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19 pages, 4855 KiB

Open AccessArticle

Development of Multi-Scale X-ray Fluorescence Tomography for Examination of Nanocomposite-Treated Biological Samples

by Si Chen, Ruben Omar Lastra, Tatjana Paunesku, Olga Antipova, Luxi Li, Junjing Deng, Yanqi Luo, Michael Beau Wanzer, Jelena Popovic, Ya Li, Alexander D. Glasco, Chris Jacobsen, Stefan Vogt and Gayle E. Woloschak

Cancers 2021, 13(17), 4497; https://doi.org/10.3390/cancers13174497 - 6 Sep 2021

Cited by 5 | Viewed by 2841

Abstract

Research in cancer nanotechnology is entering its third decade, and the need to study interactions between nanomaterials and cells remains urgent. Heterogeneity of nanoparticle uptake by different cells and subcellular compartments represent the greatest obstacles to a full understanding of the entire spectrum [...] Read more.

Research in cancer nanotechnology is entering its third decade, and the need to study interactions between nanomaterials and cells remains urgent. Heterogeneity of nanoparticle uptake by different cells and subcellular compartments represent the greatest obstacles to a full understanding of the entire spectrum of nanomaterials’ effects. In this work, we used flow cytometry to evaluate changes in cell cycle associated with non-targeted nanocomposite uptake by individual cells and cell populations. Analogous single cell and cell population changes in nanocomposite uptake were explored by X-ray fluorescence microscopy (XFM). Very few nanoparticles are visible by optical imaging without labeling, but labeling increases nanoparticle complexity and the risk of modified cellular uptake. XFM can be used to evaluate heterogeneity of nanocomposite uptake by directly imaging the metal atoms present in the metal-oxide nanocomposites under investigation. While XFM mapping has been performed iteratively in 2D with the same sample at different resolutions, this study is the first example of serial tomographic imaging at two different resolutions. A cluster of cells exposed to non-targeted nanocomposites was imaged with a micron-sized beam in 3D. Next, the sample was sectioned for immunohistochemistry as well as a high resolution “zoomed in” X-ray fluorescence (XRF) tomography with 80 nm beam spot size. Multiscale XRF tomography will revolutionize our ability to explore cell-to-cell differences in nanomaterial uptake. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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20 pages, 3727 KiB

Open AccessArticle

Variable Molecular Weight Polymer Nanoparticles for Detection and Hyperthermia-Induced Chemotherapy of Colorectal Cancer

by Santu Sarkar and Nicole Levi

Cancers 2021, 13(17), 4472; https://doi.org/10.3390/cancers13174472 - 5 Sep 2021

Cited by 5 | Viewed by 2240

Abstract

Oxaliplatin plays a significant role as a chemotherapeutic agent for the treatment of colorectal cancer (CRC); however, oxaliplatin-resistant phenotypes make further treatment challenging. Here, we have demonstrated that rapid (60 s) hyperthermia (42 °C), generated by the near-infrared stimulation of variable molecular weight [...] Read more.

Oxaliplatin plays a significant role as a chemotherapeutic agent for the treatment of colorectal cancer (CRC); however, oxaliplatin-resistant phenotypes make further treatment challenging. Here, we have demonstrated that rapid (60 s) hyperthermia (42 °C), generated by the near-infrared stimulation of variable molecular weight nanoparticles (VMWNPs), increases the effectiveness of oxaliplatin in the oxaliplatin-resistant CRC cells. VMWNP-induced hyperthermia resulted in a higher cell death in comparison to cells exposed to chemotherapy at 42 °C for 2 h. Fluorescence from VMWNPs was observed inside cells, which allows for the detection of CRC. The work further demonstrates that the intracellular thermal dose can be determined using cell luminescence and correlated with the cell viability and response to VMWNP-induced chemotherapy. Mild heating makes oxaliplatin-resistant cancer cells responsive to chemotherapy, and the VMWNPs-induced hyperthermia can induce cell death in a few minutes, compared to classical bulk heating. The results presented here lay the foundation for photothermal polymer nanoparticles to be used for cell ablation and augmenting chemotherapy in drug-resistant colorectal cancer cells. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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15 pages, 9818 KiB

Open AccessArticle

Ultrasound-Mediated Cavitation Enhances EGFR-Targeting PLGA-PEG Nano-Micelle Delivery for Triple-Negative Breast Cancer Treatment

by Libin Chen, Tao Zhang, Shan Sun, Wenzhi Ren, Aiguo Wu and Huixiong Xu

Cancers 2021, 13(14), 3383; https://doi.org/10.3390/cancers13143383 - 6 Jul 2021

Cited by 14 | Viewed by 3383

Abstract

Triple-negative breast cancer (TNBC) is highly recurring and metastatic breast cancer with overexpressing epidermal growth factor receptor (EGFR). Herein, a series of in vitro and in vivo analyses were used to explore the therapeutic effect of EGFR-targeting nano-micelles (PLGA-PEG/DOX@anti-EGFR) combined with ultrasound-mediated cavitation [...] Read more.

Triple-negative breast cancer (TNBC) is highly recurring and metastatic breast cancer with overexpressing epidermal growth factor receptor (EGFR). Herein, a series of in vitro and in vivo analyses were used to explore the therapeutic effect of EGFR-targeting nano-micelles (PLGA-PEG/DOX@anti-EGFR) combined with ultrasound-mediated cavitation (UMC). The prepared nano-micelle drug carriers have good biocompatibility and can greatly increase the drug accumulation in tumor regions, thereby reducing off-target toxicity while enhancing anti-tumor efficacy. Moreover, an in vivo analysis of the practical utility of this treatment modality was conducted by using SonoVue^TM microbubbles to achieve cavitation under different power intensity levels, with an ultrasonic power intensity of 0.5 W/cm² maximizing the intra-tumoral blood perfusion. Relative to PLGA-PEG@DOX/anti-EGFR nano-micelles treatment alone, the combination with UMC was better able to suppress tumor growth even at low concentrations. As such, combining actively targeted drug-carrier molecules with UMC represents an effective approach to enhancing therapeutic efficacy while reducing the adverse, systemic effects associated with DOX and other chemotherapeutic drugs, and it can be considered as a promising clinical prospect in the treatment of TNBC. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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14 pages, 2151 KiB

Open AccessArticle

Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine

by He Hu and Nicole F. Steinmetz

Cancers 2021, 13(12), 2909; https://doi.org/10.3390/cancers13122909 - 10 Jun 2021

Cited by 27 | Viewed by 4759

Abstract

To develop a human epidermal growth factor receptor-2 (HER2)-specific cancer vaccine, using a plant virus-like particle (VLP) platform. Copper-free click chemistry and infusion encapsulation protocols were developed to prepare VLPs displaying the HER2-derived CH401 peptide epitope, with and without Toll-like receptor 9 (TLR9) [...] Read more.

To develop a human epidermal growth factor receptor-2 (HER2)-specific cancer vaccine, using a plant virus-like particle (VLP) platform. Copper-free click chemistry and infusion encapsulation protocols were developed to prepare VLPs displaying the HER2-derived CH401 peptide epitope, with and without Toll-like receptor 9 (TLR9) agonists loaded into the interior cavity of the VLPs; Physalis mottle virus (PhMV)-based VLPs were used. After prime-boost immunization of BALB/c mice through subcutaneous administration of the vaccine candidates, sera were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) for the CH401-specific antibodies; Th1 vs. Th2 bias was determined by antibody subtyping and splenocyte assay. Efficacy was assessed by tumor challenge using DDHER2 tumor cells. We successful developed two VLP-based anti-HER2 vaccine candidates—PhMV-CH401 vs. CpG-PhMV-CH401; however, the addition of the CpG adjuvant did not confer additional immune priming. Both VLP-based vaccine candidates elicited a strong immune response, including high titers of HER2-specific immunoglobulins and increased toxicity of antisera to DDHER2 tumor cells. DDHER2 tumor growth was delayed, leading to prolonged survival of the vaccinated vs. naïve BALB/C mice. The PhMV-based anti-HER2 vaccine PhMV-CH401, demonstrated efficacy as an anti-HER2 cancer vaccine. Our studies highlight that VLPs derived from PhMV are a promising platform to develop cancer vaccines. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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Review

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16 pages, 2344 KiB

Open AccessReview

Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside

by Akanksha S. Mahajan and Alexander H. Stegh

Cancers 2022, 14(7), 1615; https://doi.org/10.3390/cancers14071615 - 23 Mar 2022

Cited by 8 | Viewed by 3453

Abstract

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in [...] Read more.

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their “free” form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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29 pages, 3320 KiB

Open AccessReview

Nanotechnology in Tumor Biomarker Detection: The Potential of Liganded Nanoclusters as Nonlinear Optical Contrast Agents for Molecular Diagnostics of Cancer

by Guillaume F. Combes, Ana-Marija Vučković, Martina Perić Bakulić, Rodolphe Antoine, Vlasta Bonačić-Koutecky and Katarina Trajković

Cancers 2021, 13(16), 4206; https://doi.org/10.3390/cancers13164206 - 21 Aug 2021

Cited by 37 | Viewed by 4484

Abstract

Cancer is one of the leading causes of premature death, and, as such, it can be prevented by developing strategies for early and accurate diagnosis. Cancer diagnostics has evolved from the macroscopic detection of malignant tissues to the fine analysis of tumor biomarkers [...] Read more.

Cancer is one of the leading causes of premature death, and, as such, it can be prevented by developing strategies for early and accurate diagnosis. Cancer diagnostics has evolved from the macroscopic detection of malignant tissues to the fine analysis of tumor biomarkers using personalized medicine approaches. Recently, various nanomaterials have been introduced into the molecular diagnostics of cancer. This has resulted in a number of tumor biomarkers that have been detected in vitro and in vivo using nanodevices and corresponding imaging techniques. Atomically precise ligand-protected noble metal quantum nanoclusters represent an interesting class of nanomaterials with a great potential for the detection of tumor biomarkers. They are characterized by high biocompatibility, low toxicity, and suitability for controlled functionalization with moieties specifically recognizing tumor biomarkers. Their non-linear optical properties are of particular importance as they enable the visualization of nanocluster-labeled tumor biomarkers using non-linear optical techniques such as two-photon-excited fluorescence and second harmonic generation. This article reviews liganded nanoclusters among the different nanomaterials used for molecular cancer diagnosis and the relevance of this new class of nanomaterials as non-linear optical probe and contrast agents. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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21 pages, 1440 KiB

Open AccessReview

Modulation of Cancer Cell Autophagic Responses by Graphene-Based Nanomaterials: Molecular Mechanisms and Therapeutic Implications

by Biljana Ristic, Ljubica Harhaji-Trajkovic, Mihajlo Bosnjak, Ivana Dakic, Srdjan Mijatovic and Vladimir Trajkovic

Cancers 2021, 13(16), 4145; https://doi.org/10.3390/cancers13164145 - 18 Aug 2021

Cited by 17 | Viewed by 3473

Abstract

Graphene-based nanomaterials (GNM) are plausible candidates for cancer therapeutics and drug delivery systems. Pure graphene and graphene oxide nanoparticles, as well as graphene quantum dots and graphene nanofibers, were all able to trigger autophagy in cancer cells through both transcriptional and post-transcriptional mechanisms [...] Read more.

Graphene-based nanomaterials (GNM) are plausible candidates for cancer therapeutics and drug delivery systems. Pure graphene and graphene oxide nanoparticles, as well as graphene quantum dots and graphene nanofibers, were all able to trigger autophagy in cancer cells through both transcriptional and post-transcriptional mechanisms involving oxidative/endoplasmic reticulum stress, AMP-activated protein kinase, mechanistic target of rapamycin, mitogen-activated protein kinase, and Toll-like receptor signaling. This was often coupled with lysosomal dysfunction and subsequent blockade of autophagic flux, which additionally increased the accumulation of autophagy mediators that participated in apoptotic, necrotic, or necroptotic death of cancer cells and influenced the immune response against the tumor. In this review, we analyze molecular mechanisms and structure–activity relationships of GNM-mediated autophagy modulation, its consequences for cancer cell survival/death and anti-tumor immune response, and the possible implications for the use of GNM in cancer therapy. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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39 pages, 7427 KiB

Open AccessReview

DNA Based and Stimuli-Responsive Smart Nanocarrier for Diagnosis and Treatment of Cancer: Applications and Challenges

by Fakhara Sabir, Mahira Zeeshan, Ushna Laraib, Mahmood Barani, Abbas Rahdar, Magali Cucchiarini and Sadanand Pandey

Cancers 2021, 13(14), 3396; https://doi.org/10.3390/cancers13143396 - 6 Jul 2021

Cited by 54 | Viewed by 6065

Abstract

The rapid development of multidrug co-delivery and nano-medicines has made spontaneous progress in tumor treatment and diagnosis. DNA is a unique biological molecule that can be tailored and molded into various nanostructures. The addition of ligands or stimuli-responsive elements enables DNA nanostructures to [...] Read more.

The rapid development of multidrug co-delivery and nano-medicines has made spontaneous progress in tumor treatment and diagnosis. DNA is a unique biological molecule that can be tailored and molded into various nanostructures. The addition of ligands or stimuli-responsive elements enables DNA nanostructures to mediate highly targeted drug delivery to the cancer cells. Smart DNA nanostructures, owing to their various shapes, sizes, geometry, sequences, and characteristics, have various modes of cellular internalization and final disposition. On the other hand, functionalized DNA nanocarriers have specific receptor-mediated uptake, and most of these ligand anchored nanostructures able to escape lysosomal degradation. DNA-based and stimuli responsive nano-carrier systems are the latest advancement in cancer targeting. The data exploration from various studies demonstrated that the DNA nanostructure and stimuli responsive drug delivery systems are perfect tools to overcome the problems existing in the cancer treatment including toxicity and compromised drug efficacy. In this light, the review summarized the insights about various types of DNA nanostructures and stimuli responsive nanocarrier systems applications for diagnosis and treatment of cancer. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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16 pages, 2745 KiB

Open AccessReview

Recent Development of Gold Nanoparticles as Contrast Agents for Cancer Diagnosis

by Dong Luo, Xinning Wang, Clemens Burda and James P. Basilion

Cancers 2021, 13(8), 1825; https://doi.org/10.3390/cancers13081825 - 11 Apr 2021

Cited by 91 | Viewed by 6349

Abstract

The last decade has witnessed the booming of preclinical studies of gold nanoparticles (AuNPs) in biomedical applications, from therapeutics delivery, imaging diagnostics, to cancer therapies. The synthetic versatility, unique optical and electronic properties, and ease of functionalization make AuNPs an excellent platform for [...] Read more.

The last decade has witnessed the booming of preclinical studies of gold nanoparticles (AuNPs) in biomedical applications, from therapeutics delivery, imaging diagnostics, to cancer therapies. The synthetic versatility, unique optical and electronic properties, and ease of functionalization make AuNPs an excellent platform for cancer theranostics. This review summarizes the development of AuNPs as contrast agents to image cancers. First, we briefly describe the AuNP synthesis, their physical characteristics, surface functionalization and related biomedical uses. Then we focus on the performances of AuNPs as contrast agents to diagnose cancers, from magnetic resonance imaging, CT and nuclear imaging, fluorescence imaging, photoacoustic imaging to X-ray fluorescence imaging. We compare these imaging modalities and highlight the roles of AuNPs as contrast agents in cancer diagnosis accordingly, and address the challenges for their clinical translation. Full article

(This article belongs to the Special Issue Development and Investigation of Nanoconstructs Suitable for Cancer Therapy and Diagnosis)

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