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Pharmaceutics
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Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges
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Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 15757

Special Issue Editor

Dr. Krizia Sagini

E-Mail Website
Guest Editor
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
Interests: exosome; extracellular vesicles; prostate cancer; biomarkers; autophagy; lysosomes; senescence

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are cell-derived lipid bilayer membrane particles that represent an additional mechanism for cell-to-cell communication. EV composition (proteins, nucleic acids, lipids and metabolites) mimics one of the cells of origin and, for this reason, has been studied as possible biomarkers for different diseases. Moreover, since discovering that EVs play a wide range of tumor-related processes and have the endogenous ability to protect their encapsulated material from the extracellular environment, overcome natural barriers, intrinsic cell targeting properties and circulation stability, the potential use of EVs as therapeutic nanoplatforms for cancer studies and drug delivery has attracted considerable interest.

Despite multiple advantages, the application of EVs for anticancer therapy has been limited by technical issues, such as obtaining large-scale standardized preparations and relatively low loading of the desired bioagents. As such, many approaches have been explored for mass production and for incorporating a substantial number of nucleic acids and small biomolecules into EVs.

This Special Issue aims to collect the latest advanced studies of EVs in diagnosing and treating cancer diseases, sharing knowledge and data with readers and scientists working in this discipline to foster an effective and safe clinical translation of these unique intercellular delivery vehicles.

Dr. Krizia Sagini
Guest Editor

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

  • extracellular vesicles
  • drug delivery
  • targeted cancer therapy
  • cancer biomarkers
  • nanomedicine
  • exosome-mimetic

Published Papers (7 papers)

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Research

Jump to: Review

27 pages, 9759 KiB  
Article
Dendritic Cell-Derived Artificial Microvesicles Inhibit RLS40 Lymphosarcoma Growth in Mice via Stimulation of Th1/Th17 Immune Response
by Oleg V. Markov, Aleksandra V. Sen’kova, Islam S. Mohamed, Elena V. Shmendel, Mikhail A. Maslov, Anastasiya L. Oshchepkova, Evgeniy V. Brenner, Nadezhda L. Mironova and Marina A. Zenkova
Pharmaceutics 2022, 14(11), 2542; https://doi.org/10.3390/pharmaceutics14112542 - 21 Nov 2022
Cited by 1 | Viewed by 1490
Abstract
Cell-free antitumor vaccines represent a promising approach to immunotherapy of cancer. Here, we compare the antitumor potential of cell-free vaccines based on microvesicles derived from dendritic cells (DCs) with DC- and cationic-liposome-based vaccines using a murine model of drug-resistant lymphosarcoma RLS40 in [...] Read more.
Cell-free antitumor vaccines represent a promising approach to immunotherapy of cancer. Here, we compare the antitumor potential of cell-free vaccines based on microvesicles derived from dendritic cells (DCs) with DC- and cationic-liposome-based vaccines using a murine model of drug-resistant lymphosarcoma RLS40 in vivo. The vaccines were the following: microvesicle vaccines—cytochalasin B-induced membrane vesicles (CIMVs) obtained from DCs loaded with total tumor RNA using cholesterol/spermine-containing cationic liposomes L or mannosylated liposomes ML; DC vaccines—murine DCs loaded with total tumor-derived RNA using the same liposomes; and liposomal vaccines—lipoplexes of total tumor-derived RNA with liposomes L or ML. Being non-hepatotoxic, CIMV- and DC-based vaccines administered subcutaneously exhibited comparable potential to stimulate highly efficient antitumor CTLs in vivo, whereas liposomal vaccines were 25% weaker CTL inducers. Nevertheless, the antitumor efficiencies of the different types of the vaccines were similar: sizes of tumor nodes and the number of liver metastases were significantly decreased, regardless of the vaccine type. Notably, the booster vaccination did not improve the overall antitumor efficacy of the vaccines under the study. CIMV- and DC- based vaccines more efficiently than liposome-based ones decreased mitotic activity of tumor cells and induced their apoptosis, stimulated accumulation of neutrophil inflammatory infiltration in tumor tissue, and had a more pronounced immunomodulatory activity toward the spleen and thymus. Administration of CIMV-, DC-, and liposome-based vaccines resulted in activation of Th1/Th17 cells as well as the induction of positive immune checkpoint 4-1BBL and downregulation of suppressive immune checkpoints in a raw PD-1 >>> TIGIT > CTLA4 > TIM3. We demonstrated that cell-free CIMV-based vaccines exhibited superior antitumor and antimetastatic activity in a tumor model in vivo. The obtained results can be considered as the basis for developing novel strategies for oncoimmunotherapy. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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17 pages, 2815 KiB  
Article
Comparative Analysis of Free-Circulating and Vesicle-Associated Plasma microRNAs of Healthy Controls and Early-Stage Lung Cancer Patients
by Luigi Pasini, Ivan Vannini, Paola Ulivi, Michela Tebaldi, Elisabetta Petracci, Francesco Fabbri, Franco Stella and Milena Urbini
Pharmaceutics 2022, 14(10), 2029; https://doi.org/10.3390/pharmaceutics14102029 - 23 Sep 2022
Cited by 1 | Viewed by 1796
Abstract
In recent years, circulating extracellular miRNAs have emerged as a useful tool for the molecular characterization and study of tumors’ biological functions. However, the high heterogeneity in sample processing, isolation of circulating fraction, RNA extraction, and sequencing hamper the reproducibility and the introduction [...] Read more.
In recent years, circulating extracellular miRNAs have emerged as a useful tool for the molecular characterization and study of tumors’ biological functions. However, the high heterogeneity in sample processing, isolation of circulating fraction, RNA extraction, and sequencing hamper the reproducibility and the introduction of these biomarkers in clinical practice. In this paper, we compare the content and the performance of miRNA sequencing in plasma-derived samples processed with different isolation protocols. We tested three different fractions of miRNA from healthy-donor human blood: whole plasma (WP), free-circulating (FC) and EV-associated, isolated by either column (ccEV) or size exclusion chromatography (secEV) miRNAs. An additional cohort of 18 lung cancer patients was analyzed. Protein profiles of ccEV and secEV were compared and miRNA expression profiles were assessed through sequencing. Slight differences were found between ccEV and secEV expressions of typical EV markers. Conversely, sequencing performance and the mirnome profile varied between RNA extracted using different isolation methods. Sequencing performance was better in FC samples. Higher varieties of miRNAs were identified in WP and FC with respect to ccEV and secEV. Analysis of free-circulating and EV-associated miRNA profiles in lung cancer patients demonstrated the reliability of the biomarkers identifiable on plasma with these approaches. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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13 pages, 1969 KiB  
Article
Atorvastatin Enhances the Efficacy of Immune Checkpoint Therapy and Suppresses the Cellular and Extracellular Vesicle PD-L1
by Eun-Ji Choe, Chan-Hyeong Lee, Ju-Hyun Bae, Ju-Mi Park, Seong-Sik Park and Moon-Chang Baek
Pharmaceutics 2022, 14(8), 1660; https://doi.org/10.3390/pharmaceutics14081660 - 09 Aug 2022
Cited by 18 | Viewed by 2273
Abstract
According to clinical studies, statins improve the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy for breast cancer; however, the underlying mechanisms are unclear. Herein, we showed that atorvastatin (ATO) decreased the content of PD-L1 in extracellular vesicles (EVs) by reducing cellular [...] Read more.
According to clinical studies, statins improve the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy for breast cancer; however, the underlying mechanisms are unclear. Herein, we showed that atorvastatin (ATO) decreased the content of PD-L1 in extracellular vesicles (EVs) by reducing cellular PD-L1 expression and inhibiting EV secretion in breast cancer cells, thereby enhancing the efficacy of anti-PD-L1 therapy. ATO reduced EV secretion by regulating the Rab proteins involved in EV biogenesis and secretion. ATO-mediated inhibition of the Ras-activated MAPK signaling pathway downregulated PD-L1 expression. In addition, ATO strongly promoted antitumor efficacy by inducing T cell-mediated tumor destruction when combined with an anti-PD-L1 antibody. Moreover, suppression of EV PD-L1 by ATO improved the reactivity of anti-PD-L1 therapy by enhancing T-cell activity in draining lymph nodes of EMT6-bearing immunocompetent mice. Therefore, ATO is a potential therapeutic drug that improves antitumor immunity by inhibiting EV PD-L1, particularly in response to immune escape during cancer. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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Review

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21 pages, 2010 KiB  
Review
Polymers in Engineering Extracellular Vesicle Mimetics: Current Status and Prospective
by Xinyue Wei, Sihang Liu, Yifeng Cao, Zhen Wang and Shengfu Chen
Pharmaceutics 2023, 15(5), 1496; https://doi.org/10.3390/pharmaceutics15051496 - 14 May 2023
Cited by 3 | Viewed by 1637
Abstract
The maintenance of a high delivery efficiency by traditional nanomedicines during cancer treatment is a challenging task. As a natural mediator for short-distance intercellular communication, extracellular vesicles (EVs) have garnered significant attention owing to their low immunogenicity and high targeting ability. They can [...] Read more.
The maintenance of a high delivery efficiency by traditional nanomedicines during cancer treatment is a challenging task. As a natural mediator for short-distance intercellular communication, extracellular vesicles (EVs) have garnered significant attention owing to their low immunogenicity and high targeting ability. They can load a variety of major drugs, thus offering immense potential. In order to overcome the limitations of EVs and establish them as an ideal drug delivery system, polymer-engineered extracellular vesicle mimics (EVMs) have been developed and applied in cancer therapy. In this review, we discuss the current status of polymer-based extracellular vesicle mimics in drug delivery, and analyze their structural and functional properties based on the design of an ideal drug carrier. We anticipate that this review will facilitate a deeper understanding of the extracellular vesicular mimetic drug delivery system, and stimulate the progress and advancement of this field. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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25 pages, 774 KiB  
Review
Lipid Biomarkers in Liquid Biopsies: Novel Opportunities for Cancer Diagnosis
by Krizia Sagini, Lorena Urbanelli, Sandra Buratta, Carla Emiliani and Alicia Llorente
Pharmaceutics 2023, 15(2), 437; https://doi.org/10.3390/pharmaceutics15020437 - 28 Jan 2023
Cited by 7 | Viewed by 1879
Abstract
Altered cellular metabolism is a well-established hallmark of cancer. Although most studies have focused on the metabolism of glucose and glutamine, the upregulation of lipid metabolism is also frequent in cells undergoing oncogenic transformation. In fact, cancer cells need to meet the enhanced [...] Read more.
Altered cellular metabolism is a well-established hallmark of cancer. Although most studies have focused on the metabolism of glucose and glutamine, the upregulation of lipid metabolism is also frequent in cells undergoing oncogenic transformation. In fact, cancer cells need to meet the enhanced demand of plasma membrane synthesis and energy production to support their proliferation. Moreover, lipids are precursors of signaling molecules, termed lipid mediators, which play a role in shaping the tumor microenvironment. Recent methodological advances in lipid analysis have prompted studies aimed at investigating the whole lipid content of a sample (lipidome) to unravel the complexity of lipid changes in cancer patient biofluids. This review focuses on the application of mass spectrometry-based lipidomics for the discovery of cancer biomarkers. Here, we have summarized the main lipid alteration in cancer patients’ biofluids and uncovered their potential use for the early detection of the disease and treatment selection. We also discuss the advantages of using biofluid-derived extracellular vesicles as a platform for lipid biomarker discovery. These vesicles have a molecular signature that is a fingerprint of their originating cells. Hence, the analysis of their molecular cargo has emerged as a promising strategy for the identification of sensitive and specific biomarkers compared to the analysis of the unprocessed biofluid. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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20 pages, 1731 KiB  
Review
Extracellular Vesicles as Drug Targets and Delivery Vehicles for Cancer Therapy
by Sai V. Chitti, Christina Nedeva, Raja Manickam, Pamali Fonseka and Suresh Mathivanan
Pharmaceutics 2022, 14(12), 2822; https://doi.org/10.3390/pharmaceutics14122822 - 16 Dec 2022
Cited by 6 | Viewed by 2060
Abstract
Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved [...] Read more.
Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved in EV biogenesis and secretion are upregulated in various tumours. Recent studies have revealed that EVs facilitate the interaction between cancer cells and their microenvironment and play a substantial role in the growth of tumours. As EVs are involved in several aspects of cancer progression including angiogenesis, organotropism, pre-metastatic niche formation, fostering of metastasis, and chemoresistance, inhibiting the release of EVs from cancer and the surrounding tumour microenvironment cells has been proposed as an ideal strategy to treat cancer and associated paraneoplastic syndromes. Lately, EVs have shown immense benefits in preclinical settings as a novel drug delivery vehicle. This review provides a brief overview of the role of EVs in various hallmarks of cancer, focusing on (i) strategies to treat cancer by therapeutically targeting the release of tumour-derived EVs and (ii) EVs as valuable drug delivery vehicles. Furthermore, we also outline the drawbacks of the existing anti-cancer treatments and the future prospective of EV-based therapeutics. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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25 pages, 1724 KiB  
Review
Extracellular Vesicles as Delivery Vehicles for Therapeutic Nucleic Acids in Cancer Gene Therapy: Progress and Challenges
by Rong Du, Chen Wang, Ling Zhu and Yanlian Yang
Pharmaceutics 2022, 14(10), 2236; https://doi.org/10.3390/pharmaceutics14102236 - 19 Oct 2022
Cited by 12 | Viewed by 3742
Abstract
Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that [...] Read more.
Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that EV-loaded nucleic acids, including RNA-based nucleic acid drugs and CRISPR/Cas gene-editing systems, can alter gene expressions and functions of recipient cells for cancer gene therapy. Here in this review, we discuss the advantages and challenges of EV-based nucleic acid delivery systems in cancer therapy. We summarize the techniques and methods to increase EV yield, enhance nucleic acid loading efficiency, extend circulation time, and improve targeted delivery, as well as their applications in gene therapy and combination with other cancer therapies. Finally, we discuss the current status, challenges, and prospects of EVs as a therapeutic tool for the clinical application of nucleic acid drugs. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges)
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