Synchronized Chemotherapy/Photothermal Therapy/Sonodynamic Therapy of Human Triple-Negative and Estrogen Receptor-Positive Breast Cancer Cells Using a Doxorubicin-Gold Nanoclusters-Albumin Nanobioconjugate.

OBJECTIVE: Novel strategies for treating triple-negative breast cancer (TNBC) are ongoing because of the lack of standard-of-care treatment. Nanoframed materials with a protein pillar are considered a valuable tool for designing multigoals of energy-absorbing/medication cargo and are a bridge to cross-conventional treatment strategies. METHODS: Nanobioconjugates of gold nanoclusters-bovine serum albumin (AuNCs-BSA) and doxorubicin-AuNCs-BSA (Dox-AuNCs-BSA) were prepared and employed as a simultaneous double photosensitizer/sonosensitizer and triple chemotherapeutic/photosensitizer/sonosensitizer, respectively. RESULTS: The highly stable AuNCs-BSA and Dox-AuNCs-BSA have ζ potentials of -29 and -18 mV, respectively, and represent valuable photothermal and sonodynamic activities for the combination of photothermal therapy and sonodynamic therapy (PTT/SDT) and synchronized chemotherapy/photothermal therapy/sonodynamic therapy (CTX/PTT/SDT) of human TNBC cells, respectively. The efficiency of photothermal conversion of AuNCs-BSA was calculated to be a promising value of 32.9%. AuNCs-BSA and Dox-AuNCs-BSA were activated on either laser light irradiation or ultrasound exposure with the highest efficiency on the combination of both types of radiation. CTX/PTT/SDT of MCF-7 and MDA-MB-231 breast cancer cell lines by Dox-AuNCs-BSA were evaluated with the MTT cell proliferation assay and found to progress synergistically. CONCLUSION: Results of the MTT assay, detection of the generation of intracellular reactive oxygen species and occurrence of apoptosis in the cells confirmed that CTX/PTT/SDT by Dox-AuNCs-BSA was attained with lower needed doses of the drug and improved tumor cell ablation, which would result in the enhancement of therapeutic efficacy and overcoming of therapeutic resistance.

Fractionated Sonodynamic Therapy Using Gold@Poly(ortho-aminophenol) Nanoparticles and Multistep Low-Intensity Ultrasound Irradiation to Treat Melanoma Cancer: In Vitro and In Vivo Studies.

OBJECTIVE: Cancer treatment using ultrasound irradiation with low intensities along with a sonosensitizer has been found to have significant advantages, such as high penetration depth in tissues, non-invasive therapeutic character, minor side effects, good patient adherence and preferential tumor area treatment. In the present study, gold nanoparticles covered by poly(ortho-aminophenol) (Au@POAP NPs) were synthesized and characterized as a new sonosensitizer. METHODS: We investigated Au@POAP NPs efficacy on fractionated ultrasound irradiation for treatment of melanoma cancer in vitro as well as in vivo. DISCUSSION: In vitro examinations revealed that although Au@POAP NPs (with a mean size of 9.8 nm) alone represented concentration-dependent cytotoxicity against the B16/F10 cell line, multistep ultrasound irradiation (1 MHz frequency, 1.0 W/cm2 intensity, 60 s irradiation time) of the cells in the attendance of Au@POAP NPs led to efficient cell sonodynamic therapy (SDT) and death. Histological analyses revealed that in vivo fractionated SDT toward melanoma tumors of male balb/c mice led to no residual viable tumor cell after 10 d. CONCLUSION: A deep sonosensitizing effectiveness of Au@POAP NPs on fractionated low-intensity ultrasound irradiation was attained with the main mechanism of tumor cell eradication of promotion of apoptosis or necrosis through dramatically increased reactive oxygen species levels.

Phenanthrotriazine Derivatives Containing Arylidine Hydrazone Moieties as Novel Potential c-Met Inhibitors with Anticancer Effect.

Cancer is the second cause of death in the world and the discovery of novel anticancer agents is of vital importance to provide better therapeutic options for cancer patients. In this study, a new series of 12 arylidene hydrazone phenanthrotriazine derivatives were designed, synthesized, and tested in-vitro for antiproliferative activity against three cancer cell lines including colorectal cancer (HT-29), breast cancer (MCF-7) and leukemia (MOLT-4) cells and also against Vero normal cells. The effect of derivatives on cell cycle and apoptosis induction were studied by flow cytometric propidium iodide/RNase assay and Hoechst 33258 staining, respectively, while docking analysis was used to investigate the interactions of synthesized derivatives with the c-Met receptor kinase domain. Some compounds showed considerable antiproliferative activity against tested cancer cells. The most potent derivative was 9k bearing pyrrole moiety with IC50 values of 14.3, 4.7 and 1.7 µM against HT-29, MCF-7 and MOLT-4 cells, respectively, while it showed negligible activity against Vero normal cells (IC50: 95.4 µM). Derivatives bearing 2-nitrophenyl (9g), 4-cyanophenyl (9j), pyrrole (9k), and thiophene (9l) moieties induced G0/G1 cell cycle arrest and also apoptosis at higher doses in MCF-7 cells. Docking study showed that the phenanthrotriazine backbone form H-bond interactions with Asn1209, while phenyl moieties of the pendants generate different hydrophobic interactions with the Asp1164 and Asp1231 residues of c-Met. In conclusion, phenanthrene 1,2,4-triazines, especially the ones with less influence on normal cells, may constitute promising compounds for the discovery of antiproliferative agents with potential c-Met inhibitory capacity.

Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met.

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5-25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.

Novel folic acid-conjugated doxorubicin loaded ß-lactoglobulin nanoparticles induce apoptosis in breast cancer cells.

Chemotherapy constitutes the main strategy in management of breast cancer (BC). Lack of specificity and high burden of adverse effects of chemotherapeutic agents remain the most important impediments to successful treatment of BC patients. Folate receptor α (FRα) could be very promising for therapeutic targeting in this type of cancer. In this study, ß-lactoglobulin nanoparticles (BNPs) conjugated with folic acid and loaded with doxorubicin (FDBNPs) were prepared. Various characterization techniques were applied to determine the size, polydispersity and doxorubicin loading of prepared FDBNPs in comparison with doxorubicin-loaded BNPs (DBNPs). The results showed that FDBNPs are 109.77 ± 2.80 nm in diameter with well dispersed and spherical shapes. The biodegradation of FDBNPs in the presence of trypsin enzyme and in PBS at different pH (4 and 7) was spectrophotometrically monitored and the results showed that the FDBNPs with encapsulation efficiency of 68.82%±1.76% could deliver doxorubicin at clinically relevant doses. Effects of DBNPs and FDBNPs against MCF-7 and MDA-MB-231, BC and triple negative BC (TNBC) cell lines, respectively, showed significant inhibition of cell proliferation as well as induction of apoptosis. Based on these findings, FDBNPs with facilitated drug release and targeted doxorubicin delivery capacities could have high therapeutic potential for BC and TNBC.

Doughnut-shaped bovine serum albumin nanoparticles loaded with doxorubicin for overcoming multidrug-resistant in cancer cells.

Traditional spherical albumin nanoparticles remain as the dominant shape of nano-carriers described in the literature at present, due to their simple desolvation method of synthesis. However, non-spherical shapes also show great promise as cancer drug delivery vectors. In this study, we report a novel synthetic strategy based on dimethyl sulfoxide (DMSO) addition during desolvation step, to produce doughnut-shaped bovine serum albumin nanoparticles (DBSA-NPs), while maintaining narrow size distributions and homogeneity. The characteristics such as size, polydispersity and doxorubicin loading of prepared DBSA-NPs in comparison with spherical ones were determined. The biodegradation of DBSA-NPs loaded with doxorubicin (Dox-DBSA-NPs) in the presence of trypsin enzyme was spectrophotometrically monitored directly based on doxorubicin release profile. The release profile was analyzed with different kinetic models and it was best fitted with Higuchi kinetics model. The anticancer effect of Dox-DBSA-NPs against lymphoblastic leukemia (MOLT-4) and multidrug resistant uterine sarcoma (MES-SA/DX-5) cell lines were also investigated and the results were comparable with doxorubicin loaded spherical BSA nanoparticles. These results showed the potential of Dox-DBSA-NPs as a novel and high potential nano-carrier for management of non-resistance and also multidrug resistant cancer cells.

Long Chain Alkyl Esters of Hydroxycinnamic Acids as Promising Anticancer Agents: Selective Induction of Apoptosis in Cancer Cells.

Cancer is the major cause of morbidity and mortality worldwide. Hydroxycinnamic acids (HCAs) are naturally occurring compounds and their alkyl esters may possess enhanced biological activities. We evaluated C4, C14, C16, and C18 alkyl esters of p-coumaric, ferulic, sinapic, and caffeic acids (19 compounds) for their cytotoxic activity against four human cancer cells and also examined their effect on cell cycle alteration and apoptosis induction. The tetradecyl (1c) and hexadecyl (1d) esters of p-coumaric acid and tetradecyl ester of caffeic acid (4c), but not the parental HCAs, were selectively effective against MOLT-4 (human lymphoblastic leukemia) cells with IC50 values of 0.123 ± 0.012, 0.301 ± 0.069 and 1.0 ± 0.1 µM, respectively. Compounds 1c, 1d, and 4c significantly increased apoptotic cells in sub-G1 phase and activated the caspase-3 enzyme in MOLT-4 cells. Compound 1c was 15.4 and 23.6 times more potent than doxorubicin and cisplatin, respectively, against the drug resistant MES-SA-DX5 uterine sarcoma cells. These p-coumarate esters were several times less effective against NIH/3T3 fibroblast cells. Docking studies showed that 1c may cause cytotoxicity by interaction with carbonic anhydrase IX. In conclusion, long chain alkyl esters of p-coumaric acid are promising scaffolds for selective apoptosis induction in cancer cells.