Clinical Applications of Carbon Nanomaterials in Diagnostics and Therapy.

Nanomaterials have the potential to improve how patients are clinically treated and diagnosed. While there are a number of nanomaterials that can be used toward improved drug delivery and imaging, how these nanomaterials confer an advantage over other nanomaterials, as well as current clinical approaches is often application or disease specific. How the unique properties of carbon nanomaterials, such as nanodiamonds, carbon nanotubes, carbon nanofibers, graphene, and graphene oxides, make them promising nanomaterials for a wide range of clinical applications are discussed herein, including treating chemoresistant cancer, enhancing magnetic resonance imaging, and improving tissue regeneration and stem cell banking, among others.

Ex Vivo Expansion of CD34 CD90 CD49f Hematopoietic Stem and Progenitor Cells from Non-Enriched Umbilical Cord Blood with Azole Compounds.

Umbilical cord blood (UCB) transplants in adults have slower hematopoietic recovery compared to bone marrow (BM) or peripheral blood (PB) stem cells mainly due to low number of total nucleated cells and hematopoietic stem and progenitor cells (HSPC). As such in this study, we aimed to perform ex vivo expansion of UCB HSPC from non-enriched mononucleated cells (MNC) using novel azole-based small molecules. Freshly-thawed UCB-MNC were cultured in expansion medium supplemented with small molecules and basal cytokine cocktail.

Lipid-dendrimer hybrid nanosystem as a novel delivery system for paclitaxel to treat ovarian cancer.

Combining lipids and dendrimers into one formulation is an emerging platform in the drug delivery field. This study aims to (i) develop and characterize a lipid-dendrimer hybrid (LDH) nanosystem for the hydrophobic anticancer drug paclitaxel, and (ii) evaluate its in vitro and in vivo anti-cancer activity in ovarian cancer models. The LDH nanosystems were prepared from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and poly (amidoamine) (PAMAM) G4.

Dual-functionalized poly(amidoamine) dendrimers with poly(ethylene glycol) conjugation and thiolation improved blood compatibility.

Objectives: This study aims to examine the blood compatibility of dual-functionalized poly(amidoamine) (PAMAM) dendrimers.

Methods: The cationic PAMAM dendrimer of generation 4.0 (PM4.

Mitochondrial superoxide reduction and cytokine secretion skewing by carbon nanotube scaffolds enhance ex vivo expansion of human cord blood hematopoietic progenitors.

Unlabelled: In this study, we report that surface functional groups of single walled carbon nanotubes (f-SWCNT) are critical for mediating survival and ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) in human umbilical cord blood (UCB). In comparison to amide (-O-NH2) and polyethylene-glycol (-PEG) functionalized SWCNT, carboxylic acid (-COOH) variants gave optimal viability support which correlated with maximal reduction of lethal mitochondrial superoxides in HSPC. Cytokine array illustrated that f-SWCNT-COOH maintained higher proportion of HSPC associated cytokines and minimal level of differentiation promoting factors.

Dendrimers in oral drug delivery application: current explorations, toxicity issues and strategies for improvement.

Dendrimers are emerging as potential novel nano-scaled material in drug delivery applications. An interesting area of application is oral drug delivery. In oral drug delivery, many drugs suffer from low bioavailability due to the presence of various biological barriers.

Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II.

In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM).

Liposome co-encapsulation of synergistic combination of irinotecan and doxorubicin for the treatment of intraperitoneally grown ovarian tumor xenograft.

Liposome co-encapsulation of synergistic anti-cancer drug combination is an emerging area that has demonstrated therapeutic benefit in clinical trials. Remote loading of two or more drugs into a single liposome constitutes a new challenge that calls for a re-examination of drug loading strategies to allow the loading of the drug combination efficiently and with high drug content. In this study, the Mn(2+) gradient coupled with A23187 ionophore was applied in the sequential co-encapsulation of doxorubicin and irinotecan, as this drug loading method is capable of remotely loading drugs by apparently two different mechanisms, namely, coordination complexation and pH gradient.

Liposomal codelivery of a synergistic combination of bioactive lipids in the treatment of acute myeloid leukemia.

Aim: The aim of this work was to develop a liposomal formulation to facilitate delivery of a synergistic safingol/C2-ceramide combination in the treatment of acute myeloid leukemia (AML).

Materials & Methods: Liposomes were prepared using the extrusion method and the bioactive lipids were encapsulated passively. Drug concentrations were determined by liquid chromatography tandem mass spectrometry.

Dual-functionalized PAMAM dendrimers with improved P-glycoprotein inhibition and tight junction modulating effect.

This study aims to surface modify poly(amido amine) or PAMAM dendrimers by sequentially grafting poly(ethylene glycol) or PEG and 4-thiobutylamidine (TBA) so as to reduce PAMAM cytotoxicity while improving the ability of PAMAM to modulate P-glycoprotein (P-gp) efflux and tight junction integrity. Conjugation of functional groups was determined by NMR spectroscopy, FT-IR, thiol group quantification and molecular weight estimation. The yield of the dual-functionalized dendrimers was >80%.

Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines as thymidine phosphorylase inhibitors.

5-Chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines were designed as new thymidine phosphorylase inhibitors based on the fragment based drug design approach. Multiple-step convergent synthetic schemes were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was synthesized by a 4-step reaction.

A structure-activity relationship study of 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues on anti-thymidine phosphorylase and associated anti-angiogenic activities.

Thirty-three 1,2,4-triazolo[1,5-a][1,3,5]triazin-5,7-dione and its 5-thioxo analogues were designed and synthesized which contained different substituents at meta- and/or para-positions of 2-phenyl or 2-benzyl ring attached to the fused ring structure. The preliminary pharmacological evaluation demonstrated that the 5-thioxo analogues of 1,2,4-triazolo[1,5-a][1,3,5]triazine exhibited a varying degree of inhibitory activity towards thymidine phosphorylase, comparable or better than reference compound, 7-Deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM).

Protective role of functionalized single walled carbon nanotubes enhance ex vivo expansion of hematopoietic stem and progenitor cells in human umbilical cord blood.

Unlabelled: In this study, carboxylic acid functionalized single walled carbon nanotubes (f-SWCNT-COOH) was shown to support the viability and ex vivo expansion of freeze-thawed, non-enriched hematopoietic stem and progenitor cells (HSPC) in human umbilical cord blood-mononucleated cells (UCB-MNC). Our in vitro experiments showed that f-SWCNT-COOH increased the viability of the CD45(+) cells even without cytokine stimulation. It also reduced mitochondrial superoxides and caspase activity in CD45(+) cells.

Role of oxidative stress, endoplasmic reticulum stress and ERK activation in triptolide-induced apoptosis.

Since its isolation from Tripterygium wilfordii in 1972, triptolide has been shown to possess potent anticancer activity against a variety of cancers, and has entered phase I clinical trial. It is a diterpenoid triepoxide that acts through multiple molecular targets and signaling pathways. The mitogen-activated protein kinases are well known for their modulation of cell survival and proliferation.

Role of reactive oxygen species in the synergistic cytotoxicity of safingol-based combination regimens with conventional chemotherapeutics.

Exploiting the sensitivity of cancer cells to reactive oxygen species (ROS) has been suggested as a strategy for the selective elimination of cancer cells. In this study, the ROS-generating sphingolipid safingol was combined with various conventional chemotherapeutics, and the potential synergism of the safingol-based combination regimen was assessed using a panel of cancer cell lines. The IC(50) values of safingol using as a single agent were 1.

Intercellular cytosolic transfer correlates with mesenchymal stromal cell rescue of umbilical cord blood cell viability during ex vivo expansion.

Background Aims: Mesenchymal stromal cells (MSC) have been observed to participate in tissue repair and to have growth-promoting effects on ex vivo co-culture with other stem cells.

Methods: In order to evaluate the mechanism of MSC support on ex vivo cultures, we performed co-culture of MSC with umbilical cord blood (UCB) mononuclear cells (MNC) (UCB-MNC).

Results: Significant enhancement in cell growth correlating with cell viability was noted with MSC co-culture (defined by double-negative staining for Annexin-V and 7-AAD; P < 0.

Lyophilization of cholesterol-free PEGylated liposomes and its impact on drug loading by passive equilibration.

The obstacles in translating liposome formulations into marketable products could be attributed to their physical instabilities upon long-term storage as aqueous dispersions. Lyophilization is the most commonly used technique to improve physical stability of liposomes. The development of stable, lyophilized liposomes is focused primarily on the cholesterol-containing liposomes or pure phosphatidylcholine-based liposomes, with minimal studies on cholesterol-free, pegylated (CF-PEG) liposomes which have emerged as an important class of liposome drug carriers.

Potent therapeutic activity of folate receptor-targeted liposomal carboplatin in the localized treatment of intraperitoneally grown human ovarian tumor xenograft.

Intraperitoneal (IP) therapy with platinum (Pt)-based drugs has shown promising results clinically; however, high locoregional concentration of the drug could lead to adverse side effects. In this study, IP administration was coupled with a folate receptor-targeted (FRT) liposomal system, in an attempt to achieve intracellular delivery of the Pt-based drug carboplatin in order to increase therapeutic efficacy and to minimize toxicity. In vitro and in vivo activity of FRT carboplatin liposomes was compared with the activity of free drug and nontargeted (NT) carboplatin liposomes using FR-overexpressing IGROV-1 ovarian cancer cells as the model.

Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer.

Background: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE).

Methods: Quercetin-loaded nanomicelles were prepared by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model.

Functionalized carbon nanomaterials: exploring the interactions with Caco-2 cells for potential oral drug delivery.

Although carbon nanomaterials (CNMs) have been increasingly studied for their biomedical applications, there is limited research on these novel materials for oral drug delivery. As such, this study aimed to explore the potential of CNMs in oral drug delivery, and the objectives were to evaluate CNM cytotoxicity and their abilities to modulate paracellular transport and the P-glycoprotein (P-gp) efflux pump. Three types of functionalized CNMs were studied, including polyhydroxy small-gap fullerenes (OH-fullerenes), carboxylic acid functionalized single-walled carbon nanotubes (f SWCNT-COOH) and poly(ethylene glycol) functionalized single-walled carbon nanotubes (f SWCNT-PEG), using the well-established Caco-2 cell monolayer to represent the intestinal epithelium.

In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia.

Prognosis of patients with acute myeloid leukemia (AML) remains poor despite the use of first-line induction chemotherapy. Therefore, it is imperative to find effective treatment for AML patients. Safingol is a bioactive sphingolipid which has demonstrated promising in vitro anti-leukemic properties; however, translation into clinical use is hampered by its low water solubility and dose-limiting hemolysis.

Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin.

Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells.

Effect of triptolide on focal adhesion kinase and survival in MCF-7 breast cancer cells.

Triptolide, a diterpene from Tripterygium wilfordii, has been shown to have potent anticancer activity, exerting its effects through multiple molecular targets and signaling pathways. Yet, its effect on focal adhesion kinase (FAK), a non-receptor tyrosine kinase overexpressed in breast cancer that regulates cellular adhesion and survival, has not been reported. The current study is the first to report on the effect of triptolide on FAK expression, cell adhesion and survival using MCF-7 breast cancer cells.

Liposome formulation of co-encapsulated vincristine and quercetin enhanced antitumor activity in a trastuzumab-insensitive breast tumor xenograft model.

Unlabelled: Hormone- and trastuzumab-insensitive breast cancer has limited and ineffective clinical treatment options. This study sought to develop a liposome formulation containing a synergistic combination of vincristine and quercetin, with prolonged drug circulation times and coordinated drug release in vivo, to develop effective treatments against this subtype of breast cancer. The 2:1 molar ratio of vincristine/quercetin showed strong synergism in the hormone- and trastuzumab-insensitive JIMT-1 cells.