Targeting Cancer Cells Overexpressing Folate Receptors with New Terpolymer-Based Nanocapsules: Toward a Novel Targeted DNA Delivery System for Cancer Therapy

Chemotherapeutics represent the standard treatment for a wide range of cancers. However, these agents also affect healthy cells, thus leading to severe off-target effects. Given the non-selectivity of the commonly used drugs, any increase in the selective tumor tissue uptake would represent a significant improvement in cancer therapy. Recently, the use of gene therapy to completely remove the lesion and avoid the toxicity of chemotherapeutics has become a tendency in oncotherapy. Ideally, the genetic material must be safely transferred from the site of administration to the target cells, without involving healthy tissues. This can be achieved by encapsulating genes into non-viral carriers and modifying their surface with ligands with high selectivity and affinity for a relevant receptor on the target cells. Hence, in this work we evaluate the use of terpolymer-based nanocapsules for the targeted delivery of DNA toward cancer cells. The surface of the nanocapsules is decorated with folic acid to actively target the folate receptors overexpressed on a variety of cancer cells. The nanocapsules demonstrate a good ability of encapsulating and releasing DNA. Moreover, the presence of the targeting moieties on the surface of the nanocapsules favors cell uptake, opening up the possibility of more effective therapies.

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Targeted delivery and enhanced gene-silencing activity of centrally modified folic acid–siRNA conjugates

Nucleic Acids Research ◽

10.1093/nar/gkz1115 ◽

2019 ◽

Vol 48 (1) ◽

pp. 75-85 ◽

Cited By ~ 1

Author(s):

Lidya Salim ◽

Golam Islam ◽

Jean-Paul Desaulniers

Keyword(s):

Folic Acid ◽

Gene Silencing ◽

Cancer Cells ◽

Targeted Delivery ◽

Target Cells ◽

Gene Target ◽

Folate Receptors ◽

Normal Tissues ◽

Sense Strand ◽

Low Cytotoxicity

Abstract One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne–azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid–siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.

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Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190731155859 ◽

2019 ◽

Vol 19 (15) ◽

pp. 1835-1845

Author(s):

Ali Hassanzadeh ◽

Adel Naimi ◽

Majid F. Hagh ◽

Raedeh Saraei ◽

Faroogh Marofi ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Cancer Cells ◽

Tumor Necrosis ◽

Lymphoblastic Leukemia ◽

Annexin V ◽

Death Receptors ◽

Target Cells ◽

Wide Range ◽

Apoptotic Proteins ◽

Necrosis Factor

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL. Material and Methods: First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique. Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells. Conclusion: We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

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Developing Picornaviruses for Cancer Therapy

Cancers ◽

10.3390/cancers11050685 ◽

2019 ◽

Vol 11 (5) ◽

pp. 685 ◽

Cited By ~ 10

Author(s):

Cormac McCarthy ◽

Nadishka Jayawardena ◽

Laura N. Burga ◽

Mihnea Bostina

Keyword(s):

Cancer Therapy ◽

Anticancer Activity ◽

Cancer Cells ◽

Rna Viruses ◽

Therapeutic Agents ◽

Oncolytic Viruses ◽

Wide Range ◽

Positive Sense

Oncolytic viruses (OVs) form a group of novel anticancer therapeutic agents which selectively infect and lyse cancer cells. Members of several viral families, including Picornaviridae, have been shown to have anticancer activity. Picornaviruses are small icosahedral non-enveloped, positive-sense, single-stranded RNA viruses infecting a wide range of hosts. They possess several advantages for development for cancer therapy: Their genomes do not integrate into host chromosomes, do not encode oncogenes, and are easily manipulated as cDNA. This review focuses on the picornaviruses investigated for anticancer potential and the mechanisms that underpin this specificity.

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Gene therapy promises accurate, targeted administration and overcoming drug resistance in diverse cancer cells

10.31219/osf.io/j34n6 ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Drug Resistance ◽

Nucleic Acid ◽

Nucleic Acids ◽

Clinical Research ◽

Cancer Cells ◽

Cationic Lipids ◽

Target Cells ◽

Genetic Components ◽

Wide Range

Nucleic acid-based therapeutics such as siRNA and miRNA employ the silencing capabilities of the RNAi mechanism to affect the expression of one gene or several genes in target cells. Nucleic acid-based therapies enable accurate, targeted administration and overcoming drug resistance in diverse cancer cells. Several studies have shown that they can be utilized alongside pharmacological therapy to increase the efficacy of existing therapies. In addition, nucleic acid-based therapies have the potential to widen the spectrum of druggable targets for a range of diseases and emerge as a novel therapeutic technique for treating a number of diseases that are today untreatable. Nucleic acids are dependent on their effective distribution to target cells, which need correct complexation and encapsulation in a delivery mechanism. Although nucleic acids exist in a variety of forms and sizes, their physical and chemical commonality allow them to be loaded into a wide range of delivery vehicles. The primary biomaterials used to encapsulate genetic components were cationic lipids and polymers. Furthermore, the experiments focused particularly on effective transfection in target cells.Recent breakthroughs in NP-based RNA therapeutics have spurred a flood of clinical research, facing many challenges. In vivo, pharmacokinetics of different RNA-based medications must be researched to establish the viability and therapeutic potential of nucleic acid-based therapeutics. The U.S. Food and Drug Administration recently authorized many NP-based gene therapy. In 2019, Novartis authorized Zolgensma (onasemnogene abeparvovec-xioi) to treat spinal muscle atrophy. The first clinical research employing siRNA began in 2004 and is considered a milestone in nucleic acid-based drug development. Thirty clinical investigations have subsequently been completed. In 2018, the US FDA cleared Onpattro (Patisiran, Alnylam Pharmaceuticals) for the treatment of polyneuropathy caused by transthyretin amyloidosis.Several new generations of nucleic acid compositions employing polymer nanoparticles or liposomes are presently undergoing clinical testing. If allowed, the debut of nucleic acid-based treatments would represent a watershed event in immunotherapy. Advances in the design and development of biocompatible nanomaterials would allow us to overcome the above-mentioned problems and so show the potential to deliver nucleic acids in the treatment of a number of illnesses.

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Redox-Sensitive Nanocomplex for Targeted Delivery of Melittin

Toxins ◽

10.3390/toxins12090582 ◽

2020 ◽

Vol 12 (9) ◽

pp. 582 ◽

Cited By ~ 1

Author(s):

Bei Cheng ◽

Peisheng Xu

Keyword(s):

Cancer Therapy ◽

Targeted Delivery ◽

Cell Permeability ◽

Peptide Drug ◽

New Approach ◽

The Poor ◽

Poor Stability ◽

Target Effects

Although peptide therapeutics have been explored for decades, the successful delivery of potent peptides in vitro and in vivo remains challenging due to the poor stability, low cell permeability, and off-target effects. We developed a redox sensitive polymer-based nanocomplex which can efficiently and stably deliver the peptide drug melittin for cancer therapy. The nanocomplex selectively targets cancer cells through lactobionic acid mediated endocytosis and releases melittin intracellularly upon the trigger of elevated redox potential. In vivo study proved that the targeted nanocomplex shows excellent potency in inhibiting tumor growth in a xenograft colon cancer mouse model. Thus, the polymer/melittin nanocomplexes will provide a new approach for melittin based cancer therapy.

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A Novel Approach to Anticancer Therapy: Molecular Modules Based on the Barnase:Barstar Pair for Targeted Delivery of HSP70 to Tumor Cells

Acta Naturae ◽

10.32607/20758251-2018-10-3-85-91 ◽

2018 ◽

Vol 10 (3) ◽

pp. 85-91 ◽

Cited By ~ 3

Author(s):

A. M. Sapozhnikov ◽

A. V. Klinkova ◽

O. A. Shustova ◽

M. V. Grechikhina ◽

M. S. Kilyachus ◽

...

Keyword(s):

Immune System ◽

Cancer Cells ◽

Tumor Cells ◽

Targeted Delivery ◽

Important Distinction ◽

Tumor Tissues ◽

Wide Range ◽

Antitumor Immunotherapy ◽

Surface Localization

One important distinction between many tumor cell types and normal cells consists in the translocation of a number of intracellular proteins, in particular the 70 kDa heat shock protein (HSP70), to the surface of the plasma membrane. It has been demonstrated that such surface localization of HSP70 on tumor cells is recognized by cytotoxic effectors of the immune system, which increases their cytolytic activity. The mechanisms behind this interaction are not fully clear; however, the phenomenon of surface localization of HSP70 on cancer cells can be used to develop new approaches to antitumor immunotherapy. At the same time, it is known that the presence of HSP70 on a cells surface is not a universal feature of cancer cells. Many types of tumor tissues do not express membrane-associated HSP70, which limits the clinical potential of these approaches. In this context, targeted delivery of exogenous HSP70 to the surface of cancer cells with the aim of attracting and activating the cytotoxic effectors of the immune system can be considered a promising means of antitumor immunotherapy. Molecular constructs containing recombinant mini-antibodies specific to tumor-associated antigens (in particular, antibodies specific to HER2/neu-antigen and other markers highly expressed on the surface of a wide range of cancer cells) can be used to target the delivery of HSP70 to tumor tissues. In order to assess the feasibility and effectiveness of this approach, recombinant constructs containing a mini-antibody specific to the HER2/ neu-antigen in the first module and HSP70 molecule or a fragment of this protein in the second module were developed in this study. Strong selective interaction between the modules was ensured by a cohesive unit formed by the barnase:barstar pair, a heterodimer characterized by an unusually high constant of association. During testing of the developed constructs in in vitro models the constructs exhibited targeted binding to tumor cells expressing the HER2/neu antigen and the agents had a significant stimulating effect on the cytotoxic activity of NK cells against the respective cancer cells.

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Magnetic Alginate / Chitosan Nanoparticles for Targeted Delivery of Curcumin into Human Breast Cancer Cells

10.20944/preprints201809.0558.v1 ◽

2018 ◽

Author(s):

Wenxing Song ◽

Xing Su ◽

David Gregory ◽

Wei Li ◽

Zhiqiang Cai ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Cancer Cells ◽

Targeted Delivery ◽

Breast Cancer Cells ◽

Chitosan Nanoparticles ◽

Cancer Drug ◽

Uptake Efficiency ◽

Anti Cancer ◽

Hdf Cells

Curcumin is a promising anti-cancer drug but its applications in cancer therapy are limited due to its poor solubility, short half-life and low bioavailability. In this study, curcumin loaded magnetic alginate / chitosan nanoparticles were fabricated to improve the bioavailability, uptake efficiency and cytotoxicity of curcumin to MDA-MB-231 breast cancer cells. Alginate and chitosan were deposited on Fe3O4 magnetic nanoparticles based on their electrostatic properties. The sizes of the nanoparticles (120-200 nm) were within the optimum range for drug delivery. Sustained curcumin release was obtained use the nanoparticles with the ability to control the curcumin release rate by altering the number of chitosan and alginate layers. Confocal fluorescence microscopy results showed that targeted delivery of curcumin with the aid of magnetic field were achieved. The FACS assay indicated that MDA-MB-231 cells treated with curcumin loaded nanoparticles had a 3-6 folds uptake efficiency to those treated with free curcumin. MTT assay indicated that the curcumin loaded nanoparticles exhibited significantly higher cytotoxicity toward MDA-MB-231 cells than toward HDF cells. The sustained release profiles, enhanced uptake efficiency and cytotoxicity to cancer cells as well as the targeting potential make MACPs a promising candidate for cancer therapy.

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Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

Cancers ◽

10.3390/cancers12040806 ◽

2020 ◽

Vol 12 (4) ◽

pp. 806 ◽

Cited By ~ 1

Author(s):

Irina V Alekseenko ◽

Igor P Chernov ◽

Sergei V Kostrov ◽

Eugene D Sverdlov

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Immune Cells ◽

Membrane Surface ◽

Target Cells ◽

Cancer Associated Fibroblasts ◽

Paradigm Change ◽

Cancer Antigens ◽

Immunological Synapses ◽

Therapeutic Possibilities

The failure of therapies directed at targets within cancer cells highlight the necessity for a paradigm change in cancer therapy. The attention of researchers has shifted towards the disruption of cancer cell interactions with the tumor microenvironment. A typical example of such a disruption is the immune checkpoint cancer therapy that disrupts interactions between the immune and the cancer cells. The interaction of cancer antigens with T cells occurs in the immunological synapses. This is characterized by several special features, i.e., the proximity of the immune cells and their target cells, strong intercellular adhesion, and secretion of signaling cytokines into the intercellular cleft. Earlier, we hypothesized that the cancer-associated fibroblasts interacting with cancer cells through a synapse-like adhesion might play an important role in cancer tumors. Studies of the interactions between cancer cells and cancer-associated fibroblasts showed that their clusterization on the membrane surface determined their strength and specificity. The hundreds of interacting pairs are involved in the binding that may indicate the formation of synapse-like structures. These interactions may be responsible for successful metastasis of cancer cells, and their identification and disruption may open new therapeutic possibilities.

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Modeling, Fabrication, and Testing of a Nanoinjection Lance Array for Simultaneous Multi-Cell Injections

Volume 5: 6th International Conference on Micro- and Nanosystems; 17th Design for Manufacturing and the Life Cycle Conference ◽

10.1115/detc2012-70471 ◽

2012 ◽

Author(s):

Nathan C. Toone ◽

Gregory H. Teichert ◽

Steven J. Brewer ◽

Brian D. Jensen

Keyword(s):

Cell Viability ◽

Cancer Cells ◽

Computer Model ◽

Genetic Research ◽

Genetic Material ◽

High Cell ◽

Unique Combination ◽

Wide Range ◽

Anisotropic Etch

A nanoinjection lance array has been developed to inject foreign genetic material into thousands of cells at once using electrophoresis to attract and repel particles to and from the lances. A unique combination of isotropic and anisotropic etch processes are used to fabricate the four million 1 μm by 8 μm solid lances on a 2 cm by 2 cm chip. Initial studies show high cell viability when the lance array is used to pierce through a culture of HeLa cancer cells, often used for genetic research. A mathematical computer model simulating motion of attracted or repelled particles informs the design of the nanoinjection lance array system. The nanoinjection lance array provides an efficient, convenient, and quick way to simultaneously inject thousands of cells for a wide range of genetic research applications.

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HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells

Cells ◽

10.3390/cells10092371 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2371

Author(s):

Shen-Han Lee ◽

Monika Golinska ◽

John R. Griffiths

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Clinical Investigation ◽

Resistance Mechanisms ◽

Metabolic Adaptation ◽

Aryl Hydrocarbon ◽

Spatial Reorganization ◽

Amp Activated Protein Kinase ◽

Future Work ◽

Target Effects

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

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