1.25-6.28; P= 0.009). Among the HER2-negative patients (n= 3825), those with the HER2 A270S mutation had a significantly worse RFS (unadjusted HR = 3.19; 95% CI = 1.42-7.16; P= 0.003) and DRFS (unadjusted HR = 3.98; 95% CI = 1.77-8.96; P< 0.001) than did those with wild type. Moreover, the A270S mutation remained an independent unfavorable factor for RFS and DRFS in the HER2-negative patients (RFS, HR = 3.30; 95% CI = 1.34-8.10; P= 0.009; DRFS, HR = 4.26; 95% CI = 1.73-10.47; P= 0.002). CONCLUSIONS: Breast cancer patients with the HER2 germline mutation A270S had a worse survival, especially in HER2-negative patients. Therefore, HER2-negative patients with a HER2 germline mutation A270S might be potential candidates for HER2-targeted therapy.

HER2 exon 27 mutations predict worse survival of breast cancer patients, especially in HER2-negative patients.

The aims of this study were to assess the prognostic value of the HER2 exon 27 mutations in breast cancer patients. Genomic DNA was isolated from peripheral blood leukocytes, and then HER2 exon 27 mutations were detected by direct sequencing. Survival curves were estimated by Kaplan-Meier curves and the differences between the curves were compared by log-rank tests. A total cohort of 892 female patients with operable primary breast cancer was included in this study. The median follow-up was 47 months. Of these 892 patients, 3.7% (33/892) had HER2 exon 27 mutations. Patients with the HER2 exon 27 mutations had a significant worse recurrence-free survival (RFS, unadjusted hazard ratio [HR] 2.42; 95% CI: 1.05-5.58; P = 0.032) and distant recurrence-free survival (DRFS, unadjusted HR 2.81; 95% CI: 1.21-6.50; P = 0.012) than the patients with the wild-type exon 27. Among the 673 patients with negative HER2 expression, 24 mutants were found. Patients with the HER2 mutations showed a worse RFS (unadjusted HR 5.08; 95% CI: 2.14-12.02; P < 0.001) and DRFS (unadjusted HR 5.62; 95% CI: 2.36-13.40; P < 0.001) than those patients with the wild-type exon 27. Furthermore, the mutations remained as unfavorable independent predictors for RFS and DRFS. Breast cancer patients with HER2 exon 27 mutations have a worse survival, especially in HER2-negative patients. HER2-negative patients with HER2 exon 27 mutations are potential subgroup of breast cancer patients benefiting from HER2-targeted therapy in future.

HER2 Pro1170Ala polymorphism is associated with decreased survival rate in HER2-negative breast cancer.

The Pro1170Ala polymorphism is one of the most common polymorphisms of human epidermal growth factor receptor 2 (HER2) and may affect the clinical outcome in breast cancer. Therefore, in the present study, the incidence of the HER2 Pro1170Ala polymorphism was determined in 3,305 female patients with operable primary breast cancer using a DNA-sequencing assay, and the potential association with survival was investigated. Of these 3,305 patients, 29% (955/3,305) were homozygous for the Pro/Pro genotype, 51% (1,679/3,305) were heterozygous for the Pro/Ala genotype and 20% (671/3,305) were homozygous for the Ala/Ala genotype. The frequency of this polymorphism conformed to the Hardy-Weinberg equilibrium (P=0.175). No significant association between the HER2 Pro1170Ala polymorphism and recurrence-free survival (RFS) or distant recurrence-free survival (DRFS) was identified in the entire cohort of 3,305 patients. HER2 status was available for 3,170/3,305 patients; no significant association between the HER2 Pro1170Ala polymorphism and survival was identified in HER2-positive patients (n=728). However, among the HER2-negative patients (n=2,442), those with the Pro/Ala or Ala/Ala genotype had a significantly decreased RFS [unadjusted hazard ratio (HR), 1.45; 95% confidence interval (CI), 1.03-2.04; P=0.033] and DRFS (unadjusted HR, 1.65; 95% CI, 1.11-2.44; P=0.012) compared with those with the Pro/Pro genotype. Multivariate analysis revealed that the Pro/Ala or Ala/Ala genotype was an independent unfavorable factor for DRFS (adjusted HR, 1.63; 95% CI, 1.05-2.53; P=0.029) in the subgroup of HER2-negative patients. The results of the present study suggest that patients with HER2-negative breast cancer with the HER2 Pro1170Ala polymorphism variant exhibit a decreased survival outcome.