Furanocoumarin compounds isolated from Dorstenia foetida potentiate irinotecan anticancer activity against colorectal cancer cells.

Although the anticancer activity of Dorstenia foetida was already observed, the chemical entity responsible for this activity remained unidentified. In this study, the cytotoxic activity of two furanocoumarin compounds, i.e., 5-methoxy--3-(3-methyl-2,3-dihydroxybutyl)-psoralen (1) and 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen diacetate (2) isolated from ethyl acetate fraction of D. foetida (whole plant) was investigated in several cancer cell lines including HN22, MDA-MB-231, HCT116, and HT29. The results revealed that compound 2 exhibited cytotoxic activity, particularly against colorectal cancer cell lines HCT116 and HT29. The interplay between compound 2 and irinotecan (Iri) showed synergism against HCT116, which was analyzed by CompuSyn software. The simulation revealed that, at the molar ratio of Iri:2 of 1:40, the concentration predicted to achieve a 90 % inhibitory effect when used in the combination would be ~28- and ~4-fold lower than the concentration of compound 2 and Iri, resp., when used individually. Finally, the percentage of apoptotic cells in the HCT116 line treated with the combination was markedly higher than in the cells treated with the individual agent (60 % apoptotic cells for the combination compared to 17 and 45 % for Iri and compound 2 monotherapy, resp). In conclusion, our results identified compound 2 as a plant-derived compound exhibiting anticancer properties that can act synergistically with Iri and warranted further research to assess the potential of this synergism for colorectal cancer treatment.

Photodynamic Antibacterial Therapy of Gallic Acid-Derived Carbon-Based Nanoparticles (GACNPs): Synthesis, Characterization, and Hydrogel Formulation.

Carbon-based nanoparticles (CNPs) have gained recognition because of their good biocompatibility, easy preparation, and excellent phototherapy properties. In biomedicine applications, CNPs are widely applied as photodynamic agents for antibacterial purposes. Photodynamic therapy has been considered a candidate for antibacterial agents because of its noninvasiveness and minimal side effects, especially in the improvement in antibacterial activity against multidrug-resistant bacteria, compared with conventional antibiotic medicines. Here, we developed CNPs from an active polyhydroxy phenolic compound, namely, gallic acid, which has abundant hydroxyl groups that can yield photodynamic effects. Gallic acid CNPs (GACNPs) were rapidly fabricated via a microwave-assisted technique at 200 °C for 20 min. GACNPs revealed notable antibacterial properties against Gram-positive and Gram-negative bacteria, including Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The minimum inhibitory concentrations of GACNPs in S. aureus and E. coli were equal at approximately 0.29 mg/mL and considerably lower than those in gallic acid solution. Furthermore, the GACNP-loaded hydrogel patches demonstrated an attractive photodynamic effect against S. aureus, and it was superior to that of Ag hydrofiber®, a commercial material. Therefore, the photodynamic properties of GACNPs can be potentially used in the development of antibacterial hydrogels for wound healing applications.

Dual-Targeted Therapy in HER2-Overexpressing Breast Cancer with Trastuzumab and Novel Cholesterol-Based Nioplexes Silencing Mcl-1.

The challenge in HER2-overexpressing breast cancer therapy lies in creating an effective target therapy to overcome treatment resistance. Monoclonal antibodies and target gene silencing by siRNA are two potential strategies that have been widely developed for treating HER2-positive breast cancer. The siRNA delivery system is a crucial factor that influences siRNA therapy's success. In this study, lipid-based nanoparticles (cationic niosomes) composed of different cholesterol-based cationic lipids were formulated and characterized for delivering siRNA into HER2-overexpressing breast cancer cells. Niosomes containing a trimethylammonium headgroup showed the highest siRNA delivery efficiency with low toxicity. The myeloid cell leukemia-1 (Mcl-1) siRNA nioplex treatment significantly decreased mRNA expression and breast cancer cell growth. Dual-targeted therapy, consisting of treatment with an Mcl-1 siRNA nioplex and trastuzumab (TZ) solution, noticeably promoted cell-growth inhibition and apoptosis. The synergistic effect of dual therapy was also demonstrated by computer modeling software (CompuSyn version 1.0). These findings suggest that the developed cationic niosomes were effective nanocarriers for siRNA delivery in breast cancer cells. Furthermore, the Mcl-1 nioplex/TZ dual treatment establishes a synergistic outcome that may have the potential to treat HER2-overexpressing breast cancer.

Rapid Microwave-Assisted Synthesis of pH-Sensitive Carbon-Based Nanoparticles for the Controlled Release of Doxorubicin to Cancer Cells.

Carbon-based nanoparticles (CNPs) are a new type of interesting nanomaterials applied in various pharmaceutical fields due to their outstanding biocompatible properties. Novel pH-sensitive CNPs were rapidly synthesized within 1 min by microwave-assisted technique for doxorubicin (DOX) delivery into five cancer cell lines, including breast cancer (BT-474 and MDA-MB-231 cell lines), colon cancer (HCT and HT29 cell lines), and cervical cancer (HeLa cell lines). CNPs and DOX-loaded CNPs (CNPs-DOX) had nano-size of 11.66 ± 2.32 nm and 43.24 ± 13.25 nm, respectively. DOX could be self-assembled with CNPs in phosphate buffer solution at pH 7.4 through electrostatic interaction, exhibiting high loading efficiency at 85.82%. The release of DOX from CNPs-DOX at pH 5.0, often observed in the tumor, was nearly two times greater than the release at physiological condition pH 7.4. Furthermore, the anticancer activity of CNPs-DOX was significantly enhanced compared to free DOX in five cancer cell lines. CNPs-DOX could induce cell death through apoptosis induction in MDA-MB-231 cells. The findings revealed that CNPs-DOX exhibited a promising pH-sensitive nano-system as a drug delivery carrier for cancer treatment.

Fabrication of polyvinyl pyrrolidone-K90/Eudragit RL100-based dissolving microneedle patches loaded with alpha-arbutin and resveratrol for skin depigmentation.

Alpha-arbutin (AA) and resveratrol (Res) are widely used in skin-lightening products. However, current topical formulations have minimal skin-lightening effects due to the low absorption and poor solubility of these active compounds. This study investigated the efficacy and safety of using dissolving microneedle (DMN) patches to improve the delivery of AA and Res for skin depigmentation. The DMN patches (F0-F3) fabricated from polyvinyl pyrrolidone-K90 (PVP-K90)/Eudragit RL100 blends successfully penetrated excised porcine skin and showed sufficient mechanical strength to resist compression forces. Loading DMNs with 10% AA and 2% Res at a ratio of 5 : 1 (F3) resulted in a synergistic interaction between the drugs with desirable dissolving ability, drug loading, and stability. Furthermore, both in vitro and in vivo studies revealed that the use of F3 DMN patches successfully enhanced the intradermal delivery of AA and Res over a 24 h period, with the delivered amount being higher (∼2.6 times) than that provided by a cream formulation (P < 0.05). After removing the DMN patches, the mice's skin was spontaneously and completely resealed within 12 h. In clinical studies, F3 DMN patches slightly decreased the melanin index of the participants without causing skin irritation or erythema at any time during the 24 h period when the patches were applied (P < 0.05). Moreover, application of the patches for 24 h was not found to affect skin hydration, transepidermal water loss, or skin elasticity. Therefore, AA/Res-loaded DMN patches could offer a promising approach for the effective local delivery of cosmetic agents for skin depigmentation.

siRNA Targeting Mcl-1 Potentiates the Anticancer Activity of Andrographolide Nanosuspensions via Apoptosis in Breast Cancer Cells.

Breast cancer is the second leading cause of cancer-related death in the US. However, recurrence is frequently found despite adjuvant therapy being available. Combination therapy with cytotoxic drugs and gene therapy is being developed to be a new promising cancer treatment strategy. Introducing substituted dithiocarbamate moieties at the C12 position of andrographolide (3nAG) could improve its anticancer selectivity in the MCF-7 breast cancer cell line. However, its hydrophobicity is one of its main drawbacks. This work successfully prepared 3nAG nanosuspension stabilized with the chitosan derivative NSC (3nAGN-NSC) to increase solubility and pharmacological effectiveness. siRNAs have emerged as a promising therapeutic alternative for interfering with particular mRNA. The 3nAGN-NSC had also induced Mcl-1 mRNA expression in MCF-7 human breast cancer cells at 8, 12, and 24 h. This indicates that, in addition to Mcl-1 silencing by siRNA (siMcl-1) in MCF-7 with substantial Mcl-1 reliance, rationally devised combination treatment may cause the death of cancer cells in breast cancer. The Fa-CI analysis showed that the combination of 3nAGN-NSC and siMcl-1 had a synergistic effect with a combination index (CI) value of 0.75 (CI < 1 indicating synergistic effects) at the fractional inhibition of Fa 0.7. The synergistic effect was validated by flow cytometry, with the induction of apoptosis as the mechanism of reduced cell viability. Our findings suggested the rational use of 3nAGN-NSC in combination with siMcl-1 to kill breast cancer cells.

Delivery of small interfering RNAs by nanovesicles for cancer therapy.

Small interfering ribonucleic acids (siRNAs) are originally recognized as an intermediate of the RNA interference (RNAi) pathway. They can inhibit or silence various cellular pathways by knocking down specific messenger RNA molecules. In cancer cells, siRNAs can suppress the expression of several multidrug-resistant genes, leading to the increased deposition of chemotherapeutic drugs at the tumor site. siRNA therapy can be used to selectively increase apoptosis of cancer cells or activate an immune response to the cancer. However, delivering siRNAs to the targeted location is the main limitation in achieving safe and effective delivery of siRNAs. This review highlights some representative examples of nonviral delivery systems, especially nanovesicles such as exosomes, liposomes, and niosomes. Nanovesicles can improve the delivery of siRNAs by increasing their intracellular delivery, and they have demonstrated excellent potential for cancer therapy. This review focuses on recent discoveries of siRNA targets for cancer therapy and the use of siRNAs to successfully silence these targets. In addition, this review summarizes the recent progress in designing nanovesicles (liposomes or niosomes) for siRNA delivery to cancer cells and the effects of a combination of anticancer drugs and siRNA therapy in cancer therapy.

Synergistic Effect of Doxorubicin and siRNA-Mediated Silencing of Mcl-1 Using Cationic Niosomes against 3D MCF-7 Spheroids.

Chemotherapy is a vital option for cancer treatment; however, its therapeutic outcomes are limited by dose-dependent toxicity and the occurrence of chemoresistance. siRNAs have emerged as an attractive therapeutic option enabling specific interference with target genes. Combination therapy using chemotherapeutic agents along with gene therapy could be a potential strategy for cancer management, which not only improves therapeutic efficacy but also decreases untoward effects from dose reduction. In this study, a cationic niosome containing plier-like cationic lipid B was used to convey siRNA against anti-apoptotic mRNA into MCF-7 and MDA-MB-231 cells. Mcl-1 silencing markedly decreased the viability of MCF-7 cells and triggered apoptosis. Moreover, computer modeling suggested that the combination of doxorubicin (Dox) and Mcl-1 siRNA exhibited a synergistic relationship and enabled a dose reduction of each agent at 1.71 and 3.91 folds, respectively, to reach a 90% inhibitory effect when compared to single-agent treatments. Synergistic antitumor activity was further verified in a 3D spheroid culture which revealed, in contrast to single-agent treatment, the combination markedly decreased spheroid volume over time. Together, the combination therapy between Mcl-1 silencing and Dox exhibits a synergistic effect that may be exploited for novel breast cancer treatment.

Effect of hydrophobic tails of plier-like cationic lipids on nucleic acid delivery and intracellular trafficking.

In the optimization of transfection efficacy, one of the crucial barriers to effective gene delivery is in fact the intracellular trafficking of nucleic acids, besides the first and the last steps of gene transfer, i.e., delivery to the cell and transcription. Modifications of cationic lipid structure have been reported to have a significant effect on gene delivery. Therefore, the plier-like cationic lipids (PCLs) have been synthesized and the effect of the different types of hydrophobic tails (chain length and unsaturated hydrocarbon) on physicochemical properties, cellular uptake, trafficking process, transfection, and silencing efficiency has been investigated. In this study, the plier-like cationic niosomes (PCNs) containing PCL (A, B, and C) were evaluated their performance to deliver pDNA and siRNA to HeLa cells. Among the PCNs, PCN-B with saturated asymmetric hydrocarbon tails (C18 and C12) provided the highest efficiency for pDNA and siRNA delivery. Furthermore, the results revealed that the structure of the cationic lipids affected the internalization pathway and the intracellular trafficking. PCL-B and PCL-C with asymmetric tails preferred clathrin- and caveolae-mediated endocytosis as the predominant internalization pathways and were also involved in the polymerization process for transfection. However, PCL-A with symmetry hydrocarbon tails (C12) was predominantly taken up via macropinocytosis. All PCNs were able to escape from endosomal-lysosomal systems through facilitation of acidification. Results obtained from the cytotoxicity test revealed that the PCNs were safe in vitro. Therefore, PCNs provide a great prospect as an alternative effective gene delivery system.