Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization.

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.

Highly Tumor-Specific and Long-Acting Iodine-131 Microbeads for Enhanced Treatment of Hepatocellular Carcinoma with Low-Dose Radio-Chemoembolization.

Transarterial radioembolization (TARE) is considered the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Iodine-131 (131I)-labeled lipiodol TARE is an effective treatment for HCC but has been withdrawn due to its poor retention in tumor lesions and significant distribution in normal tissues with severe side effects. In this work, a highly tumor-specific 131I-TARE agent with long-time retention is developed by simply introducing tyrosine to poly(vinyl alcohol) (PVA) drug-eluting microbeads (Tyr-PVA-DEBs). The labeling efficiency of 131I-labeled microbeads remains above 85% in 50% serum for 31 days. Micro-single-photon emission computed tomography/computed tomography (µSPECT/CT) evidences that the 131I-labeled microbeads accumulate in the orthotopic N1S1 hepatoma of rats for 31 days following intra-arterial injection. The cumulative radiation dose per cubic centimeter of the tumor is at least 13 678-fold higher than that of normal tissues. The highly tumor-selective radiation of the 131I-labeled microbeads allows localized delivery of 345.04 ± 139.16 Gy to the tumor following a single injection dose as low as 0.2 mCi of 131I. Moreover, the 131I-labeled microbeads are loaded with doxorubicin hydrochloride (DOX) through the carboxy groups on tyrosine of the polymer. The 131I-DOX-loaded microbeads present a synergetic antitumor effect without recurrence in comparison with the microbeads labeled with 131I or loading DOX alone, attributed to the sensitization of DOX to 131I-induced ionizing radiation damage to DNA under the embolization-induced hypoxia. Our results demonstrate a high tumor retention of 131I-labeled embolic agent for low-dose transarterial radio-chemoembolization (TARCE) with a synergetic therapeutic effect on treating HCC, showing potential for clinical application.

High Affinity of Chlorin e6 to Immunoglobulin G for Intraoperative Fluorescence Image-Guided Cancer Photodynamic and Checkpoint Blockade Therapy.

Cancer photodynamic therapy (PDT) represents an attractive local treatment in combination with immunotherapy. Successful cancer PDT relies on image guidance to ensure the treatment accuracy. However, existing nanotechnology for co-delivery of photosensitizers and image contrast agents slows the clearance of PDT agents from the body and causes a disparity between the release profiles of the imaging and PDT agents. We have found that the photosensitizer Chlorin e6 (Ce6) is inherently bound to immunoglobulin G (IgG) in a nanomolarity range of affinity. Ce6 and IgG self-assemble to form the nanocomplexes termed Chloringlobulin (Chlorin e6 + immunoglobulin G). Chloringlobulin enhances the Ce6 concentration in the tumor without changing its elimination half-life in blood. Utilizing the immune checkpoint inhibitor antiprogrammed death ligand 1 (PD-L1) (αPD-L1) to prepare αPD-L1 Chloringlobulin, we have demonstrated a combination of Ce6-based red-light fluorescence image-guided surgery, stereotactic PDT, and PD-L1 blockade therapy of mice bearing orthotopic glioma. In mice bearing an orthotopic colon cancer model, we have prepared another Chloringlobulin that allows intraoperative fluorescence image-guided PDT in combination with PD-L1 and cytotoxic T lymphocyte antigen 4 (CTLA-4) dual checkpoint blockade therapy. The Chloringlobulin technology shows great potential for clinical translation of combinatorial intraoperative fluorescence image-guided PDT and checkpoint blockade therapy.

Copper Sulfide Facilitates Hepatobiliary Clearance of Gold Nanoparticles through the Copper-Transporting ATPase ATP7B.

Metallic gold (Au) nanoparticles have great potential for a wide variety of biomedical applications. Yet, slow clearance of Au nanoparticles significantly hinders their clinical translation. Herein, we describe a strategy of utilizing the endogenous copper (Cu) clearance to improve the elimination of Au nanoparticles. Our mechanistic study reveals that a Cu-transporting P-type ATPase, ATP7B, mediates the exocytosis of CuS nanoparticles into bile canaliculi for their rapid hepatobiliary excretion. The efflux of CuS nanoparticles is adopted to facilitate the hepatobiliary clearance of Au nanoparticles through CuS-Au conjugation. Using two different CuS-Au nanoconjugates, we demonstrate that CuS increases the biliary Au excretion of CuS-Au nanospheres or CuS-Au nanorods in mice or rats in comparison to that of their respective unconjugated Au nanoparticles postintravenous injection. The current CuS-Au conjugation approach provides a feasible strategy to enhance the hepatobiliary clearance of Au nanoparticles that may be applicable to various structures.

The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer.

Compared to conventional cancer treatment, combination therapy based on well-designed nanoscale platforms may offer an opportunity to eliminate tumors and reduce recurrence and metastasis. In this study, we prepared multifunctional microspheres loading 131I-labeled hollow copper sulfide nanoparticles and paclitaxel (131I-HCuSNPs-MS-PTX) for imaging and therapeutics of W256/B breast tumors in rats. 18F-fluordeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging detected that the expansion of the tumor volume was delayed (P<0.05) following intra-tumoral (i.t.) injection with 131I-HCuSNPs-MS-PTX plus near-infrared (NIR) irradiation. The immunohistochemical analysis further confirmed the anti-tumor effect. The single photon emission computed tomography (SPECT)/photoacoustic imaging mediated by 131I-HCuSNPs-MS-PTX demonstrated that microspheres were mainly distributed in the tumors with a relatively low distribution in other organs. Our results revealed that 131I-HCuSNPs-MS-PTX offered combined photothermal, chemo- and radio-therapies, eliminating tumors at a relatively low dose, as well as allowing SPECT/CT and photoacoustic imaging monitoring of distribution of the injected agents non-invasively. The copper sulfide-loaded microspheres, 131I-HCuSNPs-MS-PTX, can serve as a versatile theranostic agent in an orthotopic breast cancer model.

131I-Labeled Copper Sulfide-Loaded Microspheres to Treat Hepatic Tumors via Hepatic Artery Embolization.

Purpose: Transcatheter hepatic artery embolization therapy is a minimally invasive alternative for treating inoperable liver cancer but recurrence is frequent. Multifunctional agents, however, offer an opportunity for tumor eradication. In this study, we were aim to synthesized poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating hollow CuS nanoparticles (HCuSNPs) and paclitaxel (PTX) that were then labeled with radioiodine-131 (131I) to produce 131I-HCuSNPs-MS-PTX. This compound combines the multi-theranostic properties of chemotherapy, radiotherapy and photothermal therapy. In addition, it can also be imaged with single photon emission computed tomography (SPECT) imaging and photoacoustic imaging. Methods: We investigated the value of therapeutic and imaging of 131I-HCuSNPs-MS-PTX in rats bearing Walker-256 tumor transplanted in the liver. After the intra-arterial (IA) injection of 131I-HCuSNPs-MS-PTX, 18F-Fluorodeoxyglucose (18F-FDG) micro-positron emission tomography/computed tomography (micro-PET/CT) imaging was used to monitor the therapeutic effect. PET/CT findings were verified by immunohistochemical analysis. SPECT/CT and photoacoustic imaging were performed to demonstrate the distribution of 131I-HCuSNPs-MS-PTX in vivo. Results: We found that embolization therapy in combination with chemotherapy, radiotherapy and photothermal therapy offered by 131I-HCuSNPs-MS-PTX completely ablated the transplanted hepatic tumors at a relatively low dose. In comparison, embolization monotherapy or combination with one or two other therapies had less effective anti-tumor efficacy. The combination of SPECT/CT and photoacoustic imaging effectively confirmed microsphere delivery to the targeted tumors in vivo and guided the near-infrared laser irradiation. Conclusion: Our study suggests that there is a clinical theranostic potential for imaging-guided arterial embolization with 131I-HCuSNPs-MS-PTX for the treatment of liver tumors.

[Pharmacokinetic study on dry powder inhalation administration of α-asarone in rats].

To study the pharmacokinetic characteristics and absolute bioavailability of α-asarone through dry powder inhalation in rats, and compare with that through oral administration and intravenous injection. A HPLC method was established for the determination of α-asarone in rat plasma to detect the changes in plasma concentrations of α-asarone through dry powder inhalation (20 mg · kg(-1)), oral administration (80 mg · kg(-1)) and intravenous injection (20 mg · kg(-1)) in rats. DAS 2.0 software was used to calculate the pharmacokinetic parameters. The absolute bioavailability of α-asarone was calculated according to AUC(0-t)) of administration routes and administration doses. According to the results, α-asarone showed good linear relations (r = 0. 999 4) at concentrations between 0.282-14.1 mg · L(-1), with the limit of detection (LOD) at 0.212 mg · L(-1). Through dry powder inhalation, oral administration and intravenous injection of α-asarone, the metabolic processes of α-asarone in rats conformed to one, two and three compartment models respectively, with the elimination half-life of (95.48 ± 48.28), (64.34 ± 27.59), (66.99 ± 29.76) min. According to the bioavailability formula, the absolute bioavailability of α-asarone through dry powder inhalation and oral administration were 78.32% and 33. 60%, respectively. This study showed that significant increase in elimination half-life and absolute bioavailability of α-asarone through dry powder inhalation, which lays a theoretical foundation for preparing α-asarone dry powder inhalers.

Distribution of α-asarone in brain following three different routes of administration in rats.

The goal of the present paper is to compare the distributions of α-asarone administered to rats through three different routes: oral, intravenous and intranasal. The concentrations of α-asarone in seven distinct brain regions, the olfactory bulb, cerebellum, hypothalamus, frontal cortex, striatum, hippocampus and medulla/pons as well as in plasma and cerebrospinal fluid (CSF), were determined by HPLC. The quantities of α-asarone accumulated in liver were measured to determine whether α-asarone could generate hepatotoxicity when administered via the three different routes. The results indicated that α-asarone could be absorbed via two different routes into the brain, after intranasal administration of dry powders. In the systemic route, α-asarone immediately entered the brain through the blood-brain barrier (BBB) after uptake into the circulatory system. In the olfactory bulb route, α-asarone traveled from the olfactory epithelium in the nasal cavity straight into brain tissue via the olfactory bulb. Furthermore, intranasal administration of α-asarone as a dry powder can ensure quick absorption and avoid excessive concentrations in the blood and liver, while achieving concentrations in the brain comparable to those attained by intravenous and oral administration routes.

[Studies on baicalin ethylcellulose microspheres for intranasal administration].

In this study, solvent evaporation method was used to preparing baicalin ethylcellulose microspheres for intranasal administration. The prepared microspheres were round with certain rough surface. The average drug loading and entrapment efficiency was (33. 31 ± 0. 045)% , (63. 34 ± 0. 11)% , respectively. As the characteristic crystalline peaks of baicalin were observed in the microspheres sample, the result of X-ray diffractometric analysis indicated that the baicalin was present in crystalline form after its entrapment in ethylcellulose matrix. By investigating the thermogram of microspheres sample, it was found that endothermic peak of baicalin was shifted from 211. 8 °C to 244. 2 °C and associated with the first broad endothermic peak of ethylcellulose. This could confirm that baicalin was loaded into ethylcellulose, nor simply physical mixture. The powder flowability test exhibited that the specific energy of microspheres was 3. 57 mJ . g-1 and the pressure drop was 2. 22 mBar when air kept the speed of 2 mm . s-1 through the powder bed with the force was 15 kPa. The consequence of the baicalin in vitro released from microspheres showed that the pure baicalin sample displayed faster (90%) release than microspheres sample (75%) in 7 h. Fitting model for release curve before 7 h, the results showed that the pure baicalin sample and the microsphere sample accorded with first order model (R2 = 0. 990 4) and Riger-Peppas model(R2 = 0. 961 2), respectively. Ex vivo rabbit nasal mucosa permeability experiment revealed that the value of cumulative release rate per unit area of the microsphere sample was 1. 56 times that of the pure baicalin sample. This provided the foundation for the in vivo pharmacokinetic study.