دورية أكاديمية
أعرض في EDS

Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA.

التفاصيل البيبلوغرافية
العنوان: Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA.
المؤلفون: Ma Y; Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, California 91010, United States., Kowolik CM, Swiderski PM, Kortylewski M, Yu H, Horne DA, Jove R, Caballero OL, Simpson AJ, Lee FT, Pillay V, Scott AM
المصدر: ACS chemical biology [ACS Chem Biol] 2011 Sep 16; Vol. 6 (9), pp. 962-70. Date of Electronic Publication: 2011 Jul 26.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2006-
مواضيع طبية MeSH: Drug Delivery Systems* , Gene Silencing*, Antibodies, Monoclonal/*immunology , Lewis Blood Group Antigens/*immunology , RNA, Small Interfering/*genetics , RNA, Small Interfering/*metabolism , STAT3 Transcription Factor/*genetics, Cell Line, Tumor ; Cell Proliferation ; Dose-Response Relationship, Drug ; Humans ; Models, Biological ; Molecular Structure ; STAT3 Transcription Factor/deficiency ; Structure-Activity Relationship
مستخلص: The clinical application of siRNA is limited largely by the lack of efficient, cell-specific delivery systems. Antibodies are attractive delivery vehicles for targeted therapy due to their high specificity. In this study we describe the use of a humanized monoclonal antibody (mAb), hu3S193, against Lewis-Y (Le(y)), as a delivery vehicle for STAT3 siRNA. This mAb is rapidly internalized into Le(y)-expressing cancer cells via antigen recognition, and when coupled to STAT3 siRNA, a potentially powerful molecularly targeted delivery agent is created. Selective silencing of STAT3 is associated with tumor suppression. Two hu3S193 based siRNA delivery systems using STAT3 siRNA as a prototype were developed and tested in Le(y)-positive cancer cells: (a) a covalent construct based on a reductive disulfide linker that is expected to undergo cleavage within cells and (b) a noncovalent construct based on (d-arginine)(9) (9r) modified hu3S193. Le(y)-specific binding and internalization of both the covalent and noncovalent constructs were confirmed by flow cytometry and confocal microscopy. Both the covalent and the noncovalent system led to efficient STAT3 silencing in Le(y)-positive cancer cells (A431) but not in Le(y)-negative cancer cells (MDA-MB-435). The covalent construct, however, required co-treatment with reagents such as chloroquine or 9r that facilitate the escape of the siRNA from endosomes to achieve significant gene silencing. The 9r modified noncovalent construct induced ∼70% STAT3 knockdown at submicromolar siRNA concentrations when used at an optimal vehicle-to-siRNA ratio of 5:1. The STAT3 knockdown also led to ∼50% inhibition of cell proliferation of Le(y)-positive cells. Noncovalent linked STAT3 siRNA-hu3S193 has great promise for targeted knockdown of STAT3 in tumor cells.
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معلومات مُعتمدة: P30 CA033572 United States CA NCI NIH HHS; R01 CA055652 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Antibodies, Monoclonal)
0 (Lewis Blood Group Antigens)
0 (Lewis Y antigen)
0 (RNA, Small Interfering)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
تواريخ الأحداث: Date Created: 20110720 Date Completed: 20120515 Latest Revision: 20211020
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC3831028
DOI: 10.1021/cb200176v
PMID: 21766840
قاعدة البيانات: MEDLINE
الوصف
تدمد:1554-8937
DOI:10.1021/cb200176v