Harnessing curcumin in a multifunctional biodegradable metal-organic framework (bio-MOF) for targeted colorectal cancer theranostics.

Despite significant advancements in managing colorectal cancer (CRC), the issues of efficient diagnosis and targeted therapy remain demanding. To address these challenges and improve treatment outcomes while reducing the cost and side effects, there is a need for more effective theranostic systems that combine diagnostic techniques with therapeutic modalities. This study introduces a pioneering approach for the synthesis of a porous bio-MOF (biodegradable metal-organic framework) using iron as the metal component and curcumin as the pharmaceutical ingredient. Subsequently, the developed drug delivery system was equipped with the anticancer drug doxorubicin (DOX), coated with biocompatible polyethylene glycol (PEG), and targeted with a CRC-specific aptamer (EpCAM). The physicochemical characterization confirmed the successful synthesis of the bio-MOF, demonstrating high encapsulation efficiency and pH-dependent release of DOX. In vitro studies for anticancer activity, cellular uptake, and mechanism of cell death demonstrated that in the case of positive EpCAM HT-29 cells, Apt-PEG-MOF@DOX had enhanced internalization that resulted in massive apoptosis. In vivo studies of the nanoparticles were then conducted in immunocompromised C57BL/6 mice bearing HT-29 tumors. These studies showed that the targeted platform could induce efficient tumor regression with reduced systemic toxicity. The targeted bio-MOF also exhibited MRI imaging properties useful for monitoring tumors. Significantly, the biocompatibility of the introduced bio-MOF was enhanced by pursuing the green synthesis method, which does not engage toxic solvents and strong acids. Overall, this multimodal system acts diversely as a tumor imaging agent and a therapeutic delivery platform suitable for CRC theranostics.

Unveiling the Promising Role of Substance P/Neurokinin 1 Receptor in Cancer Cell Proliferation and Cell Cycle Regulation in Human Malignancies.

Neurokinin receptors are a family of G protein-coupled receptors that were first identified in the central and peripheral nervous systems. However these receptors were later found in other types of cells, therefore, new perspectives concerning their novel roles were described. Mammalian has three neurokinin receptors, among which neurokinin-1 receptors [NK1R] have been indicated to be involved in most, if not all, intracellular functions, primarily the regulation of cell proliferation. By interacting with its potent agonist, substance P [SP], NK1R can engage a variety of signaling pathways and serve as a platform for cells to proliferate by regulating the expression of the cell cycle-related genes. Furthermore, the activity of SP/NK1R is stimulated by various oncogenes, indicating the involvement of this pathway in human cancers. As a result, numerous NK1R antagonists have been investigated in oncology trials, and the promising anti-- cancer effect of these receptors has opened up new possibilities for incorporating these antagonists into cancer treatment. Considering these factors, gaining a deeper understanding of the SP/NK1R pathway could offer significant advantages for cancer patients. The more knowledge we acquire about this pathway, the greater the potential for exploiting it in the development of effective treatment strategies. Here, we present a comprehensive review of the current knowledge pertaining to the biological function of the SP/NK1R, with a specific emphasis on its recently discovered role in the regulation of cell proliferation. Moreover, we provide insights into the impact of this pathway in human cancers, along with an overview of the most significant NK1R antagonists currently utilized in cancer research studies.

A new era in cancer treatment: harnessing ZIF-8 nanoparticles for PD-1 inhibitor delivery.

This review delves into the potential of zeolitic imidazolate framework-8 (ZIF-8) nanoparticles in augmenting the efficacy of cancer immunotherapy, with a special focus on the delivery of programmed cell death receptor 1 (PD-1) inhibitors. The multifunctional nature of ZIF-8 nanoparticles as drug carriers is emphasized, with their ability to encapsulate a range of therapeutic agents, including PD-1 inhibitors, and facilitate their targeted delivery to tumor locations. By manipulating the pore size and surface characteristics of ZIF-8 nanoparticles, controlled drug release can be realized. The strategic use of ZIF-8 nanoparticles to deliver PD-1 inhibitors presents a precise and targeted modality for cancer treatment, reducing off-target impacts and enhancing therapeutic effectiveness. This combined strategy addresses the existing challenges and constraints of current immunotherapy techniques, with the ultimate goal of enhancing patient outcomes in cancer therapy.

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.

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.

Kidney tissue engineering using a well-preserved acellular rat kidney scaffold and mesenchymal stem cells.

The aim of this study was to acquire an effective method for preparation of rat decellularized kidney scaffolds capable of supporting proliferation and differentiation of human adipose tissue derived mesenchymal stem cells (AD-MSCs) into kidney cells. We compared two detergents, the sodium dodecyl sulfate (SDS) and triton X-100 for decellularization. The efficiency of these methods was assessed by Hematoxylin and Eosin (H&E), 4', 6 diamidino-2-phenylindole and immunohistochemistry (IHC) staining. In the next step, AD-MSCs were seeded into the SDS-treated scaffolds and assessed after three weeks of culture. Proliferation and differentiation of AD-MSCs into kidney-specific cell types were then analyzed by H&E and IHC staining. The histological examinations revealed that SDS was more efficient in removing kidney cells at all-time points compared to triton X-100. Also, in the SDS-treated sections the native extracellular matrix was more preserved than the triton-treated samples. Laminin was completely preserved during decellularization procedure using SDS. Cell attachment in the renal scaffold was observed after recellularization. Furthermore, differentiation of AD-MSCs into epithelial and endothelial cells was confirmed by expression of Na-K ATPase and vascular endothelial growth factor receptor 2 (VEGFR-2) in seeded rat renal scaffolds, respectively. Our findings illustrated that SDS was more effective for decellularization of rat kidney compared to triton X-100. We presented an optimized method for decellularization and recellularization of rat kidneys to create functional renal natural scaffolds. These natural scaffolds supported the growth of AD-MSCs and could also induce differentiation of these cells into epithelial and endothelial cells.

Improving anti-cancer drug delivery performance of magnetic mesoporous silica nanocarriers for more efficient colorectal cancer therapy.

BACKGROUND: Improving anti-cancer drug delivery performance can be achieved through designing smart and targeted drug delivery systems (DDSs). For this aim, it is important to evaluate overexpressed biomarkers in the tumor microenvironment (TME) for optimizing DDSs. MATERIALS AND METHODS: Herein, we designed a novel DDS based on magnetic mesoporous silica core-shell nanoparticles (SPION@MSNs) in which release of doxorubicin (DOX) at the physiologic pH was blocked with gold gatekeepers. In this platform, we conjugated heterofunctional polyethylene glycol (PEG) onto the outer surface of nanocarriers to increase their biocompatibility. At the final stage, an epithelial cell adhesion molecule (EpCAM) aptamer as an active targeting moiety was covalently attached (Apt-PEG-Au@NPs-DOX) for selective drug delivery to colorectal cancer (CRC) cells. The physicochemical properties of non-targeted and targeted nanocarriers were fully characterized. The anti-cancer activity, cellular internalization, and then the cell death mechanism of prepared nanocarriers were determined and compared in vitro. Finally, tumor inhibitory effects, biodistribution and possible side effects of the nanocarriers were evaluated in immunocompromised C57BL/6 mice bearing human HT-29 tumors. RESULTS: Nanocarriers were successfully synthesized with a mean final size diameter of 58.22 ± 8.54 nm. Higher cytotoxicity and cellular uptake of targeted nanocarriers were shown in the EpCAM-positive HT-29 cells as compared to the EpCAM-negative CHO cells, indicating the efficacy of aptamer as a targeting agent. In vivo results in a humanized mouse model showed that targeted nanocarriers could effectively increase DOX accumulation in the tumor site, inhibit tumor growth, and reduce the adverse side effects. CONCLUSION: These results suggest that corporation of a magnetic core, gold gatekeeper, PEG and aptamer can strongly improve drug delivery performance and provide a theranostic DDS for efficient CRC therapy.

Investigating the effects of two novel 4-MMPB analogs as potent lipoxygenase inhibitors for prostate cancer treatment.

BACKGROUND: Lipoxygenases are one of the critical signaling mediators which can be targeted for human prostate cancer (PC) therapy. In this study, 4-methyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-MMPB) and its two analogs, 4-propyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-PMPB) and 4-ethyl-2-(4-methylpiperazinyl)pyrimido[4,5-b]benzothiazine (4-EMPB), were proposed to have anti-tumor properties in prostate cancer. METHODS: After synthesizing the compounds, cytotoxic effects of 4-MMPB and its two analogs against PC-3 cancerous and HDF normal cells were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and then mechanism of cell death was assessed by flow cytometry. Finally, the anti-tumor effects of the mentioned compounds were investigated in an immunocompromised C57BL/6 mouse model. RESULTS: 4-PMPB and 4-EMPB had similar anti-cancer effects on PC-3 cells as compared with 4-MMPB, while they were not effective on normal cells. Moreover, apoptosis and ferroptosis were the main mechanisms of induced cell death in these cancerous cells. Furthermore, in vivo results indicated that both analogs had similar anti-cancer effects as 4-MMPB, leading to delayed tumor growth without any noticeable side effects in weight loss and histological investigations. CONCLUSION: Thus, our results suggest that specific targeting of lipoxygenases via 4-MMPB analogs can be considered as a treatment of choice for PC therapy, although it requires further investigations.

Supportive properties of basement membrane layer of human amniotic membrane enable development of tissue engineering applications.

Human amniotic membrane (HAM) has been widely used as a natural scaffold in tissue engineering due to many of its unique biological properties such as providing growth factors, cytokines and tissue inhibitors of metalloproteinases. This study aimed at finding the most suitable and supportive layer of HAM as a delivery system for autologous or allogeneic cell transplantation. Three different layers of HAM were examined including basement membrane, epithelial and stromal layers. In order to prepare the basement membrane, de-epithelialization was performed using 0.5 M NaOH and its efficiency was investigated by histological stainings, DNA quantification, biomechanical testing and electron microscopy. Adipose-derived stromal cells (ASCs) and a human immortalized keratinocyte cell line (HaCaT) were seeded on the three different layers of HAM and cultured for 3 weeks. The potential of the three different layers of HAM to support the attachment and viability of cells were then monitored by histology, electron microscopy and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, mechanical strengths of the basement membrane were assessed before and after cell culture. The results indicated that the integrity of extra cellular matrix (ECM) components was preserved after de-epithelialization and resulted in producing an intact basement amniotic membrane (BAM). Moreover, all three layers of HAM could support the attachment and proliferation of cells with no visible cytotoxic effects. However, the growth and viability of both cell types on the BAM were significantly higher than the other two layers. We conclude that growth stimulating effectors of BAM and its increased mechanical strength after culturing of ASCs, besides lack of immunogenicity make it an ideal model for delivering allogeneic cells and tissue engineering applications.