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 (preinitiation) and Cisplatin delivery (5 mg/kg b.wt) started 1 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 14th week, we observed that DMBA‐painted hamsters exhibited tumor 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 signaling, 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 downregulatory role in the therapeutic action of the notch signaling 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 signaling pathway indicates that obstructing Notch signaling could potentially serve as a new and innovative therapeutic approach for oral squamous cell carcinoma (OSCC). Summary The present investigation assesses the therapeutic efficacy of PLGA‐loaded Nedaplatin (PLGA‐NDP) in treating oral cancer within a hamster model. The research highlights that PLGA‐NDP specifically targets the Notch signaling pathway and initiates apoptosis to impede oral carcinogenesis. To achieve this, we incorporate techniques such as histopathological examination, Western blot analysis, and quantitative mRNA expression analysis to visualize the presence of PLGA‐NDP nanoparticles within specific organs and tissues, evaluate their role in binding and uptake, and assess internalization and clearance. Our findings indicate that obstructing Notch signaling may represent a nove