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15 pages, 7750 KiB

Open AccessArticle

Utilizing Gold Nanoparticles as Prospective Radiosensitizers in 3D Radioresistant Pancreatic Co-Culture Model

by Abdulaziz Alhussan, Nolan Jackson, Reinali Calisin, Jessica Morgan, Wayne Beckham and Devika B. Chithrani

Int. J. Mol. Sci. 2023, 24(15), 12523; https://doi.org/10.3390/ijms241512523 - 07 Aug 2023

Cited by 2 | Viewed by 1473

Abstract

Pancreatic cancer stands among the deadliest forms of cancer, and the existing treatments fall short of providing adequate efficacy. Novel and more effective treatment approaches are urgently required to address this critical medical challenge. In this study, we aimed to evaluate the anti-cancer [...] Read more.

Pancreatic cancer stands among the deadliest forms of cancer, and the existing treatments fall short of providing adequate efficacy. Novel and more effective treatment approaches are urgently required to address this critical medical challenge. In this study, we aimed to evaluate the anti-cancer efficacy of gold nanoparticles (GNPs) in combination with radiotherapy (RT). A 3D pancreatic cancer co-culture spheroid model of MIA PaCa-2 cancer cells and patient-derived cancer-associated fibroblasts (CAF-98) was used. The spheroids were treated with GNPs (7.5 μg/mL) and 2 Gy of RT. The spheroids’ cell viability was assessed through the CellTiter-Glo 3D assay, and an immunofluorescence assay was used to assess the DNA DSBs via the expression of the DNA damage marker 53BP1. Co-culture samples showed a 10.8% (p < 0.05) increase in proliferation and a 13.0% (p < 0.05) decrease in DNA DSB when compared to monoculture samples, However, they displayed a 175% (p < 0.001) increase in GNPs uptake when compared to monoculture spheroids. Using GNPs/RT, we were able to show a significant reduction of 6.2% (p < 0.05) in spheroid size and an increase of 14.3% (p < 0.05) in DNA DSB damage in co-culture samples. The combination of GNPs with RT demonstrated remarkable radiosensitization effects, representing a promising approach to enhance cancer treatment efficacy. These effects were particularly noteworthy in the more treatment-resistant co-culture spheroid model. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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16 pages, 2973 KiB

Open AccessArticle

Lyophilization Based Isolation of Exosomes

by Rida e Maria Qazi, Zahra Sajid, Chunqiu Zhao, Irfan Hussain, Fizza Iftikhar, Muhammad Jameel, Fawad Ur Rehman and Afsar Ali Mian

Int. J. Mol. Sci. 2023, 24(13), 10477; https://doi.org/10.3390/ijms241310477 - 22 Jun 2023

Cited by 2 | Viewed by 2777

Abstract

Exosomes are nanoscale extracellular vesicles which regulate intercellular communication. They have great potential for application in nanomedicine. However, techniques for their isolation are limited by requirements for advanced instruments and costly reagents. In this study, we developed a lyophilization-based method for isolating exosomes [...] Read more.

Exosomes are nanoscale extracellular vesicles which regulate intercellular communication. They have great potential for application in nanomedicine. However, techniques for their isolation are limited by requirements for advanced instruments and costly reagents. In this study, we developed a lyophilization-based method for isolating exosomes from cultured cells. The isolated exosomes were characterized for protein content using Bradford assay, and for size distribution and shape using scanning electron microscopy (SEM) and nanoparticles tracking analysis (NTA). In addition, CD63, CD9, CD81, HSP70 and TSG101 were evaluated as essential exosomal surface markers using Western blot. Drug loading and release studies were performed to confirm their drug delivery properties using an in vitro model. Exosomes were also loaded with commercial dyes (Cy5, Eosin) for the evaluation of their drug delivery properties. All these characterizations confirmed successful exosome isolation with measurements of less than 150 nm, having a typical shape, and by expressing the known exosome surface protein markers. Finally, tyrosine kinase inhibitors (dasatinib and ponatinib) were loaded on the exosomes to evaluate their anticancer effects on leukemia cells (K562 and engineered Ba/F3-BCR-ABL) using MTT and Annexin-PI assays. The expression of MUC1 protein on the exosomes isolated from MCF-7 cells also indicated that their potential diagnostic properties were intact. In conclusion, we developed a new method for exosome isolation from cultured cells. These exosomes met all the essential requirements in terms of characterization, drug loading and release ability, and inhibition of proliferation and apoptosis induction in Ph+ leukemia cells. Based on these results, we are confident in presenting the lyophilization-based exosome isolation method as an alternative to traditional techniques for exosome isolation from cultured cells. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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11 pages, 1654 KiB

Open AccessArticle

Targeted Large-Volume Lymphocyte Removal Using Magnetic Nanoparticles in Blood Samples of Patients with Chronic Lymphocytic Leukemia: A Proof-of-Concept Study

by Stefanie Janker, Simon Doswald, Roman R. Schimmer, Urs Schanz, Wendelin J. Stark, Martin Schläpfer and Beatrice Beck-Schimmer

Int. J. Mol. Sci. 2023, 24(8), 7523; https://doi.org/10.3390/ijms24087523 - 19 Apr 2023

Cited by 1 | Viewed by 1161

Abstract

In the past, our research group was able to successfully remove circulating tumor cells with magnetic nanoparticles. While these cancer cells are typically present in low numbers, we hypothesized that magnetic nanoparticles, besides catching single cells, are also capable of eliminating a large [...] Read more.

In the past, our research group was able to successfully remove circulating tumor cells with magnetic nanoparticles. While these cancer cells are typically present in low numbers, we hypothesized that magnetic nanoparticles, besides catching single cells, are also capable of eliminating a large number of tumor cells from the blood ex vivo. This approach was tested in a small pilot study in blood samples of patients suffering from chronic lymphocytic leukemia (CLL), a mature B-cell neoplasm. Cluster of differentiation (CD) 52 is a ubiquitously expressed surface antigen on mature lymphocytes. Alemtuzumab (MabCampath^®) is a humanized, IgG1κ, monoclonal antibody directed against CD52, which was formerly clinically approved for treating chronic lymphocytic leukemia (CLL) and therefore regarded as an ideal candidate for further tests to develop new treatment options. Alemtuzumab was bound onto carbon-coated cobalt nanoparticles. The particles were added to blood samples of CLL patients and finally removed, ideally with bound B lymphocytes, using a magnetic column. Flow cytometry quantified lymphocyte counts before, after the first, and after the second flow across the column. A mixed effects analysis was performed to evaluate removal efficiency. p < 0.05 was defined as significant. In the first patient cohort (n = 10), using a fixed nanoparticle concentration, CD19-positive B lymphocytes were reduced by 38% and by 53% after the first and the second purification steps (p = 0.002 and p = 0.005), respectively. In a second patient cohort (n = 11), the nanoparticle concentration was increased, and CD19-positive B lymphocytes were reduced by 44% (p < 0.001) with no further removal after the second purification step. In patients with a high lymphocyte count (>20 G/L), an improved efficiency of approximately 20% was observed using higher nanoparticle concentrations. A 40 to 50% reduction of B lymphocyte count using alemtuzumab-coupled carbon-coated cobalt nanoparticles is feasible, also in patients with a high lymphocyte count. A second purification step did not further increase removal. This proof-of-concept study demonstrates that such particles allow for the targeted extraction of larger amounts of cellular blood components and might offer new treatment options in the far future. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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18 pages, 1922 KiB

Open AccessArticle

Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment

by Salomé Araujo-Abad, Antonio Manresa-Manresa, Enrique Rodríguez-Cañas, María Fuentes-Baile, Pilar García-Morales, Ricardo Mallavia, Miguel Saceda and Camino de Juan Romero

Int. J. Mol. Sci. 2023, 24(6), 5910; https://doi.org/10.3390/ijms24065910 - 21 Mar 2023

Cited by 3 | Viewed by 1833

Abstract

Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. [...] Read more.

Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. Therefore, more efficient ways of drug delivery have been studied to reduce the therapeutic exposure of the patients. We have isolated and fully characterized small extracellular vesicles (EVs) from seven patient-derived GBM cell lines. After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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15 pages, 4782 KiB

Open AccessArticle

Deep Learning-Based Artificial Intelligence to Investigate Targeted Nanoparticles’ Uptake in TNBC Cells

by Rafia Ali, Mehala Balamurali and Pegah Varamini

Int. J. Mol. Sci. 2022, 23(24), 16070; https://doi.org/10.3390/ijms232416070 - 16 Dec 2022

Cited by 8 | Viewed by 1890

Abstract

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer in women. It has the poorest prognosis along with limited therapeutic options. Smart nano-based carriers are emerging as promising approaches in treating TNBC due to their favourable characteristics such as [...] Read more.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer in women. It has the poorest prognosis along with limited therapeutic options. Smart nano-based carriers are emerging as promising approaches in treating TNBC due to their favourable characteristics such as specifically delivering different cargos to cancer cells. However, nanoparticles’ tumour cell uptake, and subsequent drug release, are essential factors considered during the drug development process. Contemporary qualitative analyses based on imaging are cumbersome and prone to human biases. Deep learning-based algorithms have been well-established in various healthcare settings with promising scope in drug discovery and development. In this study, the performance of five different convolutional neural network models was evaluated. In this research, we investigated two sequential models from scratch and three pre-trained models, VGG16, ResNet50, and Inception V3. These models were trained using confocal images of nanoparticle-treated cells loaded with a fluorescent anticancer agent. Comparative and cross-validation analyses were further conducted across all models to obtain more meaningful results. Our models showed high accuracy in predicting either high or low drug uptake and release into TNBC cells, indicating great translational potential into practice to aid in determining cellular uptake at the early stages of drug development in any area of research. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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34 pages, 8557 KiB

Open AccessArticle

Gold Nanosystems Covered with Doxorubicin/DNA Complexes: A Therapeutic Target for Prostate and Liver Cancer

by Rosa M. Giráldez-Pérez, Elia Grueso, Antonio J. Montero-Hidalgo, Raúl M. Luque, José M. Carnerero, Edyta Kuliszewska and Rafael Prado-Gotor

Int. J. Mol. Sci. 2022, 23(24), 15575; https://doi.org/10.3390/ijms232415575 - 08 Dec 2022

Cited by 4 | Viewed by 1619

Abstract

Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA–Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA–Doxo nanotransporters, the conditions for the [...] Read more.

Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA–Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA–Doxo nanotransporters, the conditions for the DNA–Doxo compaction process induced by gold nanoparticles were first explored using fluorescence spectroscopy, circular dichroism and atomic force microscopy techniques. The reverse process, which is fundamental for Doxo liberation at the site of action, was found to occur at higher C_Au@16-Ph-16 concentrations using these techniques. Zeta potential, dynamic light scattering and UV–visible spectroscopy reveal that the prepared compacted nanosystems are stable, highly charged and of adequate size for the effective delivery of Doxo to the cell. This fact is verified by in vitro biocompatibility and internalization studies using two prostate cancer-derived cell lines (LNCaP and DU145) and one hepatocellular carcinoma-derived cell line (SNU-387), as well as a non-tumor prostate (PNT2) cell line and a non-hepatocarcinoma hepatoblastoma cell line (Hep-G2) model used as a control in liver cells. However, the most outstanding results of this work are derived from the use of the C_I+N_I combined treatments which present strong action in cancer-derived cell lines, while a protective effect is observed in non-tumor cell lines. Hence, novel therapeutic targets based on gold nanoparticles denote high selectivity compared to conventional treatment based on free Doxo at the same concentration. The results obtained show the viability of both the proposed methodology for internalization of compacted nanocomplexes inside the cell and the effectiveness of the possible treatment and minimization of side effects in prostate and liver cancer. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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14 pages, 2903 KiB

Open AccessArticle

Nanoemulsion Co-Loaded with XIAP siRNA and Gambogic Acid for Inhalation Therapy of Lung Cancer

by Minhao Xu, Lanfang Zhang, Yue Guo, Lu Bai, Yi Luo, Ben Wang, Meiyan Kuang, Xingyou Liu, Meng Sun, Chenhui Wang and Jing Xie

Int. J. Mol. Sci. 2022, 23(22), 14294; https://doi.org/10.3390/ijms232214294 - 18 Nov 2022

Cited by 8 | Viewed by 1704

Abstract

Lung cancer is a leading cause of cancer mortality worldwide, with a 5-year survival rate of less than 20%. Gambogic acid (GA) is a naturally occurring and potent anticancer agent that destroys tumor cells through multiple mechanisms. According to the literature, one of [...] Read more.

Lung cancer is a leading cause of cancer mortality worldwide, with a 5-year survival rate of less than 20%. Gambogic acid (GA) is a naturally occurring and potent anticancer agent that destroys tumor cells through multiple mechanisms. According to the literature, one of the most potent inhibitors of caspases and apoptosis currently known is the X-linked Inhibitor of Apoptosis Protein (XIAP). It is highly expressed in various malignancies but has little or no expression in normal cells, making it an attractive target for cancer treatment. Here we report the development of a chitosan (CS)-based cationic nanoemulsion-based pulmonary delivery (p.d.) system for the co-delivery of antineoplastic drugs (GA) and anti-XIAP small interfering RNA (siRNA). The results showed that the chitosan-modified cationic nanoemulsions could effectively encapsulate gambogic acid as well as protect siRNA against degradation. The apoptosis analysis confirmed that the cationic nanoemulsions could induce more apoptosis in the A549 cell line. In addition, most drugs and siRNAs have a long residence time in the lungs through pulmonary delivery and show greater therapeutic effects compared to systemic administration. In summary, this work demonstrates the applicability of cationic nanoemulsions for combined cancer therapy and as a promising approach for the treatment of lung cancer. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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Review

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17 pages, 2241 KiB

Open AccessReview

Carbon Dots in Treatment of Pediatric Brain Tumors: Past, Present, and Future Directions

by Frederic A. Vallejo, Ganesh Sigdel, Eduardo A. Veliz, Roger M. Leblanc, Steven Vanni and Regina M. Graham

Int. J. Mol. Sci. 2023, 24(11), 9562; https://doi.org/10.3390/ijms24119562 - 31 May 2023

Cited by 1 | Viewed by 2268

Abstract

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood–brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and [...] Read more.

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood–brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and micellar molecules of varying structures and compositions, have been investigated as a potential therapy to circumvent some of these inherent challenges. Carbon dots (CDs) have recently gained popularity as a novel nanoparticle with theranostic properties. This carbon-based modality is highly modifiable, allowing for conjugation to drugs, as well as tumor-specific ligands in an effort to more effectively target cancerous cells and reduce peripheral toxicity. CDs are being studied pre-clinically. The ClinicalTrials.gov site was queried using the search terms: brain tumor and nanoparticle, liposome, micelle, dendrimer, quantum dot, or carbon dot. At the time of this review, 36 studies were found, 6 of which included pediatric patients. Two of the six studies investigated nanoparticle drug formulations, whereas the other four studies were on varying liposomal nanoparticle formulations for the treatment of pediatric brain tumors. Here, we reviewed the context of CDs within the broader realm of nanoparticles, their development, promising pre-clinical potential, and proposed future translational utility. Full article

(This article belongs to the Special Issue Nanoparticles for Tumor Targeting and Therapy)

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