The targeted nano-encapsulation of anticancer drugs can improve drug delivery and the selective targeting of cancer cells. Nuclear factor kappa B (NF-kB) is a regulator for different biological responses, including cell proliferation and differentiation. In acute myeloid leukemia (AML), constitutive NF-κB has been detected in more than 50% of cases, enabling leukemic cells to resist apoptosis and stimulate uncontrolled proliferation. We evaluated NF-kB expression in bone marrow samples from 103 patients with AML using quantitative real time polymerase chain reaction (RT-PCR) and found that expression was increased in 80.5% (83 out 103) of these patients with AML in comparison to the control group. Furthermore, overexpressed transmembrane glycoprotein (CD44) on leukemic cells in comparison to normal cells is known to play an important role in leukemic cell engraftment and survival. We designed poly lactide co-glycolide (PLGA) nanoparticles conjugated with antiCD44 and encapsulating parthenolide (PTL), a nuclear factor kappa B (NF-kB) inhibitor, in order to improve the selectivity and targeting of leukemic cells and to spare normal cells. In vitro, in leukemic cell lines Kasumi-1, KG-1a, and THP-1, proliferation was decreased by 40% (** p < 0.01) with 5 µM PLGA-antiCD44-PTL nanoparticles in comparison to the same concentration of free PTL (~10%). The higher uptake of the nanoparticles by leukemic cells was confirmed with confocal microscopy. In conclusion, PLGA-antiCD44-PTL nanoparticles improved the bioavailability and selective targeting of leukemic cells, thus holding promise as a drug delivery system to improve the cure rate of AML.

We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel^® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel^® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested.

Costunolide (COS) is a sesquiterpene lactone with anticancer properties. The present study investigated the anticancer effects of COS against the human colon (HCT116) and breast (MDA-MB-231-Luc) cancer cell lines. Inhibition of cell lines viability and IC50 of COS were assessed via an MTT assay. Furthermore, the apoptotic rate was detected by assessment of Bcl2-associated X (Bax) and B-cell lymphoma 2 (Bcl2) protein levels by flow cytometry. Xenograft mice model of HCT116 and MDA-MB-231-Luc were carried out to determine the effect of COS and its nanoparticles (COS-NPs). The results demonstrated that COS inhibited the viability of HCT116 and MDA-MB-231-Luc cells, with a half maximal inhibitory concentration value (IC50) of 39.92 µM and 100.57 µM, respectively. COS significantly increased Bax and decreased Bcl2 levels in treated cells. COS and COS-NPs, in combination with doxorubicin (DOX), significantly decreased the tumor growth of HCT116 and MDA-MB-231-Luc implants in mice. Furthermore, oral administration of COS and COS-NPs significantly decreased the viable cells and increased necrotic/apoptotic cells of HCT116 and MDA-MB-231-Luc implants. Interestingly, both COS and COS-NPs protected the cardiac muscles against DOX’s cardiotoxicity. The current results indicated the promising anticancer and cardiac muscles protection of COS and COS-NPs when administered with chemotherapy.

One of the major causes of women’s death in the world is breast cancer. Consequently, numerous regimens for the control of this severe disease have been created. The chemotherapeutic agent doxorubicin (DOX) is frequently used to treat breast cancer, but DOX can also cause cardiotoxic effects that lead to heart failure. Therefore, many research studies have been done to find a natural product that effectively potentiates or does not interfere with DOX’s anticancer effect and protects against its cardiotoxicity. We studied the impact of combined nanoformulated Ajwa (Phoenix dactylifera) selected bioactive compounds (BAC) rutin (R) and quercetin (Q) in nude mice breast cancer xenografts on DOX-mediated anticancer efficacy. We also studied if this Ajwa BAC could safeguard against DOX-mediated cardiomyopathies by evaluating plasma cardiac troponin-I (cTn-I) levels and cardiac histopathology. Nanoformulated Ajwa BAC effectively alleviated weight loss induced by DOX in mice and significantly decreased the elevated cTn-I. Furthermore, 5 mg RQ-NPs/kg of nude mice that subcutaneously daily injected for 11 days, attenuated the histopathological alterations induced in cardiac muscles due to DOX without any interference with the anticancer effects of DOX against breast cancer.

Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P₄₀₀₀-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P₁₆₀₀-bi-TAT, Compound 2) and the removal of one TAT molecule (P₁₆₀₀-m-TAT, Compound 3) versus P₄₀₀₀-bi-TAT, Compound 1. The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by >90% at all doses compared to the control (ON Treatment, *** p < 0.001) in cells treated with Compounds 1, 2, and 3 in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy.

Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10⁻⁶ tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism.