The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce ...therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody–drug conjugates, ...these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood–brain barrier.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
4.
Dexamethasone nanomedicines for COVID-19 Lammers, Twan; Sofias, Alexandros Marios; van der Meel, Roy ...
Nature nanotechnology,
08/2020, Volume:
15, Issue:
8
Journal Article
Peer reviewed
Open access
Nano-formulating dexamethasone, and administering it via intravenous injection or inhalation, may help to improve anti-COVID-19 treatment efficacy by targeting the potent corticosteroid drug to ...hyper-activated immune cells, by potentiating its anti-oedema activity and by exploiting its anti-fibrotic effects.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Extracellular vesicles (EVs) are membrane-derived particles surrounded by a (phospho)lipid bilayer that are released by cells in the human body. In addition to direct cell-to-cell contact and the ...secretion of soluble factors, EVs function as another mechanism of intercellular communication. These vesicles are able to efficiently deliver their parental cell-derived molecular cargo to recipient cells, which can result in structural changes at an RNA, protein, or even phenotypic level. For this reason, EVs have recently gained much interest for drug delivery purposes. In contrast to these ‘natural delivery systems’, synthetic (phospho)lipid vesicles, or liposomes, have been employed as drug carriers for decades, resulting in several approved liposomal nanomedicines used in the clinic. This review discusses the similarities and differences between EVs and liposomes with the focus on features that are relevant for drug delivery purposes such as circulation time, biodistribution, cellular interactions and cargo loading. By applying beneficial features of EVs to liposomes and vice versa, improved drug carriers can be developed which will advance the field of nanomedicines and ultimately improve patient outcomes. While the application of EVs for therapeutic drug delivery is still in its infancy, issues regarding the understanding of EV biogenesis, large-scale production and in vivo interactions need to be addressed in order to develop successful and cost-effective EV-based drug delivery systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Lipid nanoparticles (LNPs) are currently the most clinically advanced nonviral carriers for the delivery of small interfering RNA (siRNA). Free siRNA molecules suffer from unfavorable physicochemical ...characteristics and rapid clearance mechanisms, hampering the ability to reach the cytoplasm of target cells when administered intravenously. As a result, the therapeutic use of siRNA is crucially dependent on delivery strategies. LNPs can encapsulate siRNA to protect it from degradative endonucleases in the circulation, prevent kidney clearance, and provide a vehicle to deliver siRNA in the cell and induce its subsequent release into the cytoplasm. Here, the structure and composition of LNP–siRNA are described including how these affect their pharmacokinetic parameters and gene‐silencing activity. In addition, the evolution of LNP–siRNA production methods is discussed, as the development of rapid‐mixing platforms for the reproducible and scalable manufacturing has facilitated entry of LNP–siRNA into the clinic over the last decade. Finally, the potential of LNPs in delivering other nucleic acids, such as messenger RNA and CRISPR/Cas9 components, is highlighted alongside how a design‐of‐experiment approach may be used to improve the efficacy of LNP formulations.
Lipid nanoparticles (LNPs) are currently the most clinically advanced nonviral carriers for the delivery of small interfering RNAs (siRNAs). The current knowledge regarding LNP–siRNA design and the evolution of LNP–siRNA production methods focusing on microfluidic‐mixing techniques is reviewed. Additionally, the potential of LNPs for delivering other nucleic acids, such as messenger RNA and CRISPR/Cas9 components, is discussed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the ...tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.
Tweetable abstract Commentary just out in @fsgnnm: unleashing the full potential of #cancer #nanomedicines by reprogramming the immunosuppressive #TME using #LNP #mRNA #vaccines and via promoting ...#trainedimmunity.
Conspectus Delivering nucleic acid-based therapeutics to cells is an attractive approach to target the genetic cause of various diseases. In contrast to conventional small molecule drugs that target ...gene products (i.e., proteins), genetic drugs induce therapeutic effects by modulating gene expression. Gene silencing, the process whereby protein production is prevented by neutralizing its mRNA template, is a potent strategy to induce therapeutic effects in a highly precise manner. Importantly, gene silencing has broad potential as theoretically any disease-causing gene can be targeted. It was demonstrated two decades ago that introducing synthetic small interfering RNAs (siRNAs) into the cytoplasm results in specific degradation of complementary mRNA via a process called RNA interference (RNAi). Since then, significant efforts and investments have been made to exploit RNAi therapeutically and advance siRNA drugs to the clinic. Utilizing (unmodified) siRNA as a therapeutic, however, is challenging due to its limited bioavailability following systemic administration. Nuclease activity and renal filtration result in siRNA’s rapid clearance from the circulation and its administration induces (innate) immune responses. Furthermore, siRNA’s unfavorable physicochemical characteristics largely prevent its diffusion across cellular membranes, impeding its ability to reach the cytoplasm where it can engage the RNAi machinery. The clinical translation of siRNA therapeutics has therefore been dependent on chemical modifications and developing sophisticated delivery platforms to improve their stability, limit immune activation, facilitate internalization, and increase target affinity. These developments have resulted in last year’s approval of the first siRNA therapeutic, called Onpattro (patisiran), for treatment of hereditary amyloidogenic transthyretin (TTR) amyloidosis. This disease is characterized by a mutation in the gene encoding TTR, a serum protein that transports retinol in circulation following secretion by the liver. The mutation leads to production of misfolded proteins that deposit as amyloid fibrils in multiple organs, resulting in progressive neurodegeneration. Patisiran’s therapeutic effect relies on siRNA-mediated TTR gene silencing, preventing mutant protein production and halting or even reversing disease progression. For efficient therapeutic siRNA delivery to hepatocytes, patisiran is critically dependent on lipid nanoparticle (LNP) technology. In this Account, we provide an overview of key advances that have been crucial for developing LNP delivery technology, and we explain how these developments have contributed to the clinical translation of siRNA therapeutics for parenteral administration. We discuss optimization of the LNP formulation, particularly focusing on the rational design of ionizable cationic lipids and poly(ethylene glycol) lipids. These components have proven to be instrumental for highly efficient siRNA encapsulation, favorable LNP pharmacokinetic parameters, and hepatocyte internalization. Additionally, we pay attention to the development of rapid mixing-based methods that provide robust and scalable LNP production procedures. Finally, we highlight patisiran’s clinical translation and LNP delivery technology’s potential to enable the development of genetic drugs beyond the current state-of-the-art, such as mRNA and gene editing therapeutics.
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IJS, KILJ, NUK, PNG, UL, UM