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Aptamer-functionalized triptolide with release controllability as a promising targeted therapy against triple-negative breast cancer.
- Source :
-
Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Jul 25; Vol. 43 (1), pp. 207. Date of Electronic Publication: 2024 Jul 25. - Publication Year :
- 2024
-
Abstract
- Targeted delivery and precise release of toxins is a prospective strategy for the treatment of triple-negative breast cancer (TNBC), yet the flexibility to incorporate both properties simultaneously remains tremendously challenging in the X-drug conjugate fields. As critical components in conjugates, linkers could flourish in achieving optimal functionalities. Here, we pioneered a pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to achieve smart release of the toxin and targeted therapy against TNBC. The multifunctional acetal ester linker in the AS-TP site-specifically blocked triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the circulating stability. Furthermore, the aptamer modification endowed triptolide with favorable water solubility and bioavailability and facilitated endocytosis of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The integrated superiorities of AS-TP promoted the preferential intra-tumor triptolide accumulation in xenografted TNBC mice and triggered the in-situ triptolide release in the weakly acidic tumor microenvironment, manifesting striking anti-TNBC efficacy and virtually eliminated toxic effects beyond clinical drugs. This study illustrated the therapeutic potential of AS-TP against TNBC and proposed a promising concept for the development of nucleic acid-based targeted anticancer drugs.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Female
Xenograft Model Antitumor Assays
Cell Line, Tumor
Antineoplastic Agents, Alkylating pharmacology
Antineoplastic Agents, Alkylating therapeutic use
Diterpenes pharmacology
Diterpenes therapeutic use
Diterpenes chemistry
Epoxy Compounds pharmacology
Epoxy Compounds therapeutic use
Epoxy Compounds chemistry
Phenanthrenes pharmacology
Phenanthrenes therapeutic use
Phenanthrenes chemistry
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms metabolism
Aptamers, Nucleotide pharmacology
Aptamers, Nucleotide therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1756-9966
- Volume :
- 43
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of experimental & clinical cancer research : CR
- Publication Type :
- Academic Journal
- Accession number :
- 39054545
- Full Text :
- https://doi.org/10.1186/s13046-024-03133-5