E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases

Morita, Yoshihiro; Kamal, Mohamed; Kang, Shinae; Zhang, Roy; Lokesh, G.L.; Thiviyanathan, Varatharasa; Hasan, Nafis; Woo, Sukyung; Zhao, Daniel; Leslie, Macall; Suh, Stephen K.; Razaq, Wajeeha; Rui, Hallgeir; Gorenstein, David G.; Volk, David E.; Tanaka, Takemi

doi:10.1038/mtna.2016.103

Cited by 28 publications

(19 citation statements)

References 42 publications

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“…Similarly, conjugation of 40 kDa PEG to a 2′-fluoro-/2′- O -methyl modified aptamer resulted in an increase of the circulation half-life to 23 h in a mouse model [ 48 ]. However, high molecular weight PEG conjugation may cause a functional hindrance of the aptamer binding to its target [ 62 ]. Thus the size of PEG as well as type and length of linkage of PEG to aptamer should be determined in a case-by-case fashion.…”

Section: Challenges and Possible Solutions In Aptamer Therapeuticsmentioning

confidence: 99%

Aptamer Therapeutics in Cancer: Current and Future

Morita

Leslie

Kameyama

et al. 2018

Cancers

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170

112

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Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small—approximately one-tenth that of monoclonal antibodies—their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers’ long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen® (pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments.

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Section: Challenges and Possible Solutions In Aptamer Therapeuticsmentioning

confidence: 99%

Aptamer Therapeutics in Cancer: Current and Future

Morita

Leslie

Kameyama

et al. 2018

Cancers

Self Cite

170

112

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“…It has been shown that E-selectin assists shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow [32]. Furthermore, SCF is a potent chemokine that favors recruitment of cancer-stem cells and other inflammatory cells including MDSCs [33,34].…”

Section: Discussionmentioning

confidence: 99%

HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model

et al. 2017

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Distant metastasis is the primary cause of death in the majority of the cancer types. Recently, much importance has been given to tumor microenvironment (TME) in the development of invasive malignant tumors, as well as the metastasis potential. The ability of tumor cells to modulate TME and to escape immune-mediated attack by releasing immunosuppressive cytokines has become a hallmark of breast cancer. Our study shows the effect of IV formulation of HET0016 (HPßCD-HET0016) a selective inhibitor of 20-HETE synthesis, administered intravenously in immune-competent in vivo mouse model of murine breast cancer. 4T1 luciferase positive cells were implanted to the mammary fat pad in Balb/c mice. Treatment started on day 15, and was administered for 5 days a week for 3 weeks. The development of metastasis was detected via optical imaging. Blood, spleen, lungs, bone marrow and tumor were collected for flow cytometry, to investigate changes in myeloid-derived suppressive cells (MDSCs) populations and endothelial phenotype. Tumor and lungs were collected for protein analysis. Our results show that HPßCD-HET0016: (1) decreased tumor volume and lung metastasis compared to the vehicle group; (2) reduced migration and invasion of tumor cells and levels of metalloproteinases in the lungs of animals treated with HPßCD-HET0016 via PI3K/AKT pathway; and (3) decreased expression of pro-inflammatory cytokines, growth factors and granulocytic MDSCs population in the lung microenvironment in treated animals. Thus, HPßCD-HET0016 showed potential in treating lung metastasis in a preclinical mouse model and needs further investigations on TME.

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“…在小鼠研究中, 人们发现将2′氟-/2′-氧甲基修饰的核酸适配子与 40 kDa的PEG缀合, 能使其半衰期增加至23 h [133] . 然而, 高分子量PEG缀合也可能影响适配子与靶标分子的结合 [144] . .…”

Section: 以抗人肿瘤坏死因子Tnf的rna适配子为例未经修unclassified