Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity,Journal of the American Chemical Society

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Conversion of RNA Aptamer into Modified DNA Aptamers Provides for Prolonged Stability and Enhanced Antitumor Activity
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-05-14 , DOI: 10.1021/jacs.9b10460
Paola Amero ₁ , Ganesh L R Lokesh ₂ , Rajan R Chaudhari ₁ , Roberto Cardenas-Zuniga ₁ , Thomas Schubert ₃ , Yasmin M Attia _{1,

4} , Efigenia Montalvo-Gonzalez _{1,

5} , Abdelrahman M Elsayed _{1,

6} , Cristina Ivan ₁ , Zhihui Wang ₇ , Vittorio Cristini ₇ , Vittorio de Franciscis _{8,

9,

10} , Shuxing Zhang ₁ , David E Volk ₂ , Rahul Mitra ₁₁ , Cristian Rodriguez-Aguayo _{1,

12} , Anil K Sood _{11,

12,

13} , Gabriel Lopez-Berestein _{1,

12,

13}

Affiliation

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
McGovern Medical School, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, Texas 77030, United States.
2bind GmbH, Am BioPark 11, Regensburg 93053, Germany.
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr Al Eini Street, Fom El Khalig, Cairo 11796, Egypt.
Integral Laboratory of Food Research, Technological Institute of Tepic, Avenue Tecnologico 2595, 63175 Tepic, Nayarit Mexico.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11675, Egypt.
Mathematics in Medicine Program, The Houston Methodist Research Institute, 6670 Bertner Ave, Houston, Texas 77030, United States.
Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, 80131 Naples, Italy.
National Research Council (CNR), Institute of Genetic and Biomedical Research (IRGB)-UOS Milan via Rita Levi Montalcini, 20090 Pieve Emanuele (MI), Italy.
Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States.
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.

Aptamers, synthetic single-strand oligonucleotides that are similar in function to antibodies, are promising as therapeutics because of their minimal side effects. However, the stability and bioavailability of the aptamers pose a challenge. We developed aptamers converted from RNA aptamer to modified DNA aptamers that target phospho-AXL with improved stability and bioavailability. On the basis of the comparative analysis of a library of 17 converted modified DNA aptamers, we selected aptamer candidates, GLB-G25 and GLB-A04, that exhibited the highest bioavailability, stability, and robust antitumor effect in in vitro experiments. Backbone modifications such as thiophosphate or dithiophosphate and a covalent modification of the 5′-end of the aptamer with polyethylene glycol optimized the pharmacokinetic properties, improved the stability of the aptamers in vivo by reducing nuclease hydrolysis and renal clearance, and achieved high and sustained inhibition of AXL at a very low dose. Treatment with these modified aptamers in ovarian cancer orthotopic mouse models significantly reduced tumor growth and the number of metastases. This effective silencing of the phospho-AXL target thus demonstrated that aptamer specificity and bioavailability can be improved by the chemical modification of existing aptamers for phospho-AXL. These results lay the foundation for the translation of these aptamer candidates and companion biomarkers to the clinic.

中文翻译：

将 RNA 适配体转化为修饰的 DNA 适配体可延长稳定性并增强抗肿瘤活性

适体是功能与抗体相似的合成单链寡核苷酸，由于其副作用极小，因此有望用作治疗剂。然而，适体的稳定性和生物利用度带来了挑战。我们开发了从 RNA 适配体转化为修饰的 DNA 适配体的适配体，其靶向磷酸化 AXL，具有更高的稳定性和生物利用度。在对 17 个转化的修饰 DNA 适配体文库进行比较分析的基础上，我们选择了候选适配体 GLB-G25 和 GLB-A04，它们在体外表现出最高的生物利用度、稳定性和强大的抗肿瘤作用实验。骨架修饰如硫代磷酸盐或二硫代磷酸盐以及适体5'端与聚乙二醇的共价修饰优化了药代动力学特性，提高了适体在体内的稳定性通过减少核酸酶水解和肾脏清除率，并在非常低的剂量下实现了对 AXL 的高度和持续的抑制。在卵巢癌原位小鼠模型中用这些修饰的适体治疗显着降低了肿瘤生长和转移的数量。因此，磷酸-AXL 靶标的这种有效沉默表明，可以通过对磷酸-AXL 的现有适体进行化学修饰来提高适体特异性和生物利用度。这些结果为将这些适体候选物和伴随生物标志物转化为临床奠定了基础。

更新日期：2021-05-26

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