Nucleic acid aptamers, often termed 'chemical antibodies', are functionally comparable to traditional antibodies, but offer several advantages, including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability and lack of immunogenicity. In addition, many aptamers are internalized upon binding to cellular receptors, making them useful targeted delivery agents for small interfering RNAs (siRNAs), microRNAs and conventional drugs. However, several crucial factors have delayed the clinical translation of therapeutic aptamers, such as their inherent physicochemical characteristics and lack of safety data. This Review discusses these challenges, highlighting recent clinical developments and technological advances that have revived the impetus for this promising class of therapeutics.

Aptamers as targeted therapeutics: current potential and challenges

入侵病原体与宿主之间呈动态平衡，以维持病原体成功地寄生在宿主体内而不致宿主死亡，这是许多寄生虫感染的一个重要特征。包括曼氏血吸虫在内的许多蠕虫感染中，持续的炎症反应比病原体本身对宿主的危害更大，降低宿主的免疫反应具有重要意义。曼氏血吸虫感染后，宿主活化CD4^＋Th2细胞，分泌IL-4、IL-5和IL-13。最近研究表明IL-13是肝组织纤维化的重要调节因子。

IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A

Polymer–drug conjugates have long been a mainstay of the drug delivery field, with several conjugates successfully translated into clinical practice. The conjugation of therapeutic agents to polymeric carriers, such as polyethylene glycol, offers several advantages, including improved drug solubilization, prolonged circulation, reduced immunogenicity, controlled release and enhanced safety. In this Review, we discuss the rational design, physicochemical characteristics and recent advances in the development of different classes of polymer–drug conjugates, including polymer–protein and polymer–small-molecule drug conjugates, dendrimers, polymer nanoparticles and multifunctional systems. Current obstacles hampering the clinical translation of polymer–drug conjugate therapeutics and future prospects are also presented. The conjugation of therapeutic agents to polymer carriers, such as polyethylene glycol (PEG), can control drug delivery, enhance solubilization, increase efficacy and improve pharmacokinetics. Here, Grinstaff, Colson and Ekladious discuss recent advances in the preclinical and clinical development of different classes of polymer–drug conjugates and highlight current challenges and future directions.

Polymer–drug conjugate therapeutics: advances, insights and prospects

Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.

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Aptamers as Therapeutics

Cancer is difficult to cure due to frequent metastasis, and developing effective therapeutic approaches to treat cancer is urgently important. Long non-coding RNAs (lncRNAs) have diverse roles in regulating gene expression at both the transcriptional and translational levels and have been reported to be involved in tumorigenesis and tumor metastasis. In this article, we review the emerging roles of lncRNAs in cancer, especially in cancer immunity, cancer metabolism and cancer metastasis. We also discuss the use of novel technologies, such as antisense oligonucleotides, CRISPR-Cas9 and nanomedicines, to target lncRNAs and thus control cancers.

Emerging roles of lncRNA in cancer and therapeutic opportunities.

A nucleic acid ligand “biochip” is disclosed, consisting of a solid support to which one or more specific nucleic acid ligands is attached in a spatially defined manner. Each nucleic acid ligand binds specifically and avidly to a particular target molecule contained within a test mixture, such as a bodily fluid. The target molecules include, but are not limited to, proteins (cellular, viral, bacterial, etc.) hormones, sugars, metabolic byproducts, cofactor, and intermediates, drugs, and toxins. Contacting the test mixture with the biochip leads to the binding of a target molecule to its cognate nucleic acid ligand. The biochip may then be contacted with a reagent(s) that reacts covalently with proteins and not with nucleic acids. Each protein target in the test mixture may then detected by detecting the presence of the reagent at the appropriate address on the biochip.

Nucleic Acid Ligand Diagnostic Biochip

For any new class of therapeutics, there are certain types of indications that represent a natural fit. For nucleic acid ligands in general, and aptamers in particular, the eye has historically been an attractive site for therapeutic intervention. In this review, we recount the discovery and early development of three aptamers designated for use in ophthalmology, one approved (Macugen), and two in late-stage development (Fovista and Zimura). Every one of these molecules was originally intended for other indications. Key improvements in technology, specifically with regard to libraries used for in vitro selection and subsequent chemical optimization of aptamers, have played an important role in allowing the identification of development candidates with suitable properties. The lessons learned from the selection of these molecules are valuable for informing us about the many remaining opportunities for aptamer-based therapeutics in ophthalmology as well as for identifying additional indications for which aptamers as a class of therapeutics have distinct advantages.

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Fit for the Eye: Aptamers in Ocular Disorders

Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrat...

Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys

The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic). We show that clearance increases with the number of side chains in sequences of ≥28 synthons, but this effect is dramatically diminished in shorter sequences. These results serve as a guide for the design of new therapeutic aptamers with diversity-enhancing side chains.

Pharmacokinetic Properties of DNA Aptamers with Base Modifications

Purpose To explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA. Methods We conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured 4001 proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of 4001 proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome. Results In this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling. Conclusions We found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described. Translational relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD.

Daniel W. Drolet

Papers

Nucleic Acid Ligand Diagnostic Biochip

Fit for the Eye: Aptamers in Ocular Disorders

Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys

Pharmacokinetic Properties of DNA Aptamers with Base Modifications

Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology