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Pharmaceutics
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Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy
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Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (10 March 2022) | Viewed by 17449

Special Issue Editors

Prof. Dr. Daisuke Ishibashi

E-Mail
Guest Editor
Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma Jonan-ku, Fukuoka, Japan
Interests: prion; neuron; brain-delivery; in silico screening; immunotherapetics; in vivo model; protein aggregation; type I interferon; infection
Dr. Mai Hazekawa

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Guest Editor
Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma Jonan-ku, Fukuoka, Japan
Interests: siRNA; exosome; micelles; plga; cancer; metastasis; nanoparticles; drug delivery system; zebrafish

Special Issue Information

Dear Colleagues,

Nucleic acid medicines, including antisense oligonucleotides, small interfering RNA (siRNA), aptamers, and locked nucleic acids, have the potential to therapeutically regulate gene expressions. In recent years, new drugs for genetic diseases have been developed and are attracting a great deal of attention. However, these strategies are limited to treating localized diseases so far. That is why further development of drug delivery systems (DDSs) is essential for the clinical application of nucleic acid medicine to apply cancer treatment.

To address this challenging issue, we focus on development of DDSs to deliver siRNA for cancer therapy, and we will clarify the usefulness of cancer treatment by target gene regulation using nucleic acid medicine designed by functional nanocarrier.

This Special Issue will highlight the development of DDSs using functional nanocarriers to deliver siRNA for cancer therapy. We also expect to discuss the possibility of developing novel nanocarrier design with added value to conventional technology.

Prof. Dr. Daisuke Ishibashi
Dr. Mai Hazekawa
Guest Editors

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Keywords

  • nanocarrier
  • nanoparticles
  • small interfering RNA
  • gene silencing
  • cancer
  • drug delivery system
  • targeting
  • exosomes
  • micelles
  • zebrafish

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Published Papers (5 papers)

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Research

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14 pages, 2902 KiB  
Article
Development of an Organ-Directed Exosome-Based siRNA-Carrier Derived from Autologous Serum for Lung Metastases and Testing in the B16/BL6 Spontaneous Lung Metastasis Model
by Mai Hazekawa, Takuya Nishinakagawa, Masato Hosokawa and Daisuke Ishibashi
Pharmaceutics 2022, 14(4), 815; https://doi.org/10.3390/pharmaceutics14040815 - 7 Apr 2022
Cited by 4 | Viewed by 2540
Abstract
Exosomes are nano-sized extracellular vesicles that are known to carry various messages to distant cells. It was recently reported that cancer-derived exosomes are orientated to metastatic organs. However, there are no reports on drug carrier development using autologous serum-derived exosomes in vivo. The [...] Read more.
Exosomes are nano-sized extracellular vesicles that are known to carry various messages to distant cells. It was recently reported that cancer-derived exosomes are orientated to metastatic organs. However, there are no reports on drug carrier development using autologous serum-derived exosomes in vivo. The purpose of this study was to deliver therapeutic siRNAs for melanoma lung metastases using autologous serum-derived exosomes. Primary tumors were induced by subcutaneously injecting melanoma cells into the hindlimbs of female C57BL/6 mice. Primary tumors were surgically removed on day 14. On day 21 after tumor removal, lung metastases were evaluated. Exosomes were isolated from serum collected from mice on days 0, 3, 7, 10, and 14 after primary tumor inoculation. After isolating serum exosomes, siRNA-loaded exosomes were prepared. siRNA-loaded exosomes were intravenously injected into the B16/BL6 spontaneous lung metastasis model mice on days 0, 3, 7, and 10 after tumor removal. siRNA-loaded exosomes prepared with autologous serum-derived exosomes significantly decreased the number of metastatic lung colonies. Autologous serum-derived exosomes, which have high organ accumulation, could potentially be used as efficient carriers of therapeutic siRNAs for melanoma patients with lung metastases. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
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19 pages, 4732 KiB  
Article
Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy
by Maria Arista-Romero, Anna Cascante, Cristina Fornaguera and Salvador Borrós
Pharmaceutics 2021, 13(11), 1959; https://doi.org/10.3390/pharmaceutics13111959 - 19 Nov 2021
Cited by 5 | Viewed by 2585
Abstract
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, [...] Read more.
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
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19 pages, 26469 KiB  
Article
Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia
by Patrick Connerty, Ernest Moles, Charles E. de Bock, Nisitha Jayatilleke, Jenny L. Smith, Soheil Meshinchi, Chelsea Mayoh, Maria Kavallaris and Richard B. Lock
Pharmaceutics 2021, 13(10), 1681; https://doi.org/10.3390/pharmaceutics13101681 - 14 Oct 2021
Cited by 33 | Viewed by 4856
Abstract
Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly [...] Read more.
Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered ‘undruggable’ targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8;21) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤ 0.22 along with a >85% siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells (>95% of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
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10 pages, 1244 KiB  
Article
In Vivo Follow-Up of Gene Inhibition in Solid Tumors Using Peptide-Based Nanoparticles for siRNA Delivery
by Isabel Ferreiro, Coralie Genevois, Karidia Konate, Eric Vivès, Prisca Boisguérin, Sébastien Deshayes and Franck Couillaud
Pharmaceutics 2021, 13(5), 749; https://doi.org/10.3390/pharmaceutics13050749 - 19 May 2021
Cited by 7 | Viewed by 3633
Abstract
Small interfering RNA (siRNA) exhibits a high degree of specificity for targeting selected genes. They are efficient on cells in vitro, but in vivo siRNA therapy remains a challenge for solid tumor treatment as siRNAs display difficulty reaching their intracellular target. The present [...] Read more.
Small interfering RNA (siRNA) exhibits a high degree of specificity for targeting selected genes. They are efficient on cells in vitro, but in vivo siRNA therapy remains a challenge for solid tumor treatment as siRNAs display difficulty reaching their intracellular target. The present study was designed to show the in vivo efficiency of a new peptide (WRAP5), able to form peptide-based nanoparticles (PBN) that can deliver siRNA to cancer cells in solid tumors. WRAP5:siRNA nanoparticles targeting firefly luciferase (Fluc) were formulated and assayed on Fluc-expressing U87 glioblastoma cells. The mode of action of WRAP5:siRNA by RNA interference was first confirmed in vitro and then investigated in vivo using a combination of bioluminescent reporter genes. Finally, histological analyses were performed to elucidate the cell specificity of this PBN in the context of brain tumors. In vitro and in vivo results showed efficient knock-down of Fluc expression with no toxicity. WRAP5:siFluc remained in the tumor for at least 10 days in vivo. Messenger RNA (mRNA) analyses indicated a specific decrease in Fluc mRNA without affecting tumor growth. Histological studies identified PBN accumulation in the cytoplasm of tumor cells but also in glial and neuronal cells. Through in vivo molecular imaging, our findings established the proof of concept for specific gene silencing in solid tumors. The evidence generated could be translated into therapy for any specific gene in different types of tumors without cell type specificity but with high molecular specificity. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
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Review

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18 pages, 2299 KiB  
Review
Nanotechnology-Based siRNA Delivery Systems to Overcome Tumor Immune Evasion in Cancer Immunotherapy
by Kaili Deng, Dongxue Yang and Yuping Zhou
Pharmaceutics 2022, 14(7), 1344; https://doi.org/10.3390/pharmaceutics14071344 - 25 Jun 2022
Cited by 11 | Viewed by 2980
Abstract
Immune evasion is a common reason causing the failure of anticancer immune therapy. Small interfering RNA (siRNA), which can activate the innate and adaptive immune system responses by silencing immune-relevant genes, have been demonstrated to be a powerful tool for preventing or reversing [...] Read more.
Immune evasion is a common reason causing the failure of anticancer immune therapy. Small interfering RNA (siRNA), which can activate the innate and adaptive immune system responses by silencing immune-relevant genes, have been demonstrated to be a powerful tool for preventing or reversing immune evasion. However, siRNAs show poor stability in biological fluids and cannot efficiently cross cell membranes. Nanotechnology has shown great potential for intracellular siRNA delivery in recent years. Nano-immunotherapy can efficiently penetrate the tumor microenvironment (TME) and deliver multiple immunomodulatory agents simultaneously, which appears to be a promising method for combination therapy. Therefore, it provides a new perspective for siRNA delivery in immunomodulation and cancer immunotherapy. The current advances and challenges in nanotechnology-based siRNA delivery strategies for overcoming immune evasion will be discussed in this review. In addition, we also offer insights into therapeutic options, which may expand its applications in clinical cancer treatment. Full article
(This article belongs to the Special Issue Functional Nanocarrier Technology to Deliver siRNA for Cancer Therapy)
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