PLGA-loaded Nedaplatin (PLGA-NDP) inhibits
7,12-Dimethylbenz[a]anthracene (DMBA) induced Oral carcinogenesis
via modulating Notch signaling pathway and induces apoptosis in
experimental hamster model
Abstract
The present study is designed to evaluate the nanotherapeutic efficacy
of prepared PLGA-loaded Nedaplatin (PLGA-NDP) against 7,12-dimethyl
benz(a)anthracene (DMBA)-induced experimental oral carcinogenesis in
hamster buccal pouch (HBP) model. The buccal pouch of golden Syrian
hamsters was painted with 0.5% DMBA in liquid paraffin three times a
week for 14 weeks, ultimately leading to the development of oral
squamous cell carcinoma (OSCC). Oral administration of PLGA-NDP
(Pre-initiation) and Cisplatin delivery (5mg/kg b.wt) started one week
before the carcinogen exposure and continued on alternative days.
Post-administration of PLGA-NDP (5 mg/kg b.wt) started 2 days after
carcinogen (DMBA) induction until the end of the experiment. After the
14 th week, we observed that DMBA-painted hamsters
exhibited tumour formation, morphological alterations, and
well-differentiated OSSC in addition to the responsive molecular
proteins during oral carcinogenesis. Furthermore, immunoblotting
analysis demonstrated that PLGA-NDP inhibits Notch signalling, as
evidenced by downregulation of Bcl-Xl, Bcl-2, p21, PGE2, HGF, and CXCL12
proteins, and upregulation of p53 and Bax. This apoptotic response is
crucial for PLGA-NDP to induce apoptosis. In addition, RT-PCR results
showed that PLGA-NDP nanoparticles play a down-regulatory role in the
therapeutic action of the notch signalling gene (Notch1, Notch 2, Hes1,
Hey1, and Jagged1) at the mRNA transcription level in HBP carcinoma.
Taken together, these data indicate that PLGA-NDP is a potent inhibitor
of oral carcinogenesis and the expansion of cells that specifically
target the Notch signalling pathway indicates that obstructing Notch
signalling could potentially serve as a new and innovative therapeutic
approach for oral squamous cell carcinoma (OSCC).