Adhesive Lipophilic Gels Delivering Rapamycin Prevent Oral Leukoplakia from Malignant Transformation

Abstract

Oral leukoplakia (OLK) is the most emblematic oral potentially malignant disorder that may precede the diagnosis of oral squamous cell carcinoma (OSCC) and has an overall malignant transformation rate of 9.8%.  Early intervention is crucial to reduce the malignant transformation rate from OLK to OSCC but the lack of effective local pharmaceutical preparations poses a challenge to clinical management. Rapamycin is speculated to prevent OLK from carcinogenesis and its inherent lipophilicity facilitates its penetration into stratum corneum. However, it is often difficult for hydrophilic hydrogels to deliver lipophilic medicines.  Moreover, oral cavity is a complex environment characterized by oral motor functions, saliva-secreting cycle, dynamic changes, and barriers made from mucus and lipid layer. Therefore, muco-penetration and muco-adhesion are to be settled to establish a drug delivery system for rapamycin delivery targeting oral potentially malignant disorders.

Here, a dual-function hydrogel drug delivery system integrating adhesion and lipophilicity is successfully developed based on polyvinyl alcohol (PVA) and dioleoyl phosphatidylglycerol (DOPG) via dynamic boronic ester bonds. Rheological experiments based on orthogonal design reveal that PVA-DOPG hydrogels exhibited ideal adhesive strength (around 6 kPa) and could adhere to various surfaces in both dry and wet conditions. PVA-DOPG hydrogels also significantly promote lipophilic molecules’ penetration into stratum corneum (mean fluorescence depth of 0.96 mm) of ex-vivo porcine buccal mucosa. Furthermore, PVA-DOPG hydrogels incorporating rapamycin inhibit malignant transformation of OLK mouse model induced by 4-Nitroquinoline N-oxide (4-NQO), distinct improvements in survival (p < 0.05), decrease in neoplasm incidence density of 36.36% and inhibition rate in neoplasm volume of 75.04 ± 33.67% have been demonstrated, suggesting the hydrogels valuable candidates for potential applications in the management of OLK.

Note:
Funding Information: This work was financially sponsored by the National Key R&D Program of China (2022YFC2402900, 2022YFC2402901), National Natural Science Foundation of China (Nos: 82271035, 81970950, 82270986), China Postdoctoral Science Foundation (2022M722740) and Postdoctoral Fellowship Program of CPSF (GZB20230637).

Declaration of Interests: The authors declare no conflict of interest.

Ethics Approval Statement: All experiments were conducted in accordance with the guidelines outlined in the ''Principles of Laboratory Animal Care'' (NIH) and were approved by the Ethics Committee of West China Hospital of Stomatology, Sichuan University.

Keywords: Malignant transformation, Oral leukoplakia, Rapamycin, Hydrogels, Drug delivery systems