Gene Therapy in Cancer Treatment: Why Go Nano?
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pharmaceutics Review Gene Therapy in Cancer Treatment: Why Go Nano? Catarina Roma-Rodrigues 1 , Lorenzo Rivas-García 1,2 , Pedro V. Baptista 1,* and Alexandra R. Fernandes 1,* 1 UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Campus de Caparica, 2829-516 Caparica, Portugal; [email protected] (C.R.-R.); [email protected] (L.R.-G.) 2 Biomedical Research Centre, Institute of Nutrition and Food Technology, Department of Physiology, Faculty of Pharmacy, University of Granada, Avda. del Conocimiento s/n. 18071 Armilla, Granada, Spain * Correspondence: [email protected] (P.V.B.); [email protected] (A.R.F.); Tel.: +351-212-948-530 (P.V.B. & A.R.F.) Received: 29 January 2020; Accepted: 3 March 2020; Published: 5 March 2020 Abstract: The proposal of gene therapy to tackle cancer development has been instrumental for the development of novel approaches and strategies to fight this disease, but the efficacy of the proposed strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference, gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical development and their progress towards clinical applications. Keywords: gene therapy; gene delivery; tumor microenvironment; nanoparticles; nanomedicine 1. Introduction According to the World Health Organization, cancer is the second leading cause of death worldwide, accounting for 9.6 million deaths in 2018 [1]. The global efforts in cancer prevention, early diagnosis, screening and treatment, have been challenged by the complexity and variability of tumors (reviewed in [2]). The genomic instability of tumor cells and a pro-inflammatory environment are key factors for tumor growth [3]. Regardless of the monoclonal origin of the neoplasia, the interplay between tumor cells and the surrounding environment results in a complex tumor microenvironment (TME) that supports tumor intra-heterogeneity, with spatially different and phenotypically distinct subclones [2]. Nonetheless, major common features of tumor cells include continuous proliferative signaling, evasion of growth suppressors, resisting cell death, replicative immortality, deregulating cellular energetics, promoting angiogenesis, activating invasion and metastasis, and avoiding immune destruction [3]. These features sustain the foundation of a TME composed by a characteristic extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells, endothelial cells and pericytes, and immune system cells, such as macrophages, T and B lymphocytes and natural killer cells (reviewed in [4]). TME composition dictates tumor progression, chemotherapeutic efficacy and prognosis [5–7]. The mounting knowledge on the characteristics of tumor cells and surrounding TME have sparked the use of gene therapy to tackle cancer molecular mechanisms. Gene therapy consists of the introduction of exogenous nucleic acids, such as genes, gene segments, oligonucleotides, miRNAs or siRNAs into cells envisaging a target gene edition, expression modulation of a target gene, mRNA or synthesis of an exogenous protein [8–19]. Gene transfer into tumor cells has been demonstrated via administration of therapeutic nucleic acids (TNAs) ex vivo and/or in vivo (Figure1)[ 20]. In the Pharmaceutics 2020, 12, 233; doi:10.3390/pharmaceutics12030233 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 233 2 of 34 Pharmaceutics 2019, 11, x 2 of 36 ex vivo approach, patient-derived tumor cells are collected, propagated usually as 2D monolayers, manipulatedadministration genetically of therapeutic and then nucleic introduced acids (TNAs) back intoex vivo the and/or host [20 in]. vivo In the(Figurein vivo 1) [20].approach, In the ex TNAs mayvivo be introduced approach, patient-derivedin loco into the tumor tumor cells cells, are systemically collected, propagated via intravenous usually administration,as 2D monolayers, or in a pre-systemicmanipulated manner genetically through and oral,then introduced ocular, transdermal back into the or host nasal [20]. delivery In the in routes,vivo approach, depending TNAs of the specificmay localization be introduced of tumors in loco into and the disease tumor progression cells, systemically [20–22 ].via In intravenous the case of systemicadministration, and pre-systemic or in a deliveries,pre-systemic the administration manner through of naked oral, ocular, TNAs transder is hinderedmal or by nasal biological delivery barriers, routes, nuclease depending susceptibility, of the phagocytespecific uptake, localization renal of clearance tumors and and disease/or immune progre responsession [20–22]. stimulation In the case [23]. of Hence, systemic the and use pre- of stable systemic deliveries, the administration of naked TNAs is hindered by biological barriers, nuclease carriers/vectors that protect the nucleic acid cargo from circulatory nucleases, avoid the immune system, susceptibility, phagocyte uptake, renal clearance and/or immune response stimulation [23]. Hence, and ensurethe use of the stable efficient carriers/vectors targeting ofthat the protect therapeutic the nucleic vector acid intocargo the from tumor circulatory cells, withoutnucleases, dissipation avoid in thethe body immune through system, lymphatic and ensure and the bloodefficient systems targeting and of the avoiding therapeutic non-target vector into cells the istumor required cells, [21]. Despitewithout the apparent dissipation limitations in the body of through the in vivo lymphaticapproach, and blood it is less system invasives and andavoiding more non-target suitable forcells cancer treatmentis required than ex[21]. vivo Despite approaches, the apparent since limitations the latter of require the in avivo proliferative approach, it advantage is less invasive of transfected and more cells, whichsuitable is antagonist for cancer to the treatment major objectivesthan ex vivo of cancer approaches, gene therapeutics since the latter that require mainly a aims proliferative to inhibit the tumoradvantage progression of transfected by tackling cells, the which tumor is antagonist cell division to the ability major [ 21objectives,24–26]. of Nevertheless, cancer gene therapeutics it is important to highlightthat mainly the aims relevance to inhibit of exthe vivo tumor therapy progression in indirect by tackling immune the tumor gene-based cell division therapies ability (detailed[21,24– in Section26]. 2.7 Nevertheless,). In these itex-vivo is importantapproaches, to highlight immune the relevance cells are of collected ex vivo therapy from the in indirect patient’s immune blood and gene-based therapies (detailed in Section 2.7). In these ex-vivo approaches, immune cells are collected genetically engineered to tackle the tumor cells (reviewed in [27,28]). from the patient’s blood and genetically engineered to tackle the tumor cells (reviewed in [27,28]). FigureFigure 1. 1.Delivery Delivery strategies strategies usedused for gene therap therapyy directly directly targeting targeting tumor tumor cells cellsor tumor or tumor microenvironment components, their major advantages (preceded by a green checkmark) and microenvironment components, their major advantages (preceded by a green checkmark) and disadvantages (preceded by a red cross). disadvantages (preceded by a red cross). The success of cancer gene therapy relies on a safe, effective and controllable vector [25]. Viral The success of cancer gene therapy relies on a safe, effective and controllable vector [25]. Viral vectors were the first platform proposed for gene therapy [29]. Indeed, the nature and properties of vectorsviruses were made the firstthem platform tempting proposed vectors for for RNA gene and therapy DNA [delivery29]. Indeed, to human the nature cells, with and propertiesmultiple of virusesclinical made trials them that tempting ended-up vectors in clinical for RNA approved and DNA of some delivery gene totherapy human drugs cells, (reviewed with multiple in [29]). clinical trialsHowever, that ended-up the immunogenicity, in clinical approved limited ofgenetic-load, some gene ca therapyncer risk drugsdue to (reviewedtherapeutic in payload [29]). However,insertion the immunogenicity,near genes that limited control genetic-load, cell growth, and cancer constrai riskned due mass-production to therapeutic payload of viral vectors insertion prompted near genes the that controldevelopment cell growth, and and engineering constrained of non-viral mass-production vectors, supported of viral by vectors nanomedicine prompted [25,30]. the development and engineering of non-viral vectors, supported by nanomedicine [25,30]. Pharmaceutics 2020, 12, 233 3 of 34 NanotechnologyPharmaceutics 2019, 11, refersx to the area of science focused on the study of the synthesis, characterization3 of 36 and application of materials and functional systems of particles whose size is between 1-100 nm [31,32]. Nanotechnology refers to the area of science focused on the study of the synthesis, Nowadays,characterization