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Pharmaceutics
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Cancer Gene Therapy With Non-Viral Nanocarriers
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Cancer Gene Therapy With Non-Viral Nanocarriers

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 23590

Special Issue Editors

Dr. Sophia Hatziantoniou

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Guest Editor
Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece
Interests: nanotechnology; liposomes; nanoemulsion; model lipid membranes; drug targeting
Special Issues, Collections and Topics in MDPI journals
Dr. Eleftheria Galatou

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Guest Editor
Department of Life and Health Sciences, School of Science and Engineering, University of Nicosia, 2417 Nicosia, Cyprus
Interests: molecular pharmacology/biology; gene therapy; clinical pharmacology; toxicology; determination of molecular mechanisms of cardiovascular and metabolic diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Elena Mourelatou

E-Mail Website
Guest Editor
Department of Life & Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
Interests: pharmaceutical technology; nanotechnology; gene delivery; liposomes, nanocarrier development and characterization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is affecting millions of people worldwide and is considered to be one of the leading causes of death in the world. Conventional therapies for cancer include surgery, radiotherapy and chemotherapy but often cause severe side effects to patients due to the lack of specificity. As a result, new therapeutic treatments are needed with improved efficacy and reduced toxicity. One of these is gene therapy, which aims at delivering genetic material to cancer cells in order to reduce or eliminate a tumor, or repair errors that cause cells to become cancerous in an attempt to reverse their state. Various different gene therapy approaches are used for cancer treatment, including the replacement/correction of missing or defective genes to suppress tumor formation, modulation of the immune system to recognize cancer cells, silencing of oncogenes to suppress the formation or spreading of cancer, use of suicide genes that cause the self- destruction of cancer cells, use of antiogenetic genes for preventing tumor blood vessels to form, use of genes that increase the sensitivity of cancer cells to conventional therapies or protect healthy cells from them. The successful implementation of gene therapy needs carriers that can protect the genetic material and efficiently deliver it (alone or in combination with conventional therapeutics) specifically to cancer cells. Various delivery systems have been developed and studied, including viral vectors and non-viral systems, such as lipoplexes, polyplexes and inorganic nanoparticles. Non-viral vectors present various advantages such as their safety, low cost, ability to carry larger genetic materials and be designed with specific properties.

In this Special Issue of Pharmaceutics, we invite researchers to submit original research articles focusing on novel gene delivery strategies for cancer treatment using non-viral nanocarriers, that can include new genes or gene/conventional therapeutics combinations delivered with non-viral nanocarriers or new non-viral nanocarriers. Review articles on the latest advancements made in above-mentioned areas are also welcome.

Dr. Elena Mourelatou
Prof. Dr. Sophia Hatziantoniou
Dr. Eleftheria Galatou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nanocarriers
  • gene delivery
  • lipoplexes
  • polyplexes
  • non-viral vectors
  • cancer therapy
  • transfection

Related Special Issue

Published Papers (7 papers)

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Research

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13 pages, 2039 KiB  
Article
Non-Covalent Linkage of Helper Functions to Dumbbell-Shaped DNA Vectors for Targeted Delivery
by Pei She Loh and Volker Patzel
Pharmaceutics 2023, 15(2), 370; https://doi.org/10.3390/pharmaceutics15020370 - 21 Jan 2023
Cited by 1 | Viewed by 2228
Abstract
Covalently closed dumbbell-shaped DNA delivery vectors comprising the double-stranded gene(s) of interest and single-stranded hairpin loops on both ends represent a safe, stable and efficacious alternative to viral and other non-viral DNA-based vector systems. As opposed to plasmids and DNA minicircles, dumbbells can [...] Read more.
Covalently closed dumbbell-shaped DNA delivery vectors comprising the double-stranded gene(s) of interest and single-stranded hairpin loops on both ends represent a safe, stable and efficacious alternative to viral and other non-viral DNA-based vector systems. As opposed to plasmids and DNA minicircles, dumbbells can be conjugated via the loops with helper functions for targeted delivery or imaging. Here, we investigated the non-covalent linkage of tri-antennary N-acetylgalactosamine (GalNAc3) or a homodimer of a CD137/4-1BB-binding aptamer (aptCD137-2) to extended dumbbell vector loops via complementary oligonucleotides for targeted delivery into hepatocytes or nasopharyngeal cancer cells. Enlarging the dumbbell loop size from 4 to 71 nucleotides for conjugation did not impair gene expression. GalNAc3 and aptCD137-2 residues were successfully attached to the extended dumbbell loop via complementary oligonucleotides. DNA and RNA oligonucleotide-based dumbbell-GalNAc3 conjugates were taken up from the cell culture medium by hepatoblastoma-derived human tissue culture cells (HepG2) with comparable efficiency. RNA oligonucleotide-linked conjugates triggered slightly higher levels of gene expression, presumably due to the RNaseH-mediated linker cleavage, the release of the dumbbell from the GalNAc3 residue and more efficient nuclear targeting of the unconjugated dumbbell DNA. The RNaseH-triggered RNA linker cleavage was confirmed in vitro. Finally, we featured dumbbell vectors expressing liver cancer cell-specific RNA trans-splicing-based suicide RNAs with GalNAc3 residues. Dumbbells conjugated with two GalNAc3 residues triggered significant levels of cell death when added to the cell culture medium. Dumbbell vector conjugates can be explored for targeted delivery and gene therapeutic applications. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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22 pages, 3303 KiB  
Article
Development of WRAP5 Peptide Complexes for Targeted Drug/Gene Co-Delivery toward Glioblastoma Therapy
by Ana Raquel Neves, Tânia Albuquerque, Rúben Faria, Ana M. Gonçalves, Cecília Santos, Eric Vivès, Prisca Boisguérin, Luís A. Passarinha, Ângela Sousa and Diana Costa
Pharmaceutics 2022, 14(10), 2213; https://doi.org/10.3390/pharmaceutics14102213 - 18 Oct 2022
Cited by 4 | Viewed by 1947
Abstract
Despite the great progress over the past few decades in both the diagnosis and treatment of a great variety of human cancers, glioblastoma remains the most lethal brain tumor. In recent years, cancer gene therapy focused on non-viral vectors which emerged as a [...] Read more.
Despite the great progress over the past few decades in both the diagnosis and treatment of a great variety of human cancers, glioblastoma remains the most lethal brain tumor. In recent years, cancer gene therapy focused on non-viral vectors which emerged as a promising approach to glioblastoma treatment. Transferrin (Tf) easily penetrates brain cells of the blood–brain barrier, and its receptor is highly expressed in this barrier and glioblastoma cells. Therefore, the development of delivery systems containing Tf appears as a reliable strategy to improve their brain cells targeting ability and cellular uptake. In this work, a cell-penetrating peptide (WRAP5), bearing a Tf-targeting sequence, has been exploited to condense tumor suppressor p53-encoding plasmid DNA (pDNA) for the development of nanocomplexes. To increase the functionality of developed nanocomplexes, the drug Temozolomide (TMZ) was also incorporated into the formulations. The physicochemical properties of peptide/pDNA complexes were revealed to be dependent on the nitrogen to phosphate groups ratio and can be optimized to promote efficient cellular internalization. A confocal microscopy study showed the capacity of developed complexes for efficient glioblastoma cell transfection and consequent pDNA delivery into the nucleus, where efficient gene expression took place, followed by p53 protein production. Of promise, these peptide/pDNA complexes induced a significant decrease in the viability of glioblastoma cells. The set of data reported significantly support further in vitro research to evaluate the therapeutic potential of developed complexes against glioblastoma. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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20 pages, 5766 KiB  
Article
Histidine-Tagged Folate-Targeted Gold Nanoparticles for Enhanced Transgene Expression in Breast Cancer Cells In Vitro
by Calrin Joseph, Aliscia Daniels, Sooboo Singh and Moganavelli Singh
Pharmaceutics 2022, 14(1), 53; https://doi.org/10.3390/pharmaceutics14010053 - 27 Dec 2021
Cited by 21 | Viewed by 3204
Abstract
Nanotechnology has emerged as a promising treatment strategy in gene therapy, especially against diseases such as cancer. Gold nanoparticles (AuNPs) are regarded as favorable gene delivery vehicles due to their low toxicity, ease of synthesis and ability to be functionalized. This study aimed [...] Read more.
Nanotechnology has emerged as a promising treatment strategy in gene therapy, especially against diseases such as cancer. Gold nanoparticles (AuNPs) are regarded as favorable gene delivery vehicles due to their low toxicity, ease of synthesis and ability to be functionalized. This study aimed to prepare functionalized AuNPs (FAuNPs) and evaluate their folate-targeted and nontargeted pCMV-Luc-DNA delivery in breast cancer cells in vitro. CS was added to induce stability and positive charges to the AuNPs (Au-CS), histidine (Au-CS-His) to enhance endosomal escape and folic acid for folate-receptor targeting (Au-CS-FA-His). The FAuNP:pDNA nanocomplexes possessed favorable sizes (<135 nm) and zeta potentials (<−20 mV), strong compaction efficiency and were capable of pDNA protection against nuclease degradation. These nanocomplexes showed minimal cytotoxicity (>73% cell viability) and enhanced transgene activity. The influence of His was notable in the HER2 overexpressing SKBR3 cells, which produced higher gene expression. Furthermore, the FA-targeted nanocomplexes enhanced receptor-mediated endocytosis, especially in MCF-7 cells, as confirmed by the receptor competition assay. While the role of His may need further optimization, the results achieved suggest that these FAuNPs may be suitable gene delivery vehicles for breast cancer therapeutics. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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18 pages, 5849 KiB  
Article
Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery
by Xiaolin Yu, Lu Xue, Jing Zhao, Shuhua Zhao, Daqing Wu and Hong Yan Liu
Pharmaceutics 2021, 13(12), 2182; https://doi.org/10.3390/pharmaceutics13122182 - 17 Dec 2021
Cited by 5 | Viewed by 2609
Abstract
Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, [...] Read more.
Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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Review

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31 pages, 1569 KiB  
Review
Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy
by Yusi Wang, Rui Zhang, Lin Tang and Li Yang
Pharmaceutics 2022, 14(3), 512; https://doi.org/10.3390/pharmaceutics14030512 - 25 Feb 2022
Cited by 20 | Viewed by 4836
Abstract
In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in [...] Read more.
In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in 2019, the development of engineered mRNA and mRNA vaccines has accelerated rapidly. mRNA is easy to produce, scalable, modifiable, and not integrated into the host genome, showing tremendous potential for cancer gene therapy and immunotherapy when used in combination with traditional strategies. The core mechanism of mRNA therapy is vehicle-based delivery of in vitro transcribed mRNA (IVT mRNA), which is large, negatively charged, and easily degradable, into the cytoplasm and subsequent expression of the corresponding proteins. However, effectively delivering mRNA into cells and successfully activating the immune response are the keys to the clinical transformation of mRNA therapy. In this review, we focus on nonviral nanodelivery systems of mRNA vaccines used for cancer gene therapy and immunotherapy. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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16 pages, 3643 KiB  
Review
Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics
by Eun-Jeong Won, Hyeji Park, Tae-Jong Yoon and Young-Seok Cho
Pharmaceutics 2022, 14(1), 137; https://doi.org/10.3390/pharmaceutics14010137 - 06 Jan 2022
Cited by 4 | Viewed by 2729
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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25 pages, 926 KiB  
Review
Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment
by Anita Bakrania, Gang Zheng and Mamatha Bhat
Pharmaceutics 2022, 14(1), 41; https://doi.org/10.3390/pharmaceutics14010041 - 25 Dec 2021
Cited by 24 | Viewed by 4803
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2–9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with [...] Read more.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2–9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years. Full article
(This article belongs to the Special Issue Cancer Gene Therapy With Non-Viral Nanocarriers)
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