Electrostatic anti-CD33-antibody-protamine nanocarriers as platform for a targeted treatment of acute myeloid leukemia.
DNMT3A inhibition
Gemtuzumab
Ibrutinib
Molecular targeted therapy
RNA interference
Journal
Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
received:
08
07
2022
accepted:
22
11
2022
entrez:
2
12
2022
pubmed:
3
12
2022
medline:
6
12
2022
Statut:
epublish
Résumé
Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target "undruggable" oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML. Our AML-targeting system consists of an internalizing anti-CD33-antibody-protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application. The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton's kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation. We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.
Sections du résumé
BACKGROUND
Acute myeloid leukemia (AML) is a fatal clonal hematopoietic malignancy, which results from the accumulation of several genetic aberrations in myeloid progenitor cells, with a worldwide 5-year survival prognosis of about 30%. Therefore, the development of more effective therapeutics with novel mode of action is urgently demanded. One common mutated gene in the AML is the DNA-methyltransferase DNMT3A whose function in the development and maintenance of AML is still unclear. To specifically target "undruggable" oncogenes, we initially invented an RNAi-based targeted therapy option that uses the internalization capacity of a colorectal cancer specific anti-EGFR-antibody bound to cationic protamine and the anionic siRNA. Here, we present a new experimental platform technology of molecular oncogene targeting in AML.
METHODS
Our AML-targeting system consists of an internalizing anti-CD33-antibody-protamine conjugate, which together with anionic molecules such as siRNA or ibrutinib-Cy3.5 and cationic free protamine spontaneously assembles into vesicular nanocarriers in aqueous solution. These nanocarriers were analyzed concerning their physical properties and relevant characteristics in vitro in cell lines and in vivo in xenograft tumor models and patient-derived xenograft leukemia models with the aim to prepare them for translation into clinical application.
RESULTS
The nanocarriers formed depend on a balanced electrostatic combination of the positively charged cationic protamine-conjugated anti-CD33 antibody, unbound cationic protamine and the anionic cargo. This nanocarrier transports its cargo safely into the AML target cells and has therapeutic activity against AML in vitro and in vivo. siRNAs directed specifically against two common mutated genes in the AML, the DNA-methyltransferase DNMT3A and FLT3-ITD lead to a reduction of clonal growth in vitro in AML cell lines and inhibit tumor growth in vivo in xenotransplanted cell lines. Moreover, oncogene knockdown of DNMT3A leads to increased survival of mice carrying leukemia patient-derived xenografts. Furthermore, an anionic derivative of the approved Bruton's kinase (BTK) inhibitor ibrutinib, ibrutinib-Cy3.5, is also transported by this nanocarrier into AML cells and decreases colony formation.
CONCLUSIONS
We report important results toward innovative personalized, targeted treatment options via electrostatic nanocarrier therapy in AML.
Identifiants
pubmed: 36457063
doi: 10.1186/s13045-022-01390-5
pii: 10.1186/s13045-022-01390-5
pmc: PMC9716776
doi:
Substances chimiques
Protamines
0
RNA, Small Interfering
0
Methyltransferases
EC 2.1.1.-
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
171Informations de copyright
© 2022. The Author(s).
Références
Biomed Res Int. 2017;2017:5473197
pubmed: 28286768
Nucleic Acid Ther. 2018 Jun;28(3):109-118
pubmed: 29792572
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Oncogene. 2022 Apr;41(15):2210-2224
pubmed: 35220407
Leukemia. 2017 Sep;31(9):1855-1868
pubmed: 28607471
Clin Cancer Res. 2020 Jul 1;26(13):3371-3383
pubmed: 32054729
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
PLoS One. 2018 Jul 12;13(7):e0200163
pubmed: 30001368
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cancer Cell. 2014 Apr 14;25(4):442-54
pubmed: 24656771
Cancer Res. 2019 Jul 15;79(14):3583-3594
pubmed: 31164355
BMC Syst Biol. 2014;8 Suppl 4:S11
pubmed: 25521941
Oncogene. 2007 May 28;26(25):3679-90
pubmed: 17530021
Leuk Lymphoma. 2018 Apr;59(4):931-940
pubmed: 28750570
Nature. 2018 Aug;560(7718):387-391
pubmed: 29925955
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
Blood Cancer J. 2016 Jul 01;6(7):e441
pubmed: 27367478
Nat Protoc. 2016 Jan;11(1):22-36
pubmed: 26633129
N Engl J Med. 2010 Dec 16;363(25):2424-33
pubmed: 21067377
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Clin Oncol. 2011 Jul 20;29(21):2889-96
pubmed: 21670448
Adv Pharm Bull. 2014 Dec;4(4):313-21
pubmed: 25436185
Cold Spring Harb Perspect Med. 2017 Feb 1;7(2):
pubmed: 28003281
N Engl J Med. 2013 Aug 29;369(9):819-29
pubmed: 23984729
Nature. 2019 Nov;575(7781):217-223
pubmed: 31666701
Annu Rev Pharmacol Toxicol. 2016;56:103-22
pubmed: 26738473
Biomaterials. 2010 Feb;31(6):1429-43
pubmed: 19954842
Expert Opin Drug Discov. 2022 Jan;17(1):55-69
pubmed: 34455870
Cancers (Basel). 2020 Jul 31;12(8):
pubmed: 32751889
Blood. 2013 Jun 6;121(23):4769-77
pubmed: 23632886
Nat Cancer. 2021 May;2(5):527-544
pubmed: 35122024
Leukemia. 2020 Sep;34(9):2342-2353
pubmed: 32094466
Leukemia. 2004 Feb;18(2):316-25
pubmed: 14614514
Future Oncol. 2017 Sep;13(21):1853-1871
pubmed: 28610444
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Int J Pharm. 2021 May 15;601:120586
pubmed: 33839230
J Hematol Oncol. 2018 Dec 4;11(1):133
pubmed: 30514344
Blood. 2016 Aug 4;128(5):686-98
pubmed: 27288520
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nucleic Acids Res. 2020 Jun 19;48(11):6108-6119
pubmed: 32392345
Mol Biol Evol. 2006 Jun;23(6):1304-17
pubmed: 16613862
Nat Rev Drug Discov. 2019 Jun;18(6):421-446
pubmed: 30846871
Cell. 2009 May 29;137(5):835-48
pubmed: 19490893
Nucleic Acids Res. 2021 Jan 8;49(D1):D605-D612
pubmed: 33237311
Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18061-6
pubmed: 22011581
Nat Biotechnol. 2005 Jun;23(6):709-17
pubmed: 15908939
Front Genet. 2021 Apr 30;12:647353
pubmed: 33995482
Nat Rev Immunol. 2020 Nov;20(11):651-668
pubmed: 32433532
Pharmaceuticals (Basel). 2020 Sep 14;13(9):
pubmed: 32937862
Front Pharmacol. 2022 May 24;13:868695
pubmed: 35685630
Cell. 2017 Feb 9;168(4):584-599
pubmed: 28187282
Nat Rev Drug Discov. 2020 Oct;19(10):673-694
pubmed: 32782413
Clin Cancer Res. 2015 Mar 15;21(6):1383-94
pubmed: 25589625
Blood. 2021 Nov 25;138(21):2093-2105
pubmed: 34125889
FEBS J. 2014 Mar;281(6):1534-46
pubmed: 24447298
Cell Death Differ. 2018 Jan;25(1):3-6
pubmed: 29227986
CA Cancer J Clin. 2015 Mar;65(2):87-108
pubmed: 25651787
J Biol Chem. 2004 May 7;279(19):20088-95
pubmed: 14990583
P T. 2017 Aug;42(8):514-521
pubmed: 28781505
Cell Death Discov. 2021 May 3;7(1):90
pubmed: 33941774
Clin Lymphoma Myeloma Leuk. 2019 Aug;19(8):509-515.e1
pubmed: 31227358
J Clin Oncol. 2015 Jun 20;33(18):2072-83
pubmed: 25964253
Angew Chem Int Ed Engl. 2022 Jan 3;61(1):e202109769
pubmed: 34725904
Signal Transduct Target Ther. 2020 Jun 19;5(1):101
pubmed: 32561705
Cancer Discov. 2016 May;6(5):501-15
pubmed: 27016502
Mol Cancer Ther. 2014 Apr;13(4):880-9
pubmed: 24526162
Sci Rep. 2021 Jan 14;11(1):1331
pubmed: 33446695
Cell. 2008 Nov 28;135(5):852-64
pubmed: 19012953
N Engl J Med. 2017 Aug 3;377(5):454-464
pubmed: 28644114
Cell. 2017 Feb 23;168(5):801-816.e13
pubmed: 28215704