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International Journal of Nanomedicine 2024The design of delivery tools that efficiently transport drugs into cells remains a major challenge in drug development for most pathological conditions. Triple-negative...
INTRODUCTION
The design of delivery tools that efficiently transport drugs into cells remains a major challenge in drug development for most pathological conditions. Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with poor prognosis and limited effective therapeutic options.
PURPOSE
In TNBC treatment, chemotherapy remains the milestone, and doxorubicin (Dox) represents the first-line systemic treatment; however, its non-selective distribution causes a cascade of side effects. To address these problems, we developed a delivery platform based on the self-assembly of amphiphilic peptides carrying several moieties on their surfaces, aimed at targeting, enhancing penetration, and therapy.
METHODS
Through a single-step self-assembly process, we used amphiphilic peptides to obtain nanofibers decorated on their surfaces with the selected moieties. The surface of the nanofiber was decorated with a cell-penetrating peptide (gH625), an EGFR-targeting peptide (P22), and Dox bound to the cleavage sequence selectively recognized and cleaved by MMP-9 to obtain on-demand drug release. Detailed physicochemical and cellular analyses were performed.
RESULTS
The obtained nanofiber (NF-Dox) had a length of 250 nm and a diameter of 10 nm, and it was stable under dilution, ionic strength, and different pH environments. The biological results showed that the presence of gH625 favored the complete internalization of NF-Dox after 1h in MDA-MB 231 cells, mainly through a translocation mechanism. Interestingly, we observed the absence of toxicity of the carrier (NF) on both healthy cells such as HaCaT and TNBC cancer lines, while a similar antiproliferative effect was observed on TNBC cells after the treatment with the free-Dox at 50 µM and NF-Dox carrying 7.5 µM of Dox.
DISCUSSION
We envision that this platform is extremely versatile and can be used to efficiently carry and deliver diverse moieties. The knowledge acquired from this study will provide important guidelines for applications in basic research and biomedicine.
Topics: Doxorubicin; Triple Negative Breast Neoplasms; Humans; Nanofibers; Cell Line, Tumor; Female; Drug Delivery Systems; Cell-Penetrating Peptides; Drug Liberation; Cell Survival; Peptides; Antibiotics, Antineoplastic; ErbB Receptors; Matrix Metalloproteinase 9; Drug Carriers
PubMed: 38911501
DOI: 10.2147/IJN.S453958 -
Biology Direct Jun 2024Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have...
BACKGROUND
Most patients with acute myeloid leukemia (AML) eventually develop drug resistance, leading to a poor prognosis. Dysregulated long gene non coding RNAs (lincRNAs) have been implicated in chemoresistance in AML. Unfortunately, the effects of lincRNAs which participate in regulating the Adriamycin (ADR) resistance in AML cells remain unclear. Thus, the purpose of this study is to determine LINC00987 function in ADR-resistant AML.
METHODS
In this study, ADR-resistant cells were constructed. LINC00987, miRNAs, and HMGA2 mRNA expression were measured by qRT-PCR. P-GP, BCRP, and HMGA2 protein were measured by Western blot. The proliferation was analyzed by MTS and calculated IC50. Soft agar colony formation assay and TUNEL staining were used to analyze cell colony formation and apoptosis. Xenograft tumor experiment was used to analyze the xenograft tumor growth of ADR-resistant AML.
RESULTS
We found that higher expression of LINC00987 was observed in AML patients and associated with poor overall survival in AML patients. LINC00987 expression was increased in ADR-resistant AML cells, including ADR/MOLM13 and ADR/HL-60 cells. LINC00987 downregulation reduces ADR resistance in ADR/MOLM13 and ADR/HL-60 cells in vitro and in vivo, while LINC00987 overexpression enhanced ADR resistance in MOLM13 and HL-60 cells. Additionally, LINC00987 functions as a competing endogenous RNA for miR-4458 to affect ADR resistance in ADR/MOLM13 and ADR/HL-60 cells. HMGA2 is a target of miR-4458. LINC00987 knockdown and miR-4458 overexpression reduced HMGA2 expression. HMGA2 overexpression enhanced ADR resistance, which reversed the function of LINC00987 silencing in suppressing ADR resistance of ADR/MOLM13 and ADR/HL-60 cells.
CONCLUSIONS
Downregulation of LINC00987 weakens ADR resistance by releasing miR-4458 to deplete HMGA2 in ADR/MOLM13 and ADR/HL-60. Therefore, LINC00987 may act as the therapeutic target for treating chemoresistant AML.
Topics: Leukemia, Myeloid, Acute; Humans; HMGA2 Protein; MicroRNAs; Drug Resistance, Neoplasm; Doxorubicin; RNA, Long Noncoding; Mice; Animals; Cell Line, Tumor; HL-60 Cells; Gene Silencing; Apoptosis; Cell Proliferation; Female
PubMed: 38910243
DOI: 10.1186/s13062-024-00490-1 -
Journal of Nanobiotechnology Jun 2024Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our...
Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.
Topics: Animals; Autophagy; Mice; Exosomes; MicroRNAs; Cold Temperature; Osteogenesis; Mice, Inbred C57BL; Mesenchymal Stem Cells; Osteoporosis; Cell Differentiation; Bone and Bones; Female; Bone Density; Sirolimus
PubMed: 38910236
DOI: 10.1186/s12951-024-02640-z -
Medical Oncology (Northwood, London,... Jun 2024The purpose of the present study was in vitro determination of the combined effects of doxorubucin and 5-fluorouracil by 2D and 3D culture conditions on breast cancer...
The purpose of the present study was in vitro determination of the combined effects of doxorubucin and 5-fluorouracil by 2D and 3D culture conditions on breast cancer using MCF-7 cell line and CSCs isolated from these cells. In the first stage of this study, CSC isolation and their characterization were performed. In the next experimental period, the antiproliferative effects of 5-Fu and Dox on the MCF-7 and CSCs were demonstrated on 2D. To evaluate the synergistic/antagonistic effects of these chemotherapeutics, the CI was calculated. Additionally, 3D tumor spheroids were used as another model. In the last step, qRT-PCR analysis was performed to examine apoptosis-related gene expressions. In this study, it was clearly seen that CSCs obtained from the breast cancer cell line express stemness factors. In addition, the antiproliferative effects of 5-Fu and Dox on breast cancer and associated CSCs were very clear. Their synergistic effects were determined by CI values. Moreover, it was seen that combined theraphy changed the expression levels of genes related to apoptosis. Additionally, it was molecularly demonstrated that 3D tumoroids were more resistant than the others. In conclusion, the polychemotherapeutic approach was much more effective than the monotherapy. The fact that this effect was seen not only in breast cancer cells, but also in breast cancer stem cells. In addition, it was very promising that the results obtained were similar in both two-dimensional and three-dimensional tumoroids.
Topics: Humans; Fluorouracil; Neoplastic Stem Cells; Doxorubicin; Breast Neoplasms; Female; MCF-7 Cells; Spheroids, Cellular; Apoptosis; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Drug Synergism
PubMed: 38910198
DOI: 10.1007/s12032-024-02423-4 -
Respiratory Research Jun 2024Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However,...
BACKGROUND
Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored.
METHODS
To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.
RESULTS
c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.
CONCLUSIONS
These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
Topics: Animals; Pulmonary Fibrosis; Mice; Proto-Oncogene Proteins c-met; Pneumonia; Mice, Inbred C57BL; Humans; Bleomycin; Mice, Knockout; Male; Female; Lung; Disease Models, Animal
PubMed: 38909206
DOI: 10.1186/s12931-024-02884-1 -
European Journal of Dermatology : EJD Apr 2024
Topics: Humans; Sirolimus; Facial Dermatoses; Female; Immunosuppressive Agents; Male; Middle Aged; Administration, Topical; Administration, Cutaneous
PubMed: 38907553
DOI: 10.1684/ejd.2024.4651 -
BMC Oral Health Jun 2024Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these...
BACKGROUND
Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations.
METHODS
We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells.
RESULTS
ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53.
CONCLUSIONS
This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.
Topics: Zinc Oxide; Humans; Piperidines; Apoptosis; Alkaloids; Benzodioxoles; Mouth Neoplasms; bcl-2-Associated X Protein; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53; Biofilms; Polyunsaturated Alkamides; Nanoparticles; Antioxidants; Microbial Sensitivity Tests; Metal Nanoparticles; Antineoplastic Agents; Microscopy, Electron, Scanning; X-Ray Diffraction; Cell Line, Tumor; KB Cells
PubMed: 38907185
DOI: 10.1186/s12903-024-04399-z -
Molecular Biology Reports Jun 2024Protein nanocages resemble natural biomimetic carriers and can be engineered to act as targeted delivery systems, making them an attractive option for various drug...
Protein nanocages resemble natural biomimetic carriers and can be engineered to act as targeted delivery systems, making them an attractive option for various drug delivery and biomedical applications. Our research investigated the genetic link of a specific anti-HER2 peptide (LTVSPWY) to the exposed N-terminal region of the maize (Zea mays) ferritin 1 (ZmFer1) protein nanocage, employing either a 7-amino acid (for LTVS-ZmFer1) or 16-amino acid (for LTVS-L-ZmFer1) linker. We utilized a heat treatment method to load the chemotherapeutic drug doxorubicin into the protein nanocage. The construct with the longer linker (LTVS-L) produced a greater amount of soluble protein nanocage and was selected for further experiments. The average size, polydispersity index, and zeta potential of the engineered protein nanocage were 19.01 nm, 0.168, and - 2.13 mV, respectively. The LTVS-L-ZmFer1 protein nanocage exhibited excellent thermal stability, withstanding temperatures up to 100 °C with only partial denaturation. Furthermore, we observed that cellular uptake of the LTVS-L-ZmFer1 protein nanocages in HER2-positive breast cancer cells was significantly higher compared to ZmFer1 after labeling with FITC (fluorescein isothiocyanate) (P-value = 0.0001). In addition, we observed a significant decrease in the viability of SKBR3 cells when treated with DOX-loaded LTVS-L-ZmFer1 protein nanocages compared to cells treated with DOX-loaded ZmFer1 protein nanocages. Therefore, this new treatment strategy may prove to be an effective way to reduce both the side effects and toxicity associated with conventional cancer treatments in patients with HER2-positive breast cancer.
Topics: Humans; Receptor, ErbB-2; Doxorubicin; Drug Delivery Systems; Cell Line, Tumor; Breast Neoplasms; Recombinant Proteins; Ferritins; Zea mays; Protein Engineering; Female; Drug Carriers; Plant Proteins
PubMed: 38904710
DOI: 10.1007/s11033-024-09636-w -
Molecular Pharmaceutics Jul 2024Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a Ga-radiolabeled...
Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers Ga-FAPI-46 and Ga-DOTA-LM3 alongside the heterobivalent probe Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers Ga-FAPI-46 and Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.
Topics: Animals; Mice; Receptors, Somatostatin; Humans; Mice, Inbred C57BL; Gallium Radioisotopes; Positron-Emission Tomography; Radiopharmaceuticals; Pulmonary Fibrosis; Lung; Male; Bleomycin; Endopeptidases; Disease Models, Animal; Female; Idiopathic Pulmonary Fibrosis; Membrane Proteins; Serine Endopeptidases; Quinolines
PubMed: 38899595
DOI: 10.1021/acs.molpharmaceut.4c00405 -
Journal of Nanobiotechnology Jun 2024Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful...
Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms.
Topics: Tumor Microenvironment; Animals; Immunotherapy; Doxorubicin; Humans; Mice; Cell Line, Tumor; Female; Mice, Inbred BALB C; Nanoparticles; Breast Neoplasms; Gene Editing; CRISPR-Cas Systems; Manganese Compounds; Drug Resistance, Neoplasm; Drug Delivery Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Antineoplastic Agents; Oxides
PubMed: 38898493
DOI: 10.1186/s12951-024-02571-9