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Multifunctional approach with LHRH-mediated PLGA nanoconjugate for site-specific codelivery of curcumin and BCL2 siRNA in mice lung cancer

Multifunctional approach with LHRH-mediated PLGA nanoconjugate for site-specific codelivery of curcumin and BCL2 siRNA in mice lung cancer

Authors :
Madhuchandra Lahan
Trideep Saikia
Kalpajit Dutta
Rinku Baishya
Alakesh Bharali
Sunayana Baruah
Rituraj Bharadwaj
Subhash Medhi
Bhanu P. Sahu
Source :
Future Journal of Pharmaceutical Sciences, Vol 10, Iss 1, Pp 1-22 (2024)
Publication Year :
2024
Publisher :
SpringerOpen, 2024.

Abstract

Abstract Background Lung cancer remains a leading cancer type, but current chemotherapy is limited by issues including poor drug delivery, toxicity, and resistance. To address these challenges, we developed a novel PLGA-PEG-LHRH (PPL) nanoconjugate system for improved drug delivery. Curcumin, known for its anticancer and P-gp inhibition properties, was co-loaded with bcl2siRNA (bclsR) to inhibit the bcl2 protein, thus overcoming both resistance mechanisms. Results The PPL conjugate was successfully synthesized and characterized using FTIR, 1H NMR, XRD, XPS and BCA assay. Curcumin and bclsR-loaded PLGA nanoemulsions were prepared by double emulsion solvent evaporation method and characterized. The optimized nanoconjugate had size of 179 ± 16 nm, favorable zeta potential, high drug entrapment, and was confirmed via TEM. Controlled release studies indicated 83% drug release within 24 h. In vitro studies revealed significant cytotoxicity against A549 lung cancer cells, with the nanoconjugate showing IC50 of 8.24 µg/mL compared to 21.26 µg/mL for plain curcumin. Enhanced cellular uptake and effective targeting of A549 cells were observed. Molecular analyses demonstrated significant downregulation of MDR1 and Bcl2 RNA and protein expression, highlighting the nanoconjugates' ability to suppress resistance mechanisms. Pharmacokinetic studies in Wistar rats showed superior plasma drug concentrations, half-life, and AUC for the nanoconjugate versus pure drug suspension. Biodistribution studies showed increased drug accumulation in the lungs. In vivo efficacy studies in Balb/c mice demonstrated higher tumor inhibition ratios for CUR-siRNA PPL NPs (66.89%) and CUR-PPL NPs (59.84%) which was further confirmed with TNFα and p53 levels in blood. Histopathological studies showed good healing in the CUR-siRNA PPL NP- and CUR-PPL NP-treated mice compared to suspension. Conclusion From the study, it may be concluded that the PPL nanoconjugate system, loaded with curcumin and bcsR, can be potentially effective, multifunctional targeted approach for lung cancer therapy. Graphical Abstract

Details

Language :
English
ISSN :
23147253
Volume :
10
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Future Journal of Pharmaceutical Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.4d457fb8693642089d21c5eba1799349
Document Type :
article
Full Text :
https://doi.org/10.1186/s43094-024-00743-w