Enhanced theranostic efficacy of epirubicin-loaded SPION@MSN through co-delivery of an anti-miR-21-expressing plasmid and ZIF-8 hybridization to target colon adenocarcinoma.

Using targeted drug delivery systems has emerged as a promising approach to increase the efficacy of chemotherapy, particularly in combination with gene therapy. The overexpression of miR-21 plays a crucial role in colorectal cancer (CRC) progression, and targeted inhibition of miR-21 offers significant potential for enhancing CRC chemotherapy outcomes. In this study, a theranostic system based on mesoporous silica and superparamagnetic iron oxide nanoparticles (SPION@MSNs) was synthesized as a core-shell structure. After loading epirubicin (EPI) in the open pores of MSN, the plasmid expressing anti-miR-21 (pDNA) covered the outer surface with the help of a ZIF-8 (zeolitic imidazolate framework-8) film. Afterward, polyethylene glycol (PEG) and AS1411 aptamer were conjugated to the surface to improve the protective, biocompatibility, and targeting abilities of the nanocarrier. Moreover, the physicochemical characteristics as well as the loading capacity and release profile of EPI and pDNA were fully evaluated. The uptake of the nanoparticles by CRC and normal cell lines in addition to the anticancer effects related to targeted combinational therapy were investigated in vitro. Finally, in vivo tests were performed on BALB/c mice bearing colorectal tumors to evaluate the effectiveness of the targeted nanoparticles, their possible side effects, and also their application in fluorescence and magnetic imaging in vivo. The successful synthesis of SPION@MSN-EPI/pDNA-ZIF-8-PEG-Apt nanoparticles (∼68 nm) and good loading efficiency and controlled release of EPI and pDNA were confirmed. Moreover, hemolysis and gel retardation assays demonstrated the biocompatibility and plasmid protection. Cellular uptake and expression of copGFP illustrated selective entry and transient transfection of targeted nanoparticles, consistent with the cytotoxicity results that indicated the synergistic effects of chemo-gene therapy. The results of animal studies proved the high antitumor efficiency of targeted nanoparticles with minimal tissue damage, which was in line with fluorescence and magnetic imaging results. The novel synthesized nanoparticles containing SPION@MSN-ZIF-8 were suitable for CRC theranostics, and the combined approach of chemo-gene therapy suppressed the tumor more effectively.

Tumor-targeted delivery of SNHG15 siRNA using a ZIF-8 nanoplatform: Towards a more effective prostate cancer therapy.

Small interfering RNAs (siRNAs) can be used as a powerful tool in gene therapy to downregulate the expression of specific disease related genes. Some properties however, such as instability, and low penetration into cells can limit their efficacy, and thus reduce their therapeutic potential. Metal-organic frameworks (MOFs) such as zeolitic imidazolate framework-8 (ZIF-8), which consist of organic bridging ligands and metal cations (Zn), have a very high binding affinity with nucleic acids including siRNAs. In this study, we designed a PEGylated ZIF-8 platform that was equipped with epithelial cell adhesion molecule (EpCAM) aptamer for the targeted delivery of siRNA molecules, in order to knockdown SNHG15 in both a prostate cancer (PC) cell line, and a human PC xenograft mouse model. SNHG15 is a long noncoding RNA, with oncogenic roles in different cancers including PC. The results indicated that the depletion of SNHG15 by Apt-PEG-siRNA@ZIF-8 nanoplatfrom inhibited cell proliferation and colony formation, and increased apoptosis in PC cells. This nanoparticle facilitated the release of siRNAs into the tumor environment in vivo, and subsequently reduced the tumor growth, with no side effects observed in vital organs. We have therefore developed a novel siRNA nano-delivery system for targeted prostate cancer treatment; however further studies are required before it can be tested in clinical trials.

A potent multifunctional ZIF-8 nanoplatform developed for colorectal cancer therapy by triple-delivery of chemo/radio/targeted therapy agents.

BACKGROUND: Multimodal cancer therapy has garnered significant interest due to its ability to target tumor cells from various perspectives. The advancement of novel nano-delivery platforms represents a promising approach for improving treatment effectiveness while minimizing detrimental effects on healthy tissues. METHODS: This study aimed to develop a multifunctional nano-delivery system capable of simultaneously delivering an anti-cancer drug, a radiosensitizer agent, and a targeting moiety (three-in-one) for the triple combination therapy of colorectal cancer (CRC). This unique nano-platform, called Apt-PEG-DOX/ZIF-8@GQD, encapsulated both doxorubicin (DOX) and graphene quantum dots (GQDs) within the zeolitic imidazolate framework-8 (ZIF-8). To enhance the safety and anti-cancer potential of the platform, heterobifunctional polyethylene glycol (PEG) and an epithelial cell adhesion molecule (EpCAM) aptamer were conjugated with the system, resulting in the formation of targeted Apt-PEG-DOX/ZIF-8@GQD NPs. The physical and chemical characteristics of Apt-PEG-DOX/ZIF-8@GQD were thoroughly examined, and its therapeutic efficacy was evaluated in combination with radiotherapy (RT) against both EpCAM-positive HT-29 and EpCAM-negative CHO cells. Furthermore, the potential of Apt-PEG-DOX/ZIF-8@GQD as a tumor-specific, radio-enhancing, non-toxic, and controllable delivery system for in vivo cancer treatment was explored using immunocompromised C57BL/6 mice bearing human HT-29 tumors. RESULTS: The large surface area of ZIF-8 (1013 m2 g-1) enabled successful loading of DOX with an encapsulation efficiency of approximately ∼90%. The synthesis of Apt-PEG-DOX/ZIF-8@GQD resulted in uniform particles with an average diameter of 100 nm. This targeted platform exhibited rapid decomposition under acidic conditions, facilitating an on-demand release of DOX after endosomal escape. In vitro experiments revealed that the biocompatible nano-platform induced selective toxicity in HT-29 cells by enhancing X-ray absorption. Moreover, in vivo experiments demonstrated that the therapeutic efficacy of Apt-PEG-ZIF-8/DOX@GQD against HT-29 tumors was enhanced through the synergistic effects of chemotherapy, radiotherapy, and targeted therapy, with minimal side effects. CONCLUSION: The combination of Apt-PEG-DOX/ZIF-8@GQD with RT as a multimodal therapy approach demonstrated promising potential for the targeted treatment of CRC and enhancing therapeutic effectiveness. The co-delivery of DOX and GQD using this nano-platform holds great promise for improving the outcome of CRC treatment.

Targeted delivery of elesclomol using a magnetic mesoporous platform improves prostate cancer treatment both in vitro and in vivo.

BACKGROUND: To improve the anticancer properties of elesclomol (ELC), targeted theranostic nanoparticles (NPs; APT-PEG-Au-MMNPs@ELC) were designed to increase the selectivity of the drug delivery system (DDS). MATERIALS AND METHODS: ELC was synthesized and entrapped in the open porous structure of magnetic mesoporous silica nanoparticles (MMNPs). The pore entrance of MMNPs was then blocked using gold gatekeepers. Finally, the external surfaces of the particles were grafted with functional polyethylene glycol (PEG) and EpCAM aptamer to generate biocompatible and targeted NPs. In the next step, the physicochemical properties of prepared NPs were fully evaluated and their anticancer potential was evaluated both in vitro and in vivo. RESULTS: The targeted NPs were successfully synthesized with a final size diameter of 81.13 ± 7.41 nm. The results indicated a pH-dependent release pattern, which sustained for 72 h despite an initial rapid release. Upon exposure to APT-PEG-Au-MMNPs@ELC, higher cytotoxicity was observed in human prostate cancer cells (PC-3) as compared with control Chinese hamster ovary (CHO) cells, indicating higher specificity of targeted NPs against EpCAM-positive cancerous cells. Moreover, APT-PEG-Au-MMNPs@ELC could induce apoptosis in PC-3 cells. In vivo results on a PC-3 xenograft tumor model demonstrated that targeted NPs could significantly inhibit tumor growth and diminish severe side effects of ELC, compared to the free drug. CONCLUSION: Collectively, APT-PEG-Au-MMNPs@ELC could be considered a promising theranostic platform for the targeted delivery of ELC to improve its therapeutic effects in prostate cancer.

Elesclomol, a copper-transporting therapeutic agent targeting mitochondria: from discovery to its novel applications.

Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases; and a high amount of accumulated Cu in cells can be fatal. The production of reactive oxygen species (ROS), oxidative stress, and cuproptosis are among the proposed mechanisms of copper toxicity at high concentrations. Elesclomol (ELC) is a mitochondrion-targeting agent discovered for the treatment of solid tumors. In this review, we summarize the synthesis of this drug, its mechanisms of action, and the current status of its applications in the treatment of various diseases such as cancer, tuberculosis, SARS-CoV-2 infection, and other copper-associated disorders. We also provide some detailed information about future directions to improve its clinical performance.

Current status and future prospects of nanoscale metal-organic frameworks in bioimaging.

The importance of the early-stage diagnosis and in situ monitoring of lesion regions and transportation of bioactive molecules has a pivotal effect on successful treatment, reducing side effects, and increasing the chances of survival in the case of serious diseases such as cancer. This strongly depends on the development of contrast agents and biomarkers together with the appropriate use of bioimaging techniques. Because of their exceptionally high surface area and porosity, nanoscale metal-organic frameworks (NMOFs) have been the subject of numerous studies in the biomedical domain as drug carriers, diagnostic and therapeutic agents, and biosensors. This review provides a summary of the recent advancements in the use of MOFs as nanoscale platforms for biomedical imaging via magnetic resonance (MR) imaging, computed tomography (CT), single-photon emission computed tomography (SPECT), fluorescence (FL) imaging, positron emission tomography (PET), photoacoustic (PA) imaging, and photothermal (PT) imaging modalities. Initially, we describe the principles of a specific imaging technique in each section, and then present the recent reports on MOFs for monomodal and multimodal imaging and the following information: (i) how to synthesize MOFs and modify their surface and (ii) their utilization in bioimaging or theranostic applications.

Using magnetic mesoporous silica nanoparticles armed with EpCAM aptamer as an efficient platform for specific delivery of 5-fluorouracil to colorectal cancer cells.

Background: Theranostic nanoparticles with both imaging and therapeutic capacities are highly promising in successful diagnosis and treatment of advanced cancers. Methods: Here, we developed magnetic mesoporous silica nanoparticles (MSNs) loaded with 5-fluorouracil (5-FU) and surface-decorated with polyethylene glycol (PEG), and epithelial cell adhesion molecule (EpCAM) aptamer (Apt) for controlled release of 5-FU and targeted treatment of colorectal cancer (CRC) both in vitro and in vivo. In this system, Au NPs are conjugated onto the exterior surface of MSNs as a gatekeeper for intelligent release of the anti-cancer drug at acidic conditions. Results: Nanocarriers were prepared with a final size diameter of 78 nm, the surface area and pore size of SPION-MSNs were calculated as 636 m2g-1, and 3 nm based on the BET analysis. The release of 5-FU from nanocarriers was pH-dependent, with an initial rapid release (within 6 h) followed by a sustained release for 96 h at pH 5.4. Tracking the cellular uptake by flow cytometry technique illustrated more efficient and higher uptake of targeted nanocarriers in HT-29 cells compared with non-targeted formula. In vitro results demonstrated that nanocarriers inhibited the growth of cancer cells via apoptosis induction. Furthermore, the targeted NPs could significantly reduce tumor growth in immunocompromised C57BL/6 mice bearing HT-29 tumors, similar to those injected with free 5-FU, while inducing less side effects. Conclusion: These findings suggest that application of Apt-PEG-Au-NPs@5-FU represents a promising theranostic platform for EpCAM-positive CRC cells, although further experiments are required before it can be practiced in the clinic.

Smart metal organic frameworks: focus on cancer treatment.

Metal-organic frameworks (MOFs), as a prominent category of hybrid porous materials constructed from metal clusters or ions with organic linkers, have been broadly employed as controlled systems of drug delivery due to their inherent interesting properties. These properties, such as high loading capability and tremendous biocompatibility, offer an exceptional opportunity for the treatment of cancer. In this review, we focus on the latest advancement of smart MOFs as systems of drug delivery for cancer treatment, diagnosis or both (theranostics). Furthermore, different methods and strategies for synthesizing smart MOFs with various mechanisms of drug release under diverse stimuli, such as pH, temperature, redox, magnetic field, enzyme, and light, were summarized and discussed. The current review helps in a better understanding of smart MOFs systems that would be useful for their smart design toward medical applications.

Coordination complexes of zinc and manganese based on pyridine-2,5-dicarboxylic acid N-oxide: DFT studies and antiproliferative activities consideration.

We report here the design, synthesis, and antiproliferative activity of three coordination complexes [Mn2(pydco)2(bpy)2(H2O)2]·2H2O (1), [Zn(bpy)(Hpydco)2] (2), and [Zn(bpy)Cl(Hpydco)]·2H2O (3) (H2pydco = pyridine-2,5-dicarboxylic acid N-oxide, bpy = 2,2'-bipyridine). Molecular structures of these complexes have been characterized by elemental analysis, Fourier transform infrared spectroscopy, thermogravimetric analysis, and powder and single-crystal X-ray diffraction. According to the structural analysis, 1-3 are discrete complexes containing N- and O-donor ligands (bpy and pydco2-) in which pydco2- can be coordinated to the metal centres via the N-oxide oxygen and one carboxylate oxygen to generate a six-membered chelate ring. Also, these structures benefit from extensive intermolecular interactions such as hydrogen bonds and π-interactions which are the major forces to make them more stable in the solid state. The energetic features of the π-stacking interactions observed in compounds 1-3 have been computed and compared to the H-bonds. The interactions in the solid state have been also studied using the independent gradient model approach (IGM plot). The IGM-δg approach uses a new descriptor (δg) that locally represents the difference between a virtual upper limit of the electron density gradient and the true electron density gradient. This newly developed IGM methodology automatically extracts the signature of interactions between two given fragments. Finally, the antiproliferative properties of these complexes were tested on several cancer cell lines by MTT assay and flow cytometry. Also, to compare the antiproliferative activities of these complexes with common chemotherapy drugs, the antiproliferative property of cisplatin was evaluated as a reference and positive control.

Fabrication of deferasirox-decorated aptamer-targeted superparamagnetic iron oxide nanoparticles (SPION) as a therapeutic and magnetic resonance imaging agent in cancer therapy.

In the current study, the synthesis of a theranostic platform composed of superparamagnetic iron oxide nanoparticles (SPION)-deferasirox conjugates targeted with AS1411 DNA aptamer was reported. In this regard, SPION was amine-functionalized by (3-aminopropyl)trimethoxysilane (ATPMS), and then deferasirox was covalently conjugated onto its surface. Finally, to provide guided drug delivery to cancerous tissue, AS1411 aptamer was conjugated to the complex of SPION-deferasirox. The cellular toxicity assay on CHO, C-26 and AGS cell lines verified higher cellular toxicity of targeted complex in comparison with non-targeted one. The evaluation of in vivo tumor growth inhibitory effect in C26 tumor-bearing mice illustrated that the aptamer-targeted complex significantly enhanced the therapeutic outcome in comparison with both non-targeted complex and free drug. The diagnostic capability of the prepared platform was also evaluated implementing C26-tumor-bearing mice. Obtained data confirmed higher tumor accumulation and higher tumor residence time for targeted complex through MRI imaging due to the existence of SPION as a contrast agent in the core of the prepared complex. The prepared multimodal theranostic system provides a safe and effective platform for fighting against cancer.

Chelation of Thallium (III) in Rats Using Combined Deferasirox and Deferiprone Therapy.

Thallium and its compounds are a class of highly toxic chemicals that cause wide-ranging symptoms such as gastrointestinal disturbances; polyneuritis; encephalopathy; tachycardia; skin eruptions; hepatic, renal, cardiac, and neurological toxicities; and have mutagenic and genotoxic effects. The present research aimed to evaluate the efficacy of the chelating agents deferasirox (DFX) and deferiprone (L1) in reducing serum and tissue thallium levels after the administration of thallium (III), according to two different dosing regimens, to several groups of Wistar rats for 60 days. It was hypothesized that the two chelators might be more efficient as a combined therapy than as monotherapies in removing thallium (III) from the rats' organs. The chelators were administered orally as either single or combined therapies for a period of 14 days. Serum and tissue thallium (III) and iron concentrations were determined by flame atomic absorption spectroscopy. Serum and tissue thallium (III) levels were significantly reduced by combined therapy with DFX and L1. Additionally, iron concentrations returned to normal levels and symptoms of toxicity decreased.

Cu(ii) immobilized on Fe3O4@APTMS-DFX nanoparticles: an efficient catalyst for the synthesis of 5-substituted 1H-tetrazoles with cytotoxic activity.

Cu(ii) immobilized on deferasirox loaded amine functionalized magnetic nanoparticles (Cu(ii)/Fe3O4@APTMS-DFX) as a novel magnetically recyclable heterogeneous catalyst is able to catalyze the [3 + 2] cycloaddition reactions of various organic nitriles with sodium azide. Using this method, a series of 5-substituted-1H-tetrazoles under mild conditions in DMSO were prepared. The reaction involves mild reaction conditions with efficient transformation capability. The developed catalyst could be easily separated by applying an external magnetic field. Furthermore, it could be recycled for 5 runs with negligible leaching of copper from the surface of the catalyst. The catalyst was characterized by various techniques such as FT-IR, TGA, VSM, SEM-EDX, and ICP-OES. Several derivatives of 1H-tetrazoles were prepared using this catalyst, and their structures were confirmed using different techniques. Then, the synthesized anthraquinones were evaluated for their cytotoxicity against several cell lines including MCF-7, MAD-MD-231, HT-29, HeLa, neuro-2a and L-929. The results obtained from the MTT assay revealed that the 6 derivatives exhibited a high level of cytotoxicity. In order to determine the cytotoxicity mechanism, 2 derivatives with the highest cytotoxic activity were selected, and an apoptosis assay was carried out by flow cytometry, which supported that apoptosis is the major mechanism.

Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator.

Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.

Removal of thallium by deferasirox in rats as biological model.

The present research aimed to characterize the potential efficiency of deferasirox in removing thallium after its administration for 30 days following two dose levels of 20 and 160 µm of thallium (III) chloride to male Wistar rats every day. After thallium administration some abnormal clinical signs such as red staining around the eyes, greenish mottling on the liver, weakness, loss of hair and weight, were observed in animals. Deferasirox was given orally to different groups of rats for a period of one week immediately after thallium administration. After chelation therapy, animals were killed by exsanguination from the abdominal aorta, and then thallium and iron concentrations in various tissues were determined by standard addition method. The chelation therapy results showed that deferasirox was able to remove thallium ions from the body and clinical symptoms were also reduced.