Acridine Orange Encapsulated Mesoporous Manganese Dioxide Nanoparticles to Enhance Radiotherapy.

Manganese dioxide (MnO2) nanoparticles are a promising type of radiosensitizer for they can catalyze H2O2 decomposition to produce O2. Combining MnO2 nanoparticles with conventional, small molecule radiosensitizers would further enhance radiotherapy (RT) efficacy due to complementary mechanisms of action. However, solid MnO2 nanoparticles are suboptimal at drug loading, limiting the related progress. Herein we report a facile method to synthesize mesoporous MnO2 (mMnO2) nanoparticles, which can efficiently encapsulate small molecule therapeutics. In particular, we found that acridine orange (AO), a small molecule radiosensitizer, can be loaded onto mMnO2 nanoparticles at very high efficiency and released to the surroundings in a controlled fashion. We show that mMnO2 nanoparticles can efficiently produce O2 inside cells. This, together with AO-induced DNA damage, significantly enhances RT outcomes, which was validated both in vitro and in vivo. Meanwhile, mMnO2 nanoparticles slowly degrade in acidic environments to release Mn2+, providing a facile way to keep track of the nanoparticles through magnetic resonance imaging (MRI). Overall, our studies suggest mMnO2 as a promising nanoplatform that can be exploited to produce composite radiosensitizers for RT.

Wet/Sono-Chemical Synthesis of Enzymatic Two-Dimensional MnO2 Nanosheets for Synergistic Catalysis-Enhanced Phototheranostics.

2D nanomaterials have attracted broad interest in the field of biomedicine owing to their large surface area, high drug-loading capacity, and excellent photothermal conversion. However, few studies report their "enzyme-like" catalytic performance because it is difficult to prepare enzymatic nanosheets with small size and ultrathin thickness by current synthetic protocols. Herein, a novel one-step wet-chemical method is first proposed for protein-directed synthesis of 2D MnO2 nanosheets (M-NSs), in which the size and thickness can be easily adjusted by the protein dosage. Then, a unique sono-chemical approach is introduced for surface functionalization of the M-NSs with high dispersity/stability as well as metal-cation-chelating capacity, which can not only chelate 64 Cu radionuclides for positron emission tomography (PET) imaging, but also capture the potentially released Mn2+ for enhanced biosafety. Interestingly, the resulting M-NS exhibits excellent enzyme-like activity to catalyze the oxidation of glucose, which represents an alternative paradigm of acute glucose oxidase for starving cancer cells and sensitizing them to thermal ablation. Featured with outstanding phototheranostic performance, the well-designed M-NS can achieve effective photoacoustic-imaging-guided synergistic starvation-enhanced photothermal therapy. This study is expected to establish a new enzymatic phototheranostic paradigm based on small-sized and ultrathin M-NSs, which will broaden the application of 2D nanomaterials.

Acidity/Reducibility Dual-Responsive Hollow Mesoporous Organosilica Nanoplatforms for Tumor-Specific Self-Assembly and Synergistic Therapy.

Featured with a large surface area, uniform interpenetrating mesopores, diverse organic framework hybridization, and well-defined surface properties, the hollow mesoporous organosilica nanoparticle (HMON) represents a promising paradigm in drug delivery systems with excellent biocompatibility. However, effective tumor accumulation and precise cancer theranostics of the HMON still remain a challenge. In this study, an "ammonia-assisted hot water etching" method is applied for the successful construction of sub-50 nm thioether/phenylene dual-hybridized HMON with low hemolytic effect. Particularly, the surface modification with Mo(VI)-based polyoxometalate (POM) clusters drives the self-assembly of HMON in the mild acidic tumor microenvironment (TME) to achieve enhanced tumor retention and accumulation. More importantly, the reducibility-activated Mo(VI)-to-Mo(V) conversion within POM not only endows the POM-anchored HMON with outstanding TME-responsive photoacoustic (PA) imaging contrast and photothermal therapy (PTT) performance but also plays an indispensable role in controllably triggering the decomposition of the Mn2(CO)10 payload for CO release, which gives rise to remarkable synergistic PTT-enhanced CO gas therapy for complete tumor eradication. By harnessing the unique acidic and redox properties of TME, the judiciously designed smart POM-anchored HMON nanoplatform is expected to act as a "magic bomb" to selectively destroy cancer without damaging normal tissues. This nanoplatform holds significant potential in realizing TME-responsive self-assembly for enhanced tumor accumulation and precise tumor-specific synergistic therapy, which is very promising for clinical translation.

Multi-parameter MRI to investigate vasculature modulation and photo-thermal ablation combination therapy against cancer.

Nanotransducer-mediated photothermal therapy (PTT) has emerged as an attractive therapy modality against cancer, but its efficacy is often limited by the amount of nanoparticles delivered to tumors. Previous studies showed a vasculature modulation treatment, which dilates or prunes tumor blood vessels, may enhance tumor uptake of nanoparticles. However, exploiting these approaches for improved PTT has seldom been studied. In this study, we investigated the impact of mild hyperthermia or anti-angiogenesis therapy on PTT. Briefly, we gave tumor-bearing balb/c mice low doses of sunitinib or submerged tumors in a 42 °C water bath. Next, we injected PEGylated reduced graphene oxide (RGO-PEG) and irradiated the tumors to induce PTT. We then followed up the treatment with multi-parameter MRI. Contrary to expectation, both vessel modulation strategies led to diminished PTT efficacy. Our results show that vessel modulation does not warrant improved PTT, and should be carefully gauged when used in combination with PTT.

Gold nanorods and curcumin-loaded nanomicelles for efficient in vivo photothermal therapy of Barrett's esophagus.

AIM: Provide an enhanced local drug delivery, nanoparticle(s) to minimize systemic effects and achieve enhanced permeability and drug retention into abnormal cells and stroma. MATERIALS & METHODS: Here a simultaneous loading of lipophilic gold nanorods (GNRs) and curcumin into polymeric nanomicelles made of biocompatible PLGA-b-PEG copolymer through a double re-emulsification process has been developed. RESULTS: Initial results in vitro on Barrett's esophagus and esophageal adenocarcinoma cell lines demonstrated a significant reduction in cell viability with curcumin and GNRs exposure (p < 0.05). In vivo Barrett's-associated animal model confirmed these results with successful in vivo demonstrated eradication of all high-grade dysplastic premalignant cancer cells. CONCLUSION: The synthesis of this novel nanosystem containing GNRs and curcumin is safe and effective in treating and eradicating premalignant esophageal adenocarcinoma.

Study on insulin resistance and genetic polymorphisms in essential hypertension patients of two different kinds of TCM constitution.

OBJECTIVE: To investigate the relationship of insulin resistance and the polymorphisms of insulin receptor-related genes in essential hypertension patients of two different kinds of TCM constitution. METHODS: Oral glucose tolerance test (OGTT) and insulin release test (InRT) were conducted in 217 essential hypertensive patients of either sluggish meticulous (SM) constitution (139 cases) or prosperous impetuous (PI) constitution (78 cases), and the polymorphism of three genes, including insulin-like growth factor-1 receptor (IGF-1R), insulin receptor substrate-1 (IRS-1) and 2 (IRS-2) genes were detected. RESULTS: (1) OGTT, InRT and insulin resistance index (Homa-IR) were higher and insulin sensitive index (ISI) was lower in the patients of SM constitution than those in patients of PI constitution. (2) Significant difference of ISI and Homa-IR was shown in patients of both constitutions with genotype G of the 3 genes. CONCLUSION: Decrease of insulin sensitivity and increase of insulin resistance are more obvious in hypertensive patients with genotype G of the 3 genes of SM constitution than in those of PI constitution. Therefore, the difference in constitution might be one of the genetic characteristics for insulin resistance in hypertensive patients.

[Relationship between the polymorphism of alpha-adducin gene and the two phenotypes of constitutions in patients with essential hypertension classified by TCM].

OBJECTIVE: To investigate the relationship between the polymorphism of alpha-adducin (ADD1) gene and the two phenotypes of constitution in patients with essential hypertension, the Yang-hyperactive (YH) type and phlegm-dampness (PD) type, classified by traditional Chinese medicine (TCM) approach. METHODS: Two hundred and seven patients differentiated by TCM approach as YH type (113 cases) or PD type (94 cases) were observed, with the systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), fasting blood glucose (FBG), serum creatinine (Cr), uric acid (UA), total cholesterol (TC) and triglycerides (TG) as the criteria of observation. Gly460Trp polymorphism of the ADD1 gene was detected by MALDI-TOF mass spectrometry. Results The levels of BMI, DBP, FBG and UA, etc. in the PD group were significantly higher than those in the YH group respectively. The rate of GG, GT and TT type of ADD1 gene was 29.2%, 41.6% and 29.2% in the YH group, 28.7%, 48.9% and 22.3% in the PD group, showing no significant difference in ADD1 genotype distribution between the two groups, while there was also no difference in the hypertension phenotype distribution among different genotypes (both P > 0.05). For the patients with TT genotype, there were significant differences between the YH group and the PD group in BMI (24.11 +/- 3.04 kg/m2 vs 26.20 +/- 2.30 kg/m2), DBP (96.79 +/- 4.05 mmHg vs 99.56 +/- 3.90 mmHg), FBG (5.01 +/- 0.53 mmol/L vs 5.51 +/- 1.07 mmol/L) and UA level (302.22 +/- 71.95 micromol/L vs 358.25 +/- 88.75 micromol/L, all P < 0.05). CONCLUSION: There was no relation between ADD1 gene polymorphism and the TCM genotype of constitution in patients with essential hypertension. However, it is likely that for hypertension patients with TT genotype, those of PD type are more susceptible to cardiovascular disease and have worse prognosis than those of YH type.