Improved Antitumor Efficacy of a Dextran-based Docetaxel-Coupled Conjugate Against Triple-Negative Breast Cancer.
conjugate
dextran
docetaxel
docosahexaenoic acid
nanomedicine.
triple-negative breast cancer
Journal
Current drug delivery
ISSN: 1875-5704
Titre abrégé: Curr Drug Deliv
Pays: United Arab Emirates
ID NLM: 101208455
Informations de publication
Date de publication:
22 Jun 2023
22 Jun 2023
Historique:
received:
26
10
2022
revised:
10
04
2023
accepted:
19
04
2023
medline:
23
6
2023
pubmed:
23
6
2023
entrez:
23
6
2023
Statut:
aheadofprint
Résumé
Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations. This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer. DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice. The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8±5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triple-negative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects. This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.
Sections du résumé
BACKGROUND
BACKGROUND
Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations.
OBJECTIVE
OBJECTIVE
This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer.
METHODS
METHODS
DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice.
RESULTS
RESULTS
The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8±5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triple-negative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects.
CONCLUSION
CONCLUSIONS
This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.
Identifiants
pubmed: 37349996
pii: CDD-EPUB-132611
doi: 10.2174/1567201820666230622105503
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
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