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- Heavy Chain Only Antibodies: A New Paradigm in Personalized HER2+ Breast Cancer Therapy. [Journal Article]
- Bioimpacts 2013; 3(1):1-4.
Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen-binding fragments in cancer targeting and therapy. VHHs express low immunogenicity, are highly robust and easy to manufacture and have the ability to recognize hidden or uncommon epitopes. We highlight the utility of VHH in design of new molecular, multifunctional particulate and immune cell-based systems for combating HER2+ breast cancer.
- Structural modulation of the biological activity of gold nanoparticles functionalized with a carbonic anhydrase inhibitor. [Journal Article]
- Eur Phys J E Soft Matter 2013 May; 36(5):9862.
Gold nanoparticles (AuNPs) have gained attention for their potential and application in different fields, e.g. nanomedicine. This study explores the surface functionalization of AuNP with inhibitors of carbonic anhydrases (CAs, EC 22.214.171.124). Some CA transmembrane isoforms have been recognized as therapeutic targets for the treatment of hypoxic tumors. Embedding a CA inhibitory function onto a nanosized unit has been proved to enable selective targeting of transmembrane isoforms. We report the preparation in aqueous media, the characterization and CA inhibition tests of AuNPs coated with a sulfonamide (SA) derivative, already known for its inhibitory activity toward CAs. The physico-chemical characterization of SA-coated AuNPs was performed with a combination of scattering and spectroscopic techniques. We detect a threshold effect of the SA concentration on the final hydrodynamic and core sizes of the capped nanoparticles and on their stability over aggregation. These modified nanoparticles were assayed for inhibition of some CA transmembrane isoforms (CA IX and XII) as well as of two cytosolic isoforms (CA I and II), and show interesting inhibitory efficiency in the submicromolar range and some selectivity for transmembrane isoforms.
- The synergistic effect and mechanism of doxorubicin-ZnO nanocomplexes as a multimodal agent integrating diverse anticancer therapeutics. [Journal Article]
- Int J Nanomedicine 2013.:1835-41.
Nanomaterials have emerged as ideal multimodal nanomedicine platforms, each one combining different designs and therapeutic approaches in a single system against cancer. The aim of the current study was to explore the synergistic effect and mechanism of a doxorubicin (Dox)-ZnO nanocomplex as a multimodal drug delivery system, integrating Dox chemotherapy and ZnO-mediated photodynamic therapy, in anticancer therapeutics.Dox was loaded onto ZnO nanomaterials, forming complexes with the transition metal Zn to yield the Dox-ZnO nanocomplexes. After culture with SMMC-7721 hepatocarcinoma cells, the cellular uptake was quantitatively detected by flow cytometry and visualized by fluorescence microscopy. The synergistic effects of the different anticancer therapeutic modalities on the proliferation of SMMC-7721 hepatocarcinoma cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of B-cell lymphoma 2 protein (Bcl-2), Bcl-2 associated X protein (Bax), caspase 9, and caspase 3 were examined by Western blot, to elucidate the possible molecular mechanisms involved.Our observations demonstrated that Dox-ZnO nanocomplexes could act as an efficient drug delivery system for importing Dox into SMMC-7721 cells, enhancing its potential chemotherapy efficiency by increasing the intracellular concentration of Dox. With the addition of ultraviolet (UV) illumination, the ZnO nanomaterials showed excellent photodynamic therapeutic properties, attacking the cancer cells further. Thus the caspase-dependent apoptosis was synergistically induced, resulting in distinct improvement in anticancer activity.The Dox-ZnO nanocomplex presents a promising multimodal agent for comprehensive cancer treatment.
- Cyclodextrin-based supramolecular systems for drug delivery: Recent progress and future perspective. [JOURNAL ARTICLE]
- Adv Drug Deliv Rev 2013 May 11.
The excellent biocompatibility and unique inclusion capability as well as powerful functionalization capacity of cyclodextrins and their derivatives make them especially attractive for engineering novel functional materials for biomedical applications. There has been increasing interest recently to fabricate supramolecular systems for drug and gene delivery based on cyclodextrin materials. This review focuses on state of the art and recent advances in the construction of cyclodextrin-based assemblies and their applications for controlled drug delivery. First, we introduce cyclodextrin materials utilized for self-assembly. The fabrication technologies of supramolecular systems including nanoplatforms and hydrogels as well as their applications in nanomedicine and pharmaceutical sciences are then highlighted. At the end, the future directions of this field are discussed.
- Nanoscale effects of Caspofungin against two yeast species; Saccharomyces cerevisiae and Candida albicans. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2013 May 13.
Saccharomyces cerevisiae and Candida albicans are model yeasts for biotechnology and human health, respectively. We used Atomic Force Microscopy to explore the effects of caspofungin, an antifungal drug used in hospitals, on these two species. Our nanoscale investigation revealed similar but also different behavior of the two yeasts in response to the treatment with this drug. While administration of caspofungin induced a deep cell wall remodeling in both yeast species, as witnessed by a dramatic increase of chitin and decrease in β-glucan content, changes in cell wall composition were more pronounced with Candida albicans cells. Notably, the increase of chitin was proportional to the increase in the caspofungin dose. In addition, the Young modulus of the cell was three times lower for C. albicans cells than for S. cerevisiae cells, and increased proportionally with the increase of chitin, suggesting differences in the molecular organization of the cell wall between these two yeast species. Also, at low dose of caspofungin (i.e. 0.5×MIC), the cell surface of C. albicans exhibited a morphology that was reminiscent to cells expressing adhesion proteins. Interestingly, this morphology was lost at high dose of the drug (i.e. 4×MIC). However, the treatment of S. cerevisiae cell with high doses of caspofungin resulted in an impairment of cytokinesis. Altogether, the use of AFM for investigating the effect of antifungal drug is relevant in nanomedicine, as it should help understanding their mechanism of action on the fungal cells, as well as unraveling unexpected effects on cell division and fungal adhesion.
- In vivo nanoneurotoxicity screening using oxidative stress and neuroinflammation paradigms. [JOURNAL ARTICLE]
- Nanomedicine 2013 May 10.
Iron oxide nanoparticles (IONPs) are promising neuroimaging agents and molecular cargo across neurovascular barriers. Development of intrinsically safe IONP chemistries requires a robust in vivo nanoneurotoxicity screening model. Herein, we engineered four IONPs of different surface and core chemistries: DMSA-Fe2O3, DMSA-Fe3O4, PEG-Fe3O4 and PEG-Au-Fe3O4. Capitalizing on the ability of the peripheral nervous system to recruit potent immune cells from circulation, we characterized a spatiotemporally controlled platform for the study of in vivo nanobiointerfaces with hematogenous immune cells, neuroglial and neurovascular units after intraneural IONP delivery into rat sciatic nerve. SQUID magnetometry and histological iron stain were used for IONP tracking. Among the IONPs, DMSA-Fe2O3 NPs were potent pro-apoptotic agents in nerve, with differential ability to regulate oxidative stress, inflammation and apoptotic signaling in neuroglia, macrophages, lymphocytes and endothelial cells. This platform aims to facilitate the development of predictive paradigms of nanoneurotoxicity based on mechanistic investigation of relevant in vivo bio-nanointerfaces.
- Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine. [JOURNAL ARTICLE]
- Nanomedicine 2013 May 10.
Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, were demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin.
- Efficient drug-delivery using magnetic nanoparticles - biodistribution and therapeutic effects in tumour bearing rabbits. [JOURNAL ARTICLE]
- Nanomedicine 2013 May 10.
To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterially. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200 nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (p=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies.
- Conjugation of Dexamethasone to C60 for the Design of an Anti-inflammatory Nanomedicine with Reduced Cellular Apoptosis. [JOURNAL ARTICLE]
- ACS Appl Mater Interfaces 2013 May 13.
Dexamethasone(DEX) is a well known anti-inflammatory drug, whose widespread clinical use is nevertheless restricted by its serious side effects. By conjugation of DEX with C60, we found that this nanomedicine retained the anti-inflammatory activity of DEX while redcued side effects in the animal model. In mouse thymocytes, the CCK-8 assay showed that the cytotoxicity of DEX-C60 was significantly lower than that of free DEX. Flow cytometric studies revealed that incubation with DEX-C60 induced much less apoptotic thymocytes. Interestingly, such reduced cytotoxicity and apoptosis were not observed when equal moles of free C60 and free DEX were co-incubated with thymocytes, suggesting that the conjugation alters the signal pathway of DEX. Indeed, we found that the binding of DEX-C60 and glucocorticoid receptor (GR) was partially blocked in the thymocytes, which resulted in down-regulation of several apoptosis-related genes. These findings help understand the mechanism of beneficial effects of this new nanomedicine, DEX-C60, and promote its clinical applications.
- Plasmonic photothermal therapy for atheroregression below Glagov threshold. [Journal Article]
- Future Cardiol 2013 May; 9(3):405-25.
The advent of nanomedicine allowed for the development and design of tools that enhance detailed diagnosis and target treatment of atherosclerosis. Given the rapid progress in nanoagent synthesis and utility, clinical application of these technologies can be anticipated in the near future. This review article focuses on the development of these technologies in interventional cardiology, with the main goal of achieving atheroregression below a Glagov threshold of 40%. Special attention is given to plasmonic photothermal therapy. Vascular remodeling maintains the lumen dimension as long as the external elastic membrane can accommodate an increase in plaque burden that does not surpass a certain threshold. We propose that this threshold becomes the target for the development of strategies that reverse atherosclerosis, especially for the generation of devices and tools of nanomedicine.