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Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Daniel Bobo, Kye J. Robinson, Jiaul Islam, Kristofer J. Thurecht, Simon R. Corrie
Rexin-G® is a targeted gene therapy system in phase I/II trials. Its active targeting relies on a collagen-binding peptide from human von Willebrand factor (vWF). This protein normally induces platelet aggregation in the instance of vascular injury. In Rexin-G®, vWF serves to enhance particle deposition by guiding the whole particle into a tumor where exposed collagen is often found [62]. In contrast to previous protein nanoparticles, Rexin-G® is a mixed system that is based on the murine leukemia virus. The vWF-derived binding motif is expressed in the modified viral envelope for particle delivery. The proteinaceous envelop is responsible for nanoparticle accumulation and ultimate transfection of a cytotoxic cyclin G1 gene. This therapeutic is in phase I/II trials. Leveraging the body’s platelet activation system by using the vWF as a form of targeting general disease states is an interesting shift away from nontargeted protein nanoparticles and the cell-specific receptor targeting used in antibody-drug conjugates. As opposed to receptor-specific targeting, Rexin-G® is targeted against the general disease state characteristics found in tumor environments. Avoiding reliance on a specific receptor may avoid the confounding effects of mutation and adaptation. Rexin-G®’s proponents have stated this general targeting of invasive cancer characteristics has improved delivery of the genetic payload to where it is needed while reducing target selection of normal tissues and tumor adaptation [63].
Nanoparticles in Cancer Treatment: Types and Preparation Methods
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Jyoti Ahlawat, Emmanuel Zubia, Mahesh Narayan
Rexin-G is a retroviral based nanomedicine for the treatment of cancers such as bone, soft tissue and pancreatic cancers. The main disadvantage of this murine leukemia virus-based nanomedicine is the lack of tissue specificity [39]. It is engineered to achieve targeted delivery by attaching high-affinity collagen-binding motif on its surface. It acts by interfering with mutant cyclin G1 gene of the cell cycle in tumor cells [40]. Rexin-G was observed to inhibit tumor growth and enhance survival compared to control formulation in human tumor xenografts [41]. Interestingly, improvement in physiological conditions such as wound healing and liver function were reported. This can be attributed to the targeting of collagen by the engineered retrovirus [42].
Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
Starting 30 years ago, researchers explored the use of gene therapy to treat severe combined immunodeficiency (SCID), a disorder in which the patient’s immune system never fully develops making the person prone to acquiring life-threatening infections. Researchers focused on two forms of SCID, caused by different genes. For adenine deaminase–severe combined immunodeficiency (ADA-SCID), a retroviral vector was used to replace the defective ADA gene, using an ex vivo approach where the patient’s T cells were modified and then transplanted back into the body. It is believed that the therapy worked, but patients were receiving an enzyme-based treatment during the entire gene therapy course. Another form of SCID involving a mutation in a gene on the X chromosome (X-SCID) was also treated using a retroviral vector. However, several children in the trial developed leukemia a few years after treatment, most likely due to a viral integration event affecting cell growth regulation (Minkoff and Baker 2004; Lostroh 2019; Colavito 2007; Kurreck and Stein 2016; Anguela and High 2019; Dunbar et al. 2018). An adverse outcome was also seen with a gene therapy trial to treat a deficiency in the metabolic enzyme ornithine transcarbamylase in 1999. One patient died and the trial was halted (Lostroh 2019; Colavito 2007; Mukherjee 2016; Minkoff and Baker 2004). This tragedy prompted a period of basic research into new viral vector delivery systems and more oversight of gene therapy trials that continues to this day (Collins and Gottlieb 2019). Since that time, new technologies have been used to tackle SCID. Strimvelis is a type of gene therapy product using an updated viral vector delivery system to treat ADA-SCID patients. However, demand for this new therapy is quite low due to the small number of patients with the disease, and it is unclear how long the product will be marketed (Anguela and High 2019; Li and Samulski 2020; Aiuti, Roncarolo, and Naldini 2017; Dunbar et al. 2018). Another gene therapy product, alipogene tiparvovec, also known as Glybera, is used to treat familial lipoprotein lipase deficiency using an AAV vector. It was approved for use in Europe in 2012 (Lostroh 2019; Kurreck and Stein 2016; Wang, Tai, and Gao 2019; Li and Samulski 2020). However, the treatment is quite expensive, costing over a million dollars a treatment (Kurreck and Stein 2016). Glybera is no longer being marketed in Europe (Shahryari et al. 2019). Rexin-G is an anti-cancer gene therapy that works by blocking cell cycle progression by expressing a modified version of a gene called cyclin G using a retroviral vector. It is being tested right now in clinical trials of people with advanced pancreatic cancer (Lostroh 2019; Shahryari et al. 2019). Although the development of gene therapy treatments is a long road with many possible setbacks, several gene therapy products are approved for use in the United States right now, as described next.
Actively targeted nanocarriers for drug delivery to cancer cells
Published in Expert Opinion on Drug Delivery, 2019
Stefania Biffi, Rebecca Voltan, Barbara Bortot, Giorgio Zauli, Paola Secchiero
It is finally important to consider that nanotechnology based on active targeting hold promises for improving the rapidly expanding field of genetic medicine. More than 100 investigational new drug applications (INDs) were filed last year for gene-therapy products [115], leading to advancement on the design engineering of the biotechnology platforms used for gene therapy. Noteworthy is the clinical performance achieved by Rexin-G®, the world’s first tumor-targeted injectable gene therapy vector, which combines the enhanced selectivity for the tumor microenvironment and the toxicity of the genetic payload. The evidence that the gene delivery function of Rexin-G® remains active as it accumulates inside metastatic lesions within sentinel lymph nodes, and does not interfere with but appears to work in concert with the immune system, support the potentiality of future cancer vaccinations in situ, using this targeted gene delivery system bearing an immunomodulatory cytokine gene [116].