Capturing Amyloid-ß Oligomers by Stirring with Microscaled Iron Oxide Stir Bars into Magnetic Plaques to Reduce Cytotoxicity toward Neuronal Cells.

Soluble amyloid-ß oligomers (oAß42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer's disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAß42 into magnetic plaques (mpAß42) and activation of microglia on cellular plaque clearance was developed. With oAß42 being effectively converted into mpAß42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAß42, neurons treated with oAß42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAß42. The phagocytic uptake of mpAß42 by microglia was enhanced significantly as compared to the counterpart of oAß42, and the M1 polarization of microglia often occurring after the uptake of oAß42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.

Indocyanine green/doxorubicin-encapsulated functionalized nanoparticles for effective combination therapy against human MDR breast cancer.

To overcome low therapeutic efficacy of chemotherapy against multidrug resistance (MDR) breast cancer, a combination therapy system based upon functionalized polymer nanoparticles comprising poly(γ-glutamic acid)-g-poly(lactic-co-glycolic acid) (γ-PGA-g-PLGA) as the major component was developed. The NPs were loaded with doxorubicin (DOX) and indocyanine green (ICG) for dual modality cancer treatment and coated with cholesterol-PEG (C-PEG) for MDR abrogation in treatment of human MDR breast cancer. The in vitro cellular uptake of the DOX/ICG loaded nanoparticles (DI-NPs) by MDR cancer cells was significantly enhanced owing to effective inhibition of the P-gp activity by C-PEG and γ-PGA receptor-mediated endocytosis. DOX localization in cytoplasm and nucleus was observed particularly with the photo-thermal effect that facilitated intracellular drug release. As a result, the C-PEG coated DI-NPs after photo-irradiation exhibited a synergistic effect of combination (chemo/thermal) therapy to depress the proliferation of MDR cancer calls. The ex vivo biodistribution study revealed an enhanced tumor accumulation of C-PEG (2000) coated DI-NPs in MCF-7/MDR tumor-bearing nude mice due to the excellent EPR effects by the NP surface PEGylation. The MDR tumor growth was almost entirely inhibited in the group receiving combination therapy from CP2k-DI-NPs and photo-irradiation along with substantial cell apoptosis of tumor tissues examined by immunohistochemical staining. The results demonstrate a promising dual modality therapy system, CP2k-DI-NPs, developed in this work for effective combination therapy of human MDR breast cancer.

Hierarchically targetable polysaccharide-coated solid lipid nanoparticles as an oral chemo/thermotherapy delivery system for local treatment of colon cancer.

Although oral formulations of anticancer chemotherapies are clinically available, the therapeutic action relies mostly on drug absorption, being inevitably accompanied with systemic side effects. It is thus desirable to develop oral therapy systems for the local treatment of colon cancers featured with highly selective delivery to cancer cells and minimized systemic drug absorption. The present study demonstrates the effective accumulation and cell uptake of the doxorubicin and superparamagnetic iron oxide nanoparticles-loaded solid lipid nanoparticle (SLN) delivery system for chemo/magnetothermal combination therapy at tumors by hierarchical targeting of folate (FA) and dextran coated on SLN surfaces in a sequential layer-by-layer manner. Both the in vitro and in vivo characterizations strongly confirmed that the dextran shells on SLN surfaces not only retarded the cellular transport of the FA-coated SLNs by the proton-coupled FA transporter on brush border membranes in small intestine, but also enhanced the particle residence in colon by specific association with dextranase. The enzymatic degradation and removal of dextran coating led to the exposure of the FA residues, thereby further facilitating the cellular-level targeting and uptake of the SLNs by the receptor-mediated endocytosis. The evaluation of the in vivo antitumor efficacy of the hierarchically targetable SLN therapy system by oral administration showed the effective inhibition of primary colon tumors and peritoneal metastasis in terms of the ascites volume and tumor nodule number and size, along with the absence of systemic side effects.

Radiotherapy-Controllable Chemotherapy from Reactive Oxygen Species-Responsive Polymeric Nanoparticles for Effective Local Dual Modality Treatment of Malignant Tumors.

Radiotherapy is one of the general approaches to deal with malignant solid tumors in clinical treatment. To improve therapeutic efficacy, chemotherapy is frequently adopted as the adjuvant treatment in combination with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive nanoparticle (NP) drug delivery system was developed to synergistically enhance the antitumor efficacy of radiotherapy by local ROS-activated chemotherapy, taking advantages of the enhanced concentration of reactive oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation after X-ray irradiation. The ROS-responsive polymers, poly(thiodiethylene adipate) (PSDEA) and PEG-PSDEA-PEG, were synthesized and employed as the major components assembling in aqueous phase into polymer NPs in which an anticancer camptothecin analogue, SN38, was encapsulated. The drug-loaded NPs underwent structural change including swelling and partial dissociation in response to the ROS activation by virtue of the oxidation of the nonpolar sulfide residues in NPs into the polar sulfoxide units, thus leading to significant drug unloading. The in vitro performance of the chemotherapy from the X-ray irradiation preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed comparable cytotoxicity to free drug and appreciably enhanced effect on killing cancer cells while the X-ray irradiation being incorporated into the treatment. The in vivo tumor growth was fully inhibited with the mice receiving the local dual modality treatment of X-ray irradiation together with SN38-loaded NPs administered by intratumoral injection. The comparable efficacy of the local combinational treatment of X-ray irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment corroborated the effectiveness of ROS-mediated drug release from the irradiated NPs at tumor site. The IHC examination of tumor tissues confirmed the significant reduction of VEGFA and CD31 expression with the tumor receiving the local dual treatment developed in this work, thus accounting for the absence of tumor regrowth compared to other single modality treatment.

Multifunctional GQDs-Concanavalin A@Fe3O4 nanocomposites for cancer cells detection and targeted drug delivery.

Multifunctional nanocomposites containing intrinsic property for serving as the sensing elements as well as targeted nanoconjugates are highly preferred in various therapeutic applications. In this work, nanocomposites of graphene quantum dots (GQDs) and Fe3O4 with conjugation of lectin protein, concanavalin A, to form GQD-ConA@Fe3O4 nanocomposites are developed for both detection of cancer cell and release of drugs to HeLa cells. The GQD-ConA@Fe3O4 nanocomposites deposited on Pt electrode can detect cancerous HeLa cells over normal endothelial cells with a dynamic linear range of 5 × 102 to 1 × 105 cells mL-1 with a detection limit of 273 cell mL-1. The GQD-ConA@Fe3O4 also can serve as nanocarriers for loading and delivering doxorubicin (Dox). The in vitro cell images show that the Dox concentration in HeLa cells is enhanced more than double in the presence of external magnetic field due to the incorporation of Fe3O4 in the nanocarrier. The cytotoxicity assay indicates that the susceptibility of cancerous HeLa cells to Dox is 13% higher than that of normal cells, confirming the selective role of ConA in nanocarriers. Results clearly indicate the GQD-ConA@Fe3O4 nanocomposites as a promising material for cancer cell detection and targeted Dox release toward HeLa cells which can serve as the multifunctional platform for novel cancer cell diagnostic and therapeutic applications.

Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma.

Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.

Tumortropic adipose-derived stem cells carrying smart nanotherapeutics for targeted delivery and dual-modality therapy of orthotopic glioblastoma.

Chemotherapy is typically used to treat malignant brain tumors, especially for the tumors in surgically inaccessible areas. However, owing to the existence of blood-brain barrier (BBB), the tumor accumulation and therapeutic efficacy of clinical therapeutics is still of great concerns. To this end, we present herein a prominent therapeutic strategy adopting adipose-derived stem cells (ADSCs) capable of carrying nanotherapeutic payloads selectively toward brain tumors for thermo/chemotherapy. The nanoparticle (NP) payload was obtained from co-assembly of poly(γ-glutamic acid-co-distearyl γ-glutamate) with poly(lactic-co-glycolic acid), paclitaxel (PTX), and oleic acid-coated superparamagnetic iron oxide NPs in aqueous solution. The particle size and drug loading content were ca 110nm and 8.4wt%, respectively. After being engulfed by ADSCs, the nanotherapeutics was found rather harmless to cellular hosts at a PTX concentration of 30µM over 48h in the absence of pertinent stimulus. Nevertheless, the ADSC-based approach combined with high frequency magnetic field exhibits a sound therapeutic performance with a 4-fold increase in therapeutic index on brain astrocytoma (ALTS1C1)-bearing mice (C57BL/6J) as compared to the typical chemotherapy using a current first-line chemodrug, temozolomide. Immunohistochemical examination of brain tumor sections confirms the successful cellular transport and pronounced cytotoxic action of therapeutics against tumor cells in vivo. This work demonstrates the promise of ADSC-mediated chemo/thermal therapy against brain tumors.

Radiosensitization of non-small cell lung cancer by kaempferol.

The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyl-tetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.