Enhanced docetaxel therapeutic effect using dual targeted SRL-2 and TA1 aptamer conjugated micelles in inhibition Balb/c mice breast cancer model.
Animals
Micelles
Female
Aptamers, Nucleotide
/ chemistry
Mice
Docetaxel
/ pharmacology
Mice, Inbred BALB C
Cell Line, Tumor
Breast Neoplasms
/ drug therapy
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Nanoparticles
/ chemistry
Drug Delivery Systems
Humans
Tumor Microenvironment
/ drug effects
Polymers
DTX
Delivery
Drug resistance
GSH/pH responsive
SRL-2
Smart
TA1 aptamer
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 Oct 2024
19 Oct 2024
Historique:
received:
16
07
2024
accepted:
01
10
2024
medline:
20
10
2024
pubmed:
20
10
2024
entrez:
19
10
2024
Statut:
epublish
Résumé
Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (β-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (β-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue < 0.001) which further confirmed by in vivo biodistribution and fluorescent TUNEL assay experiments. NPs treated groups demonstrated notable tumor growth inhibition in 4T1 tumor bearing Balb/c mice by only 1/10th of the DTX therapeutic dose (TD) as a drug model. In conclusion, cleverly designed nanostructures here demonstrated improved anticancer effects by enhancing tumor targeting, delivering chemotherapeutic agents more accurately, promoting drug release, reducing the therapeutic dosage, and lowering side effects of anticancer drugs.
Identifiants
pubmed: 39427007
doi: 10.1038/s41598-024-75042-8
pii: 10.1038/s41598-024-75042-8
doi:
Substances chimiques
Micelles
0
Aptamers, Nucleotide
0
Docetaxel
15H5577CQD
Antineoplastic Agents
0
poly(beta-amino ester)
0
Polymers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
24603Informations de copyright
© 2024. The Author(s).
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